Pharmacology Flashcards
What are the 3 principal efferent outputs from the CNS?
Autonomic NS (PNS and SNS) Somatic NS Neuroendocrine system
What are the principal target organs of the ANS?
Exocrine glands
Smooth muscle
Cardiac muscle
What are the principal target organs of the somatic NS?
Skeletal muscle
Including the diaphragm and respiratory muscle
What are the principal roles of the neuroendocrine system?
Growth Metabolism Reproduction Development Salt and water balance Host defence
What are the principal roles of the ANS?
Metabolism
Host defence
PNS= Rest and digest SNS= Fight or flight
What are the sympathetic and parasympathetic effects on pupillary constriction?
Pupillary constriction= response to light
Sympathetic= need dilated (get info in) Parasympathetic= constrict in bright room
What cranial nerve is involved in parasympathetic control of pupillary constriction?
Oculomotor
What cranial nerve is involved in mediating cephalic and gastric phases of gastric secretion?
Vagus (PNS)
How does the PNS control the gastric secretion?
PNS drives gut including stomach
Vagus mediates:
- Cephalic secretions
- Gastric motility and secretion
What branch of ANS is dominant at rest?
Parasympathetic
Resting HR is about 70bpm
BUT should be 100-110bpm if it was based on the midpoint of the intrinsic rates of vagal (50) and sympathetic (200)
What receptors influence the ANS control of the heart?
Barorecptors
How do baroreceptors affect heart rate speed?
Parasympathetic= slows heart Sympathetic= speeds up heart
Do the PNS and SNS always innervate different tissues?
No
PNS and SNS often innervate the same tissues and do different things
How does the SNS act on blood vessels?
2 different ways dependent on receptors
Dilation in skeletal muscles
Constriction in skin. mucous membranes and splanchic areas
What do all preganglionic fibres of the ANS release?
Acetylcholine
What are the neurotransmitters released by the postganglionic fibres in the PNS and SNS?
PNS= cholinergic (ACh) SNS= adrenergic (NA)
What are the lengths of the pre and postganglionic fibres in the PNS and SNS?
PNS= long pregang, short postgang SNS= short pregang, long postgang
Where do parasympathetic nerve fibres extend from on the spine?
Cranial/sacral
Where do sympathetic nerve fibres extend from on the spine?
Thoracic/lumbar
Outline the 3 possible ways neurotransmitters are released in the SNS
Short preganglionic fibre-> ACh
Long postganglionic fibre-> NA (acts on effector organ)
Short preganglionic fibre-> ACh (on adrenal medulla but acts like ganglion)
Long postganglionic fibre-> A and NA (via bloodstream, acts on effector organ)
Short preganglionic fibre-> ACh
Long postganglionic fibre-> ACh (acts on effector organ e.g. sweat gland)
DIAGRAM IN LECTURE
What is the difference in divergence between the PNS and SNS?
PNS= discrete/localised (little
divergence, 1:1 pre vs post)
SNS= coordinated
response (very divergent, up to 1:20 pre vs post)
What is the name of the NS of the gut?
Enteric
Works with SNS and PNS
What neurotransmitters are involved in the somatic nervous system?
ACh
Released by 1 long motor neurone from spinal cord to effector organ
What is the aim of the somatic nervous system?
Skeletal muscle contraction
What cholinoceptors and adrenoceptors are located in the ANS?
Muscarinic and nicotinic
These are membrane-bound receptors
What do muscarinic receptors do?
Mediate an affect (found at effector organ)
What do nicotinic receptors do?
Mediate connection between pre and post ganglionic fibre (found at start of post gang fibre)
What stimulates nicotinic and muscarinic receptors?
Nicotinic= nicotine/acetylcholine Muscarinic= muscarine/acetylcholine
Where are nicotinic and muscarinic receptors found?
Nicotinic= at all autonomic ganglia
Muscarinic=At all effector organs innervated by
post ganglionic parasympathetic fibres
What signalling systems are employed by nicotinic and muscarinic receptors?
Nicotinic= type 1- ionotropic (speed important)
Muscarinic= type 2- G protein coupled (slower)
-> generation of 2nd messenger-> activation of cell signalling
If you blockade nicotinic AChRs in a person at rest, what would the effect be on the bowel?
Constipation
Rest and digest so PNS response
Blocking nicotinic-> blocking PNS (PNS should make gut work well)
If you blockade nicotinic AChRs in a person, what would the effect be on heart rate…
a) at rest
b) during exercise
a) Blockade at rest: PNS will be dominant at rest (low HR) but blocking means take out this dominant effect so increased HR
b) Blockade during exercise: SNS will be domininant in exercise (increased HR) but blocking means reduced HR
What are the subtypes of muscarinic cholinoceptors?
M1-M5
Where are the subtypes of muscarinic cholinoceptors found?
M1= Neural
M2= Cardiac
M3= Exocrine, smooth muscle
M4= Periphery: prejunctional nerve endings (inhibitory)
M5= Striatal dopamine release
What do M1, M2 and M3 do?
M1= Neural= forebrain – learning and memory (salivary glands, stomach, CNS)
M2= Cardiac= brain – inhibitory autoreceptors (heart)
M3= Exocrine and smooth muscle= hypothalamus – food intake (salivary glands, bronchial/visceral SM, sweat glands, eye)
What signalling systems are employed by M1, M2 and M3?
M1= Gq STIM (IP3 DAG) M2= Gi INHIB (cAMP) M3= Gq STIM (IP3 DAG)
Where are adrenoceptors found?
All effector organs innervated by post ganglionic fibres
Which allows for more selective drugs to be used; adrenoceptors or muscarinic cholinoceptors?
Andrenoceptors
There are multiple subtypes
Very selective drugs available
What stimulates adrenoceptors?
NA/A
What signalling system is employed by adrenoceptors?
Type 2- GPCR
What are the subtypes of adrenoceptors?
alpha 1 alpha 2 beta 1 beta 2 (beta 3)
What neurotransmitters do nicotinic Rs, muscarinic Rs and adrenoceptors respond to?
Nicotinic= ACh Muscarinic= ACh Adrenoceptors= NA/A
What happens to heart rate and sweat production during exercise if muscarinic receptors are blocked?
Increased HR
Reduced sweat production
Summarise biosynthesis, release and metabolism of acetylcholine
SEE DIAGRAM
Acetyl CoA + Choline -> (choline acetyl transferase, CAT)-> ACh + CoA
ACh in vesicle-> released into synapse (because of AP Ca release)
ACh binds to R on effector cell
ACh-> (acetylcholinesterase)-> choline + acetate
Choline + acetate reabsorbed into presynaptic neurone
Summarise biosynthesis, release and metabolism of noradrenaline
SEE DIAGRAM
Tyrosine -> (tyrosine hydroxylase) -> DOPA-> (DOPA decarboxylase)-> Dopamine
Dopamine -> (dopamine B hydroxylase)-> NA
NA released into synapse (because of AP Ca release)
NA binds to adrenoceptor on effector cell
- Uptake 1= presyn neuron -> NA-> (monamine oxidase A) -> metabolites
- Uptake 2= postsyn (degradation by COMT)
What causes a reduction in synaptic NA concentrations?
Tyrosine hydroxylase
DOPA decarboxylase
What causes an increase in synaptic NA concentrations?
Uptake 1 transport protein (most increase)
Monoamine oxidase
Cathecol-O-methyl transferase
Define: pharmacokinetics
The study of how drugs are handled within the body
Including their absorption, distribution, metabolism and excretion (ADME)
Define: pharmacodynamics
The interactions of drugs with cells and their mechanism of action on the body
Define: drug
A chemical that affects physiological function in a specific way
OR
A chemical that interacts with a biological system to produce a physiological effect
Define: drug target sites
Protein complexes key to drug mechanisms of action
What are the 4 target sites of drugs?
Cell receptors
Ion channels
Transport systems
Enzymes
What do the 4 target sites of drugs have in common?
They are all proteins
What are drug receptors activated by?
(Endogenous) NT or hormone
What is the general structure of drug receptors?
Proteins with cell membranes (usually)
What are the 4 subtypes of drug receptors and how are they coupled?
Ionotropic (ligand-gated)= DIRECT
E.g. nAChR and GABAR
Metabotropic= G PROTEIN
E.g. mAChR and B1-adrenoceptors
Kinase-linked= DIRECT OR INDIRECT
E.g. Insulin receptors
IC steroid type= VIA DNA
E.g. Steroid/thyroid receptors
Location and effectors of ionotropic drug receptors
LOCATION= Membrane EFFECTOR= Channel
Location and effectors of metabotropic drug receptors
LOCATION= Membrane EFFECTOR= Enzymes or channel
Location and effectors of kinase-linked drug receptors
LOCATION= Membrane EFFECTOR= Enzyme
Location and effectors of IC steroid type drug receptors
LOCATION= Intracellular EFFECTOR= Gene transcription
What affect is hijacking drug receptors useful pharmacologically?
Stimulate or stop a response
What kind of drug receptors are nAChRs and GABAAR?
Ionotropic (msec)
What kind of drug receptors are mAChRs and B1 adrenoceptors?
Metabotropic (sec)
What kind of drug receptors are insulin receptors?
Kinase-linked (mins)
What kind of drug receptors are steroid/thyroid receptors?
IC steroid type (hours)
How are ion channels target sites for drugs?
Selective pores
Allow transfer of ions down electrochem gradients
What are the 2 types of ion channels (drug target sites)?
Voltage-sensitive e.g. VSCC
Receptor-linked e.g nAChR
What drugs act on ion channels? (2 e.g.s)
Local anaesthetics
Calcium channel blockers (-dipine)
How do transport systems act as drug target sites?
Transport against conc gradients
What drugs act on transport systems? (2 e.g.s)
Tricyclic anti-depressants (TCAs)
Cardiac glycosides
What are examples of transport systems used as drug target sites?
Na+/K+-ATPase (Na out, K in)
NA uptake 1
How can drugs interact with enzymes (3 ways with examples)?
Enzyme inhibitors e.g. anticholinestarases (neostigmine)
False substrates-> ‘false’ productes e.g. methyldopa
Prodrugs e.g. chloral hydrate-> trichloroethanol
What are the unwanted effects of paracetamol?
Overload metabolism-> toxic metabolites-> irreversible damage to liver and kidney
How can drugs act non-specifically (i.e. not on target sites)? (2 e.g.s)
Physiochemical properties e.g. antacids and osmotic purgatives
Define: affinity
Strength (avidity) of drug binding to R
Define: efficacy (intrinsic activity)
Ability of the drug to induce a response in the R post-binding
I.e. through conformational change in the R
Define: potency
Powerfulness of a drug
Depends on affinity and efficacy
Define: full agonist
Agonist which has the ability to induce a max response in tissue post-binding
Define: partial agonist
Agonist which can only produce a partial response in tissue
AND
In conjunction with a full agonist may act with antagonism activity
Define: selectivity
The preference of a drug for a receptor
NOT THE SAME AS SPECIFICITY)
Define: structure-activity relationship
The activity of the drug is closely related to the structure of the drug
Small changes in the structure may produce large effects on its action
Like LOCK AND KEY theory
What does the receptor reserve refer to?
The fact that in many tissues, not all Rs need to be occupied in order to achieve the maximal tissue response
What does the receptor reserve cause in physiological tissue?
Increased sensitivity and speed of response
GRAPH: In a log dose response curve, what is the relationship between full agonist and partial agonists?
Partial= lower maximum
GRAPH: In a log dose response curve, what is the relationship between full agonist and full agonist with lower affinity?
Need higher concentration for full agonist with lower affinity (so shift curve to R)
Same maximums
Do antagonists have affinity or efficacy?
Affinity but no efficacy
What are the 2 types of receptor antagonist (i.e. receptor blockade)?
Competitive
Irreversible
How does competitive antagonism work? What is the affect on DR curve?
Same site as agonist
Surmountable
Shifts DR curve to right
2 examples of competitive antagonists
Atropine
Propranolol
How does irreversible antagonism work?
Binds tightly OR at different site
Insurmountable
1 example of an irreversible antagonist
Hexamethonium
Which of the following statements is most accurate?
A: A partial agonist will always have a higher efficacy than a full agonist
B: Agonists have higher affinities than antagonists
C: Full agonists that are selective for a given receptor will have the same efficacy
D: Antagonists possess better efficacy than their respective agonists
E: Competitive antagonists will preferentially occupy the relevant receptor in the presence of agonist
C: Full agonists that are selective for a given receptor will have the same efficacy
A drug acting as an inhibitor at a particular drug target site prevents the removal of neurotransmitter from the synapse. Which type of drug target is this drug acting on?
A: Receptor B: Voltage-sensitive ion channel C: Receptor-linked ion channel D: Transport protein E: Non-proteinaceous target
D: Transport protein
What are the 4 types of drug antagonism?
Receptor blockade
Physiological antagonism
Chemical antagonism
Pharmacokinetic antagonism
What is physiological antagonism? (1 example)
Different receptors have opposite effects in the same tissue
E.g. NA and histamine on blood pressure
What is chemical antagonism? (1 example)
Interaction in solution
E.g. Dimercaprol-> heavy metal complexes (chelating agent)
What is pharmacokinetic antagonism? (1 example)
Antagonist leads to decreased conc of active drug at site of action
Reduced absorption-> increased metabolism and increased excretion
E.g. barbiturates
What is drug tolerance?
Gradual decrease in responsiveness to drug with repeated administration (days/weeks)
What are the 5 main factors underlying drug tolerance?
Pharmacokinetic factors Loss of receptors Change in receptors Exhaustion of mediators Physiological adaption
How do pharmacokinetic factors lead to drug tolerance? (2 examples)
Increased rate of metabolism
Barbiturates
Alcohol
What is an example of exhaustion of mediator stores leading to drug tolerance?
Amphetamine
How does loss of receptors lead to drug tolerance?
By membrane endocytosis
Receptor down-regulation
Beta-adrenoceptors
How do change in receptors lead to drug tolerance?
Receptor desensitization-> conformational change
E.g. nAChR at NMJ
How do physiological adaption lead to drug tolerance?
Homeostatic responses
Tolerance to drug side effects
What determines the distinction between the 4 receptor families?
Type 1-4 (ionotropic, metabotropic, kinase-linked, IC steroid)
Based on molecular structure and signal transduction systems
A 4 year old girl is bitten by a Tiger snake whilst holidaying in Australia. An anti-venom (harvested antibodies) is administered. Which form of antagonism is utilised by the anti-venom?
A: Competitive receptor blockade B: Physiological antagonism C: Chemical antagonism D: Pharmacokinetic antagonism E: Irreversible receptor blockade
C: Chemical antagonism
Tolerance to the euphoric effects of drugs of abuse (e.g. heroin & cocaine) can occur after repeated use. Which form of tolerance would not involve any change in the cells that mediate the euphoric effects? A: Receptor desensitisation B: Receptor down-regulation C: Exhaustion of mediator stores D: Receptor up-regulation E: Increased metabolic degradation
E: Increased metabolic degradation
How does a drug achieve its effect?
ADME
Administration
Absorption
Distribution (to site of action)
Metabolism
Excretion
Removal
What are the most common forms of administration for drugs?
Ingestion
Inhalations
Intravenous
Injections (dermal, intramuscular, subcutaneous, intraperitoneal)
What are the limitations of drug administration?
Ingestion (easy)
Inhalations (very easy but lots exhaled particularly if volatile drugs)
Intravenous (good straight into blood and lymph)
Injections (dermal, intramuscular, subcutaneous, intraperitoneal)= require skill
Primary site of drug metabolism
Liver
What is the difference between systemic and local drugs?
Systemic affect entire organism
Local restricted to one area of organism e.g. topical
Why is IV the most effective way to get drugs into systemic circulation?
Rapid absorption
Directly into blood and lymph
How do drug molecules move around the body (2 ways)?
Bulk flow transfer i.e. bolus in bloodstream
Diffusional transfer i.e. molecule by moluecule over short distances
Why are the characteristics of drugs important to allow their transport within the body?
Have to cross aqueous and lipid environment
Compartments= aqueous e.g. blood, lymph, ECF, ICF
Barriers= lipid e.g. cell membranes
How do drugs cross barriers to allow for absorption?
MOST IMPORTANT
Diffusion through lipid
Carrier molecules
ALSO
Diffusing through aqueous pores in the lipid
Pinocytosis
How are non-polar substances absorbed?
Freely dissolve in non-polar solvents
Penetrate lipid membranes freely
What does the ratio of ionised and non-ionised drugs depend on?
Most are weak acids or weak bases
Drugs exist in ionised (polar) and non-ionised (non-polar forms)
Ratio depends on pH
What are the difference types of aspirin used for and why?
Soluble= relief for headache (rapid), effectively absorbed in stomach because of stomach’s pH
Enteric coated= arthritis, slower releasing, slowly absorbed in intestine
How does aspirin act in the stomach?
Aspirin is a weak acid so in stomach most aspirin is uncharged
Can diffuse across membranes into cells
How does aspirin act in the intestine?
Aspirin release is slow because aspirin mainly ionised (charged-> slower) in the neutral ph (7.4) of the intestine
Define: ion trapping
Build up of a high conc of a chemical across a cell membrane due to the pKa value of the chemical and difference of pH across the cell membrane
Ion is trapped so slow release in dynamic equilibrium
What factors influence drug distribution?
Regional blood flow
EC binding (plasma-protein binding)
Capillary permeability
Localisation in tissues
How does regional blood flow affect drug distribution?
High metabolically active tissues have denser capillary networks
Blood perfusion changes rapidly in stress
How does extracellular (plasma-protein) binding affect drug distribution?
If drug is heavily bound to plasma-protein then will persist in bloodstream for a long time
May need to give more drug
How does capillary permeability affect drug distribution?
Ionised drugs can go through pore
Unionised can diffuse through cell wall unless bound
Capillary can be continuous, fenestrated or discontinuous
What are the 2 main routes of drug excretion?
Kidney (most drug elimination)
Liver (some are concentrated in the bile, usually large molecular weight conjugates)
NB. entero-hepatic circulation
How is the kidney involved in drug excretion?
Glomerulus= drug-protein complexes not filtered
Proximal tubule= active secretion of acids and bases
Proximal and distal tubules= lipid soluble drugs reabsorbed
Why is iv sodium bicarbonate given with aspirin and what will this do?
Na bicarb increases urine pH Increased urine pH ionizes the aspirin Ionized aspirin= less lipid soluble -> less reabsorbed from the tubule -> increased rate of excretion
Increase pH of urine in clinic to remove drugs
How is the liver involved in drug excretion?
Bile doesn’t have a size limit that it can deal with (unlike kidney)
Large molecular weight drugs excreted through bile because kidney can’t handle it
How can excretion happen outside the kidney and liver?
Lungs, skin, GI secretions, saliva, sweat, milk, genital secretions
Insignificant amounts
Why can entero-hepatic cycling be problematic for drug design?
Drug/metabolite excreted into gut (via bile) then reabsorbed, take in to liver, excreted again
Leads to drug persistence
What pharmacokinetic factors are important in predicting the time course of drug action?
Bioavailability (linked to absorption)
Apparent volume of distribution (linked to distribution)
Biological half life (linked to metabolism)
Clearance (linked to excretion)
Bioavailability
Linked to absorption
Proportion of the administered drug that is available within the body to exert its pharmacological effect
Apparent volume of distribution
Linked to distribution
The volume in which a drug appears to be distributed- an indicator of the pattern of distribution (how much has been distributed and to where)
Biological half-life
Linked to metabolism/excretion
Time taken for the concentration of drug (in blood/plasma) to fall to half its original value
Clearance
Linked to excretion
Blood (plasma) clearance is the volume of blood (plasma) cleared of a drug (i.e. from which the drug is completely removed) in a unit time
(Related to volume of distribution and rate at which drug is eliminated. If clearance involves several processes, then total clearance is the sum of these processes)
Which of the following drugs would be least likely to penetrate lipid membranes?
Ionised drug Non-ionised drug Protein bound drug (still correct but not best) Lipophilic drug Hydrophilic drug
Ionised drug
What is first-order kinetics?
SEE GRAPH
First-order kinetics describes the rate of elimination of a drug where the amount of a drug decreases at a rate that is proportional to the concentration of the drug remaining in the body
Dependent on the conc of drug at any given time
Applies to most clinical drugs
What is zero-order kinetics?
Half life doesn’t really apply to zero order kinetics
There is a constant amount of drug eliminated per unit time
Implies that there is a saturable metabolic process (applies to very few drugs)
What is the difference between first and zero order kinetics?
First order= most common= rate of elimination is proportional to the plasma drug conc
Zero order= constant amount of drug is eliminated per unit time
What is an important use of ethanol phenytoin and why?
Police use to check drunk drivers
Rate of elimination is constant
Can use to calculate how much alcohol someone has drunk
Is kinetics (1st order and 0 order) drawn on a log or linear graph? What would happen if it were the other?
Drug-conc axis is linear
If it were log…
1st order would be straight
0 order would be curved
What chemical property does a xenobiotic usually have?
Lipophilic foreign compound
What does metabolism do to allow lipophilic xenobiotics to be excreted?
Metabolism converts lipophilic chemicals to polar derivatives
By reducing or eliminating pharmacological/toxicological activity
Polar derivatives can be readily excreted
What is ‘first pass’ metabolism?
First time the drug goes through system before entering circulation (normally first metabolism is in the liver but could be skin, gut, kidneys, brain)
‘Clearing the drug’
When is ‘first pass’ metabolism not a problem?
When drugs don’t need to get into circulation
What are the 3 types/stages of metabolic change that drugs undergo?
Phase I
Phase II
Excretion
Phase I of metabolic change of drugs
Oxidation (creates new functional groups)
Reduction (creates new functional groups)
Hydrolysis (unmasks new functional groups)
- functional group serves as point of attachment for phase II reactions
Often generate a biologically inactive product
Have little effect on drug polarity
Sometimes produce toxic metabolites
Phase II of metabolic change of drugs
Glucuronidation Acetylation Amino acid conjugation Sulphation Methylation Glutathione conjugation
Are conjugation reactions which utilise -OH, -NH2, -SH and -COOH.
Involve a high energy intermediate e.g. UDPGA or PAPS
What do Phase I reactions usually do in drug metabolism?
Often inactive chemicals but can activate (e.g. prodrug)
After phase I, there is little change in polarity of the drug
Phase I prepares a drug for Phase II metabolism by introducing a functional group (handle) such as –OH, -NH2, -SH or –COOH.
Where are cytochrome P450?
Family of enzymes embedded in SER
How many cytochrome P450 enzymes are there?
57
What do all cytochrome p450 enzymes have in common?
All have a haem
Can all metabolise drugs
Predominantly found in liver
NB. Multiple isozymess
Why does smoking affect metabolism of some drugs?
Smoking-> induces enzymes (p450)-> metabolism of drug changes
What effects do drugs have the CYP450 system?
Inhibit or induce the system
What does cytochrome P450 often mediate?
Oxidation
SEE DIAGRAMS OF OXIDATION BY CYP
True or false: Metabolism of prodrugs activates their pharmacological activity
TRUE
True or false: Xenobiotic metabolism only occurs in the liver
FALSE
True or false: Hydrolysis is a Phase 1 reaction
TRUE
True or false: Cytochrome P450 uses NADH+ as cofactor
TRUE but prefers NAPH
True or false: Cytochrome P450 contains Cu2+ at its active site
FALSE
What effect do Phase I reactions have on drug polarity?
Little effect
What can be produced by Phase I reactions?
Toxic metabolites
What enzymes are used for the following processes: Glucuronidation Acetylation Amino acid conjugation Sulphation Methylation Glutathione conjugation
Glucuronidation= glucuronyl transferase
Acetylation= acetyl transferase
Amino acid conjugation= acyl transferase
Sulphation= sulphotransferase
Methylation= methyl transferase
Glutathione conjugation= glutathione-S-transferase
What are 3 main features of Phase II reactions?
Conjugate is almost always pharmacologically inactive
Less lipid soluble
Easier to excrete
How does glucuronidation in Phase II occur? (incl. formula)
ROH + very reactive UDPGA -> RO-D-glucuronide
Generate high energy phosphate compound
Glucuronic acid part transferred to an electron rich atom (N, O or S)
This is very important
UDP-glucuronate often excreted in bile
How does acetylation in Phase II occur? (incl. formula)
RNH2 + high energy CH3COSCoA -> RNHCOCH3 + CoASH
Acetyl CoA acts as donor compound
Donates acetyl group
Acetyl group transferred to an electron rich atom (N, O or S)
How does methylation in Phase II occur? (incl. formula)
RZH + S-adenosyl -> RZ-CH3 + S-adenosylhomocysteine
S-adenosyl methionine acts as donor compound
Methyl group transferred to an electronrich atom (N, O or S)
How does sulphation in Phase II occur? (incl. formula)
ROH + PAPS -> ROSO3- + PAP
Energy rich donor required
Paracetamol is very lipophilic so need to make it possible to excrete in urine
Sulfotransferases catalyse transfer of sulphate to substrates
How does conjugation with glutathione in Phase II occur? (incl. formula)
R-X + GSH -> R-SG + XH
X can be any leaving group
Glutathione is a protective factor, used for the removal of potentially toxic compounds
(Glycine + glutamine + cysteine tripeptide)
True or false: Metabolism of lipophilic chemicals facilitates their excretion
TRUE
True or false: Metabolism of drugs prior to entering the systemic circulation is known as “first pass metabolism.”
TRUE
True or false: Phase 2 metabolism includes reduction and acetylation
FALSE
True or false: Phase 2 metabolism generally increases the polarity of drugs
TRUE
True or false: Conjugation of drugs with glutathione is the most common Phase 2 route of metabolism
FALSE
What phase of drug metabolism uses a high energy intermediate e.g. UDPGA or PAPS?
Phase II
What phase of drug metabolism are conjugation reactions which use -OH, -NH2, -SH and -COOH?
Phase II
What phase of drug metabolism prepare a drug by introducing a functional group (handle) such as –OH, -NH2, -SH or –COOH?
Phase I
Why is drug metabolism important?
Biological half-life of the chemical is decreased
Duration of exposure is reduced
Accumulation of the compound in the body is avoided
Potency/duration of the biological activity of the chemical can be altered
Pharmacology/ toxicology of the drug can be governed by its metabolism
What are muscarinic effects?
Correspond to those of parasympathetic stimulation
Those replicated by muscarine
Can be abolished by low doses of antagonist atropine
What are nicotinic effects?
After atropine bloackage of muscarinic actions larger doses of acetylcholine can induce effects similar to those caused by nicotine
Nicotinic responses are smaller (need higher doses of ACh)
What do nicotinic receptors look like?
Ligand gated ion channels 5 subunits (α β γ δ ε) Subunit combo depends on properties
Subunits are found in:
Muscle type nicotinic Rs
Ganglion (neuronal) type nicotinic Rs
Muscle type nicotinic Rs= 2α β δ ε
Ganglion (neuronal) type nicotinic Rs= 2α 3β
What are the muscarinic cholinergic target systems? (8)
Eye Salivary glands Lung Sweat glands Heart Gut Bladder Vasculature
What are the muscarinic effects on the eye?
Contraction of the ciliary muscle (lens bulges) -> accommodation for near vision
Contraction of the sphincter pupillae (circular muscle of the iris)= constricts pupil (miosis) and improves drainage of intraocular fluid
Lacrimation
What causes Glaucoma?
Poor drainage of aqueous humour-> increased intraocular pressure
NORMALLY
Aqueous humour drains into anterior and posterior chamber to bathe lens (nutrients and oxygen) and to cornea
Drained through canal of Schlemm into vascular system
GLAUCOMA
Usually occurs when the fluid in the eye cannot drain properly-> increased pressure inside the eye and puts pressure on the optic nerve
The drainage angle is narrowed but production of aqueous humour doesn’t change
Muscarinic drugs affect aqueous humour in eye
What are the muscarinic effects on the heart?
M2 AChR in atria and nodes (inhibitory action)
Decreased cAMP
1) Decreased Ca2+ entry-> decreased cardiac output
2) Increased K+ efflux-> decreased heart rate
What are the muscarinic effects on the vasculature?
Most blood vessels do not have parasympathetic innervation
ACh acts on vascular endothelial cells to stimulate NO release (via M3 AChR, stimulatory)
NO induces vascular smooth muscle relaxation-> decreased TPR
Important clinically
What are the muscarinic effects on the CV system? (4)
Decreased heart rate (bradycardia)
Decreased cardiac output (due to decreased atrial contraction)
Vasodilatation (stimulation of NO production)
Sharp drop in blood pressure (due to all the above factors)
What are the muscarinic effects on the non-vascular smooth muscle (lung, gut, bladder)?
Smooth muscle that does have parasympathetic innervation responds in the opposite way to vascular muscle (IT CONTRACTS)
Lung= bronchoconstriction
Gut= increased peristalsis (motility)
Bladder= increased bladder emptying (increased urination in response to bladder filling)
What are the muscarinic effects on exocrine glands?
Salivation
Increased bronchial secretions
Increased GI secretions (including HCl production)
Increased sweating (SNS-mediated)
What are the overall muscarinic effects? (7)
Decreased HR Decreased BP Increased sweating Difficulty breathing Bladder contraction GI pain Increased salivation and tears
What are the typical, DIRECTLY acting cholinomimetic agonists at muscarinic receptors?
Choline esters (bethanechol= M3 selective) Alkaloids (pilocarpine= non-selective)
Both have chem structure similar to acetylcholine
How does pilocarpine work? What is it used for? Side effects?
Non-selective muscarinic agonist (half life 3-4h, lipid soluble)
Local treatment for glaucoma
SEs= blurred vision, sweating, GI disturbance/pain, hypotension, respiratory distress
How does bethanechol work? What is it used for? Side effects?
*NB cevimeline= newer version
M3 AChR selective agonist (half life 3-4h) Resistant to degradation (slower than ACh) Orally administered (limited access to brain)
Used to assist bladder emptying and enhance gastric motility
SEs= sweating, impaired vision, nausea, bradycardia, hypotension, respiratory difficulty
What are the typical, INDIRECTLY acting cholinomimetic agonists at muscarinic receptors?
Increase effect of normal parasympathetic nerve stimulation
Reversible anticholinesterases: physostigmine, neostigmine, donepezil (‘Aricept’)
Irreversible anticholinesterases: ecothiopate, dyflos, sarin
What do cholinesterase enzymes do?
Metabolise acetylcholine to choline and acetate
How many types of cholinesterases are there and what are they?
Two types which differ in distribution, substrate specificity and function:
Acetylcholinesterase (true or specific cholinesterase)
Butyrylcholinesterase (pseudocholinesterase)
Where do clinically relevant cholinomimetics act?
Muscarinic Rs
Where is acetylcholinesterase found and how does it work?
Found in all cholinergic synapses (peripheral and central)
Very rapid action (hydrolysis; >10 000 reactions per sec)
Highly selective for acetylcholine
Where is butyrylcholinesterase found and how does it work?
Found in plasma and most tissues but not cholinergic synapses
Broad substrate specificity - hydrolyses other esters e.g. suxamethonium
Is principal reason for low plasma acetylcholine
Shows genetic variation
What effects do cholinesterase inhibitors have?
Low dose
Moderate dose
High dose
Low dose
= enhanced muscarinic activity
Moderate dose
= further enhancement of muscarinic activity
= increased transmission at all autonomic ganglia (nAChRs)
High dose
= depolarising block at autonomic ganglia and NMJ
How do reversible anticholinesterase drugs (e.g. physostigmine and neostigmine) work?
Compete with ACh for active site on cholinesterase enzyme
Donate a carbamyl group to the enzyme, blocking the active site and preventing acetylcholine from binding
Carbamyl group removed by slow hydrolysis (mins rather than msecs)
Increase duration of ACh activity in the synapse
What are physostigmine and neostigmine?
Reversive anticholinesterase drugs
Where does physostigmine work and what is it used for?
Primarily acts at the postganglionic parasympathetic synapse (half life= 30mins)
Used in the treatment of glaucoma, aiding intraocular fluid drainage
Also used to treat atropine poisoning, particularly in children
How do irreversible anticholinesterase drugs (e.g. organosphosphate compounds- ecothiopate, dyflos, parathion and sarin) work?
Rapidly react with the enzyme active site, leaving a large blocking group
This is stable and resistant to hydrolysis - recovery may require the production of new enzymes (days/weeks)
Only ecothiopate in clinical use, but the others are commonly used as insecticides (and nerve gas)
What kind of drugs are ecothiopate and sarin?
Irreversible anticholinesterase drugs
Where do ecothiopate work and what is it used for? Side effects?
Potent inhibitor of acetylcholinesterase
Slow reactivation of the enzyme by hydrolysis takes several days
Used as eye drops in treatment of glaucoma, acting to increase intraocular fluid drainage with a prolonged duration of action
Systemic SEs= sweating,
blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty
How do anti-cholinesterase drugs affect the CNS?
Low doses
High doses
Non-polar anticholinesterases (e.g. physostigmine; nerve agents) can cross BBB
Low doses
= excitation with possibility of convulsions
High doses
= unconsciousness, respiratory depression, death
Why are donepezil and tacrine used to treat Alzheimer’s disease?
ACh is important in learning and memory
Potentiate central cholinergic transmission-> relieves AD symptoms BUT does not affect degeneration
What happens in organophosphate poisoning and how is it treated?
Organophosphate poisoning e.g. from insecticides or sarin
-> severe toxicity (increases muscarinic activity, CNS excitation, depolarising NM block)
Treatment= IV atropine, articificial respiration, IV pralidoxime
- pralidoxime works at pre and post ganglionic AChRs
- atropine works at effector organ
What are the 2 main classes of cholinomimetics?
Direct (agonists)
Indirect (inhibitors of cholinesterase enzymes)
What can high doses of cholinomimetics do?
High doses of cholinomimetics activate the parasympathetic NS
BUT ALSO
Can activate all autonomic ganglia and ultimately cause depolarising blockade of nAChRs
Anticholinesterase drugs have the ability to increase activity at which synapses within the autonomic nervous system?
A: All autonomic synapses
B: Pre- and post-ganglionic parasympathetic synapses
C: Pre- and post-ganglionic sympathetic synapses
D: Post-ganglionic parasympathetic synapses only
E: Pre-ganglionic sympathetic synapses only
B: Pre- and post-ganglionic parasympathetic synapses
Anticholinesterase drugs can be used to treat which of the following conditions?
A: Asthma B: Glaucoma C: Hypotension D: Motion Sickness E: Peptic Ulcer Disease
B: Glaucoma
Do agonists and antagonists possess affinity and efficacy?
Agonists and antagonists possess affinity
Agonists possess efficacy
Which of the following drugs has efficacy for the muscarinic acetylcholine receptor? Acetylcholine Atropine Acetyl-cholinesterase Adrenaline Acetate
Acetylcholine
What is ganglion blocking drugs another name for?
Nicotinic receptor antagonists
How do ganglion blocking drugs/ nicotinic receptor antagonists?
Prevent ion from getting through by binding to R and blocking it but also get into ion channel and block it themselves
Nicotinic so not at effector organ (refer to diagram)
Give 2 examples of nicotinic receptor antagonists?
Hexamethonium
Trimetaphan
When are nicotinic receptor antagonists most effective?
When channel is open
More ACh present, the more active the channel so the more effective the antagonist
Why is the nicotinic receptor antagonist block described as ‘incomplete’?
Not a total blockade just slows the process down
Do nicotinic receptor antagonists have affinity?
Technically but affinity is irrelevant if blockading
Physical blockade doesn’t require receptor binding
What are the parasympathetic and/or sympathetic effects on the eye?
SYMP= dilatation (pupil) PARA= constriction (pupil), contraction (ciliary muscle)
What are the parasympathetic and/or sympathetic effects on the trachea and broncheoles?
SYMP= dilates (Ad) PARA= constriction
What are the parasympathetic and/or sympathetic effects on the liver?
SYMP= glycogenolysis, gluconeogenesis
What are the parasympathetic and/or sympathetic effects on the adipose tissue?
SYMP= lipolysis
What are the parasympathetic and/or sympathetic effects on the kidney?
SYMP= increased renin secretion
What are the parasympathetic and/or sympathetic effects on the ureters and bladder?
SYMP= relaxes detrusor, constriction of trigone and sphincter PARA= contraction of detrusor, relaxation of trigone and sphincter
What are the parasympathetic and/or sympathetic effects on the salivary glands?
SYMP= thick, viscous secretion PARA= copious, watery secretion
What are the parasympathetic and/or sympathetic effects on the skin?
SYMP (CHOLINERGIC)= increased sweating
PARA= piloerection
What are the parasympathetic and/or sympathetic effects on the heart?
SYMP=increased HR and contractility
PARA= decreased HR and contractility
What are the parasympathetic and/or sympathetic effects on the GI system?
SYMP= decreased motility and tone, sphincter contraction PARA= increased motility and tone, increased secretions
What are the parasympathetic and/or sympathetic effects on the blood vessels?
PARA (skeletal muscle)= dilatation
PARA (skin, mucous membranes and splanchnic are)= constriction
What does the effect of a blocking nicotinic R depend on?
Which arm of the NS is active
E.g. in eye, trachea, ureters/bladder, heart, GI
Which 2 of the following effects would be observed at rest after treatment with a ganglion blocking drug? Increased heart rate Pupil constriction Bronchodilation Detrusor contraction Increased gut motility
Increased HR and bronchodilation
Why do ganglion blocking drugs cause hypotension?
Increased renin secretion
Constriction of blood vessels (skin, mucous membranes, splanchnic areas)
What are the effects of ganglion blocking drugs (nicotinic R antagonists) on smooth muscle?
Pupil dilation
Decreased GI tone
Bladder dysfunction (relaxes detrusor, constriction of trigone and sphincter
Bronchodilation
What are the effects of ganglion blocking drugs (nicotinic R antagonists) on exocrine tissue?
Decreased exocrine secretions
E.g. from skin, salivary glands, GI system
How are hexamethonium and trimetaphan used clinically?
Hexamethonium= 1st anti-hypertensive, predominantly a nicotinic R blockage
Trimetaphan= hypotension during surgery, predominantly a R antagonist (very short acting)
Both can do both
Why are so few nicotinic receptor antagonists used clinically?
Many side effects
Only hexamethonium and trimetaphan used clinically
What is a-bungarotoxin? How does it work?
From common krait snake venom
Very potent
Irreversible R antagonist-> permanent nicotinic blockade
Useful to snakes because prey can’t move and can’t breathe (diaphragm paralysed)
Affect somatic nervous system
Which is more clinically useful, nicotinic or muscarinic receptor antagonists?
Muscarinic receptor antagonists
What are two examples of muscarinic receptor antagonists?
Atropine
Hyoscine
What is atropine derived from?
Atropa belladonna
What is hyoscine derived from?
Hyoscyamus niger
What physiological responses could be influenced by muscarinic receptor antagonists?
ALL PARASYM (+SWEAT= cholinergic sympathetic)
Eye= contriction (pupil), contraction (ciliary muscle)
Trachea and broncheoles= constriction
Ureters and bladder= contraction of detrusor, relaxation of trigone and sphincter
Salivary glands= copious, watery secretion
Skin= increased sweating*
Heart= decreased rate and contractility
GI= increased motility, tone and secretions
Which antagonist is more specific; muscarinic or nicotinic?
Muscarinic
What are the clinical uses of atropine?
Muscarinic receptor antagonist
CNS effects
Normal dose- little effect
Toxic dose- mild restlessness-> agitation
What are the clinical uses of hyoscine?
Muscarinic receptor antagonist
CNS effects
Normal dose- sedation, amnesia
Toxic dose- CNS depression or paradoxical CNS excitation (associated with pain)
Why does hyoscine have more CNS effects than atropine?
Atropine= not very M1 selective (M1R seems to do a lot in brain) Hyoscine= greater permeation into CNS, influence at therapeutic dose, more lipid soluble and M1 selective
What are the clinical uses of muscarinic receptor antagonists?
Ophthalmic= examination of retina with tropicamide
Anaesthetic premedication
Neurological= motion sickness, hyoscine patch,
Parkinson’s= cholinergic/dopaminergic balance in basal ganglia
Respiratory= asthma/obstructive airways disease
GI= IBS
Muscarinic receptor antagonists in ophthalmic exam of retina
Tropicamide
Pupil dilates (parasympathetic effect blocked) Examine back of retine
Muscarinic receptor antagonists in anaesthetic premedication
Antagonist interferes with parasympathetic effects including…
Trachea and bronchioles (blocks constriction)
Salivary glands (blocks copious, water secretion)
Heart (blocks heart rate decrease and contractility decrease)
Also-> sedation
Muscarinic receptor antagonists in neurological motion sickness
Hyoscine patch
Cholinergic sensory mismatch still occurs but won’t be sick
Controls eye movement to maintain vision whilst in motion
Muscarinic receptor antagonists in Parkinson’s disease
Normally cholinergic and dopaminergic systems work together
Cholinergic system is generally inhibitory to dopaminergic system
In PD, lose DAergic neurons so less D1 R activation-> fine control of movement is impeded
At same time cholinergic (parasymp) system is trying to dampen DAergic response
Need to block M4R (cholinergic muscarinic R4) to stop the cholinergic inhibition of DA
Muscarinic receptor antagonists in asthma/obstructive airway disease
Ipratropium bromide (polar so can’t leave lungs easily, given as aerosol)
Antagonist blocks constriction of trachea and bronchioles -> lungs dilate
Muscarinic receptor antagonists in GI system (IBS)
M3 selective antagonist
IBS= overactive bowel so want to suppress that
Block increased motility, tone and secretions
What are the unwanted effects of muscarinic receptor antagonists?
Hot as hell= sweating, thermoregulation
Dry as a bone= secretions
Blind as a bat= cyclopegia
Mad as a hatter= CNS disturbance
Which of the following drugs would you administer to treat an atropine overdose? Bethanechol Ecothiopate Hyoscine Physostigmine Pralidoxime
Bethanechol
NB.
Ecothiopate= irreversible (toxic, nasty drug but would cure atropine overdose)
Hyoscine
Physostigmine= reversible
Pralidoxime= can reverse anticholinesterase poisoning
What happens following poisoning with anti-cholinesterase (e.g. physostigmine)?
Acetylcholinesterase blocked
So ACh doesn’t get broken down to choline and acetate
ACh outcompetes atropine
More ACh binding than atropine
What is botulinum toxin an example of?
A parasympatholytic
How does botulinum toxin work?
Drug that prevents ACh being exocytosed by interfering with the SNARE complex
Vesicles can’t dock with the membrane
ACh can’t be released
Very toxic
What are the subtypes of nicotinic cholinoceptors?
a1, a2, B1, B2
Where are nicotinic cholinoceptors found?
On the effector organs of sympathetic pathways
Directly with NA and indirectly via adrenal medulla with A and NAin bloodtream
How do directly acting sympathomimetics?
Mimic the actions of NA/A by binding to and stimulating adrenoceptors (GPCRs)
What are the main uses of directly acting sympathomimetics?
Principally for their actions in the CVS, eyes and lungs
What happens at each type of nicotinic cholinoceptor? a1 a2 b1 B2
a1= PLC, IP3, DAG a2= decreased cAMP B1= increased cAMP B2= increased cAMP
Nicotinic cholinoceptor subtypes at.... Eye Trachea Liver Adipose Kidney Urinary bladder Ureter Male genitalia Female genitalia Lacrimal glands Salivary glands Skin Heart GI Blood vessels (skeletal and skin/mucous)
Use + symbols to show the relative importance of adrenergic activity
SEE DIAGRAM
Eye= a1 ++ Trachea= B2 + Liver= a1, B2 ++ Adipose= a1, B1 ++ Kidney= B1 ++ Urinary bladder= B2 + (relaxes detrusor), a1 ++ (constricts trigone and sphincter) Ureter= a1 + Male genitalia= a1 +++ Female genitalia= a/B Lacrimal glands= a1+ Salivary glands= a/B Skin= a1 +++ Heart= B1+++ GI= a/B Blood vessels= B2 ++ (skeletal), a1 +++ (skin/mucous)
What are the adrenergic effects on female and male genitalia?
Male- stimulates ejaculation (a1 +++)
Female- relaxation of uterus (B2)
What activates adrenoceptors?
NA and A
How does selectivity for NA and A differ by subtype of adrenoceptor?
Selectivity for NA:
α1 = α2 > β1 = β2
Selectivity for A:
β1 = β2 > α1 = α2
Describe the NA metabolism feedback system
Tyrosine (with tyrosine hydroxylase)->DOPA
DOPA (with dopa-decarboxylase)-> DA
DA (in vesicle with DBH)-> NA
NA-> diffusion into blood, postsynaptic R, extraneuronal uptake, metabolised, presynaptic uptake R
List 5 directly acting SNS agonists and state what subtype of adrenoceptor they act on
Adrenaline (non-selective) Phenylephrine (α1) Clonidine (α2) Dobutamine (β1) Salbutamol (β2)
Why is adrenaline used in treatment of anaphylaxis?
β2 – broncho dilation
β1 – tachycardia
α1 – vasoconstriction
Suppression of mediator release
(A= airways B= breathing C= circulation)
How can SNS agonists be used to treat pulmonary obstructive conditions?
In asthma (emergencies) Acute bronchospasm associated with chronic bronchitis or emphysema
B2-> bronchdilation
Suppression of mediator release
Selective B2 agonists preferable
How can adrenaline be used to treat glaucoma?
a1-mediated vasoconstriction
What can adrenaline be used for clinically?
Glaucoma
Cardiogenic shock
Spinal anaesthesis
Local anaesthesia
How can adrenaline treat cardiogenic shock?
Cardiogenic shock= sudden inability of heart to pump sufficient oxygen-rich blood
Severe heart attack/MI
Cardiac arrest
β1 – positive inotropic actions
How can adrenaline be used during spinal anaesthesia and local anaesthesia?
Spinal anaesthesia
Maintenance of blood pressure
Local anaesthesia
Prolongs duration of action
α1 – vasoconstrictor properties
What are the unwanted actions of adrenaline?
Secretions= reduced and thickened mucous
CVS effects= tachycardia, palpitations, arrhythmias, cold extremities, hypertension, overdose -> cerebral haemorrhage, pulmonary oedema
Skeletal muscle= tremor
GIT and CNS= minimal
What is phenylephrine? What is it resistant to?
Drug related chemically to adrenaline
Resistant to COMT but not MAO
Selective α1»α2»>β1/β2
What is phenylephrine selective for?
α1»α2»>β1/β2
What are the clinical uses of phenylephrine?
Vasoconstriction
Mydriatic
Nasal decongestant
E.g. sudafed
What is clonidine selective for?
α2»α1»>β1/2
What are the clinical uses of clonidine?
Treatment of hypertension and migraine (now superseded)
Reduces sympathetic tone
How does clonidine reduce sympathetic flow?
α2 adrenoceptor mediated
presynaptic inhibition of NA release
Central action in brainstem within
Baroreceptor pathway to reduce
Sympathetic outflow
What is isoprenaline selective for?
ß1=ß2»»α1/2
How do isoprenaline and adrenaline differ?
Chemically similar but isoprenaline is less susceptible to uptake 1 and MAO breakdown
Plasma half life 2 hours
What are the clinical uses of isoprenaline?
Cardiogenic shock
Acute heart failure
Myocardial infarction
Why does reflex tachycardia result form isoprenaline treatment?
β2-stimulation in vascular smooth muscle and skeletal muscle results in fall in venous blood pressure which triggers a reflex tachycardia via the stimulation of baroreceptors
Dobutamine better as doesn’t cause reflex tachycardia
What is dobutamine selective for?
β1»β2»>α1/2
What is dobutamine used for clinically?
Cardiogenic shock
Lacks isoprenaline’s reflex tachycardia
Administration by i.v. infusion. Plasma half life 2 minutes (rapidly metabolised by COMT)
What is salbutamol (ventolin) selective for?
β2»β1»>α1/2
What is salbutamol relatively resistant to?
MAO and COMT
What are the clinical uses of salbutamol?
Treatment of asthma
Treatment of threatened premature labour
How does salbutamol treat asthma?
β2-relaxation of bronchial smooth muscle
Inhibition of release of brochoconstrictor substances from mast cells
How does salbutamol treat threatened premature labour?
β2-relaxation of uterine smooth muscle
What are the side effects of salbutamol?
Reflex tachycardia
Tremor
Blood sugar dysregulation
What are cocaine and ‘cheese’ examples of?
Indirectly acting SNS agonists
Where do indirectly acting sympathomimetics act?
Indirectly acting sympathomimetics are drugs that act at the adrenergic nerve terminal as opposed to the adrenoceptors
What does cocaine do?
Uptake 1 blocker
Affects DA, NA, A
What are the effects of cocaine on the CNS and CVS in low and high doses?
CNS
Low= euphoria, excitement, increased motor activity
High= activation of CTZ, CNS depression, respiratory failure, convulsions and death
CVS
Low= tachycardia, vasoconstriction, raised blood pressure
High= ventricular fibrillation and cardiac arrest
What is the ‘cheese reaction’?
Tyramine
A dietary AA (in cheese, red wine and soy sauce) acts a ‘false’ neurotransmitter
Not problematic when normal mechanisms for degradation of monoamines are in operation but problem with MAO treatment
How does the cheese reaction lead to increased NA release from tyramine?
- Some weak agonistic activity by cheese false NT at post synaptic adrenoceptors
- Competes with catecholamines for Uptake 1, i.e. it is taken up into adrenergic nerve terminals
- Displaces NA from intracellular storage vesicles into cytosol
- NA and tyramine compete for sites on MAO
- Cytoplasmic NA leaks through the neuronal membrane to act at postsynaptic adrenoceptors
INCREASED NA RELEASE overall but issue is if you’re taking MAO inhibitors
What is caused by the cheese reaction in someone taking MAO inhibitors?
Hypertensive crisis
Adrenoceptor functions: a1
Vasoconstriction
Relaxation of GIT
Adrenoceptor functions: a2
Inhibition of transmitter release
Contraction of vascular smooth muscle
CNS actions
Adrenoceptor functions: b1
Increased cardiac rate and force
Relaxation of GIT
Renin release from kidney
Adrenoceptor functions: b2
Bronchodilation
Vasodilation
Relaxation of visceral smooth muscle
Hepatic glycogenolysis
Adrenoceptor functions: b3
Lipolysis
What adrenoceptor antagonists act on the following?: a1 and b1 a1 and a2 a1 b1 and b2 b1
a1 and b1= labetalol (really non-selective but predominantly these two) a1 and a2= phentolamine a1= prazosin b1 and b2= propranolol b1= atenolol
What does propranolol act on?
Adrenoceptor antagonist
B1 and B2
What are SNS antagonists and false transmitters useful for clinically?
Hypertension
Cardiac Arrhythmias
Angina
Glaucoma
What is hypertension?
Increased BP associated with increased risk of other disease
Sign rather than a disease
Sustained diastolic arterial pressure >90mmHg (140/90mmHg or higher)
What are the main elements that contribute to hypertension?
Blood volume
Cardiac output
Peripheral vascular tone
What are the tissue targets for antihypertensives?
Sympathetic nerves that release NA (vasoconstrictor)
Kidney
Heart
Arterioles (determine peripheral resistance)
CNS (determines BP pressure set point)
What are the 3 main categories of beta adrenoceptor antagonists?
Cardioselective
Nonselective
Drugs with additional a1 antagonist activity
How do b-adrenoceptor antagonists act?
Competitive antagonism of B1 adrenoceptors (B2 antagonism’s importance is unclear)
What do b-adrenoceptor antagonists do to the CNS, heart and kidney?
CNS
Reduce sympathetic tone
HEART
B1- reduce HR and CO (disappears in chronic treatment)
KIDNEY
B1- reduce renin-production-> reduced peripheral resistance
What are the pre-synaptic effects of b-adrenoceptor antagonists?
Antagonist blocks facilitatory effects of presynaptic b-adrenoceptors on NA release
Contributes to antihypertensive effect
What are the main unwanted effects of b-adrenoceptor antagonists?
Bronchoconstriction Cardiac failure Hypoglycaemia Fatigue Cold extremities Bad dreams
Why is bronchoconstriction an unwanted effect of b-adrenoceptor antagonists?
Problematic with asthmatics and patients with obstructive lung disease e.g. bronchitis
Why is cardiac failure an unwanted effect of b-adrenoceptor antagonists?
Heart disease patients may need some sympathetic drive to the heart to maintain adequate CO
Why is hypoglycaemia an unwanted effect of b-adrenoceptor antagonists? How can this be reduced?
B-antagonists mask the symptoms of hypoglycemia (sweating, palpitations, tremor)
Use of non-selective b-antagonists are more dangerous in such patients since they will also block the b2- receptors driven breakdown of glycogen
B1- selective agents may have advantages since glucose release from the liver is controlled by b2- receptors
Why is fatigue caused by b-adrenoceptor antagonists?
Due to reduced CO and reduced muscle perfusion
Why are cold extremities caused by b-adrenoceptor antagonists?
Loss of b-receptor mediated vasodilation in cutaneous vessels
What is propranolol? What does it do?
Non-selective beta adrenoceptor antagonist
At rest, very little change in HR, CO or BP but reduces the effect of exercise or stress on these variables
Produces adverse effects (non-selective)
What is atenolol? What does it do?
Cardio-selective (historical name)
B1-selective (selectivity is concentration dependent)
Antagonises NA effects on heart
Affects any tissue with b1 receptors e.g. kidney
BUT most side effects are caused by B2 Rs
(Still not safe for asthmatic patients despite less effect on airways)
What is labetalol? What does it do?
B1 and a1 antagonists (4:1 b1 to a1)
Lowers BP by reducing peripheral resistance
a1- in peripheral vascular muscles
b1- in kidney-> decreases renin production
Induces change in HR or CO (effect wanes with chronic use)
What do a-adrenoceptor antagonists cause?
Non-selective
Mediate peripheral resistance (-> fall in arterial pressure)
Postural hypotension
CO/HR increases *reflex response to fall in arterial pressure)
Blood flow through cutaneous and splanchnic vascular beds increased
Very small effects on vascular smooth muscle
What is phentolamine? What does it do?
Non-selective a-antagonist
Causes vasodilatation and fall in BP (blockade of a1 receptors)
Concomitant blockade of a2-Rs tends to increase NA release-> enhances reflex tachycardia
Increased GIT motility-> diarrhoea
NOT USED CLINICALLY NOW
What is prazosin? What does it do?
Highly selective a1-antagonist
Vasodilatation and fall in arterial pressure= DRAMATIC HYPOTENSIVE EFFECT
Dilation of capacitance vessles-> fall in venous pressure-> CO output decreases
Modest decrease in LDL and increase in HDL cholesterol
Less tachycardia than non-selective antagonists (don’t increase NA release via a2)
Some postural hypotension
What is methyldopa? What does it do?
False transmitter
Antihypertensive agent taken up by noradrenergic neurons
Decarboxylated and hydroxylated to form false transmitter, α-methyl-noradrenaline
Not de-aminated by MAO so accumulates in larger quantities than NA and displaces NA from synaptic vesicles
Some CNS effects, stimulates vasopressor centre in the brainstem to inhibit sympathetic outflow
How does methyldopa work? How does the false transmitter differ from NA?
False transmitter released in same way as NA
BUT less active than NA on a1-Rs (so less effective in causing vasoconstriction)
AND more active on presyn a2 Rs (auto-inhibitory fb mechanism stronger-> reduces transmitter release below normal levels)
What are the beneficial results of methyldopa?
Antihypertensive
Renal and CNS blood flow well maintained
Suitable for hypertensive pregnant women (no adverse effects on foetus despite crossing blood-placenta barrier)
What are the adverse effects of methyldopa?
Dry mouth
Sedation
Orthostatic hypotension
Male sexual dysfunction
What is an arrhythmia?
Abnormal/irregular heart beats
Main cause= myocardial ischaemia
What affect does symapthetic activity have on arrhythmias and AV conductance?
Increased sympathetic drive to the heart via b1 precipitates or aggravates arrhythmias (especially common after myocardial infarction)
Sympathetic activity also affects AV conductance and the AV refractory period is increased by b-adrenoceptor antagonists (interferes with AV conduction in atrial tachycardias)
What class II antiarrhythmics are used and why?
Propranolol (non-selective b-antagonist drug)
Effects many attributed to b1 antagonism
Reduce mortality of patients with myocardial infarction
Particularly successful in arrhythmias that occur during exercise or mental stress
What is angina?
Pain that occurs when O2 supply to myocardium is insufficient for its needs
Pain= chest, arm, neck
Brought on by exertion or excitement
What are the 3 types of angina?
Stable
Unstable
Variable
What is stable angina?
Pain on exertion
Increased demand on heart
Due to fixed narrowing of the coronary vessels e.g. atheroma
What is unstable angina?
Pain with less and less exertion, culminating with pain at rest
Platelet-fibrin thrombus associated with a ruptured atheromatous plaque but without complete occlusion of the vessel
Risk of infarction
What is variable angina?
Occurs at rest
Caused by coronary artery spasm
Associated with atheromatous disease
How do b-adrenoceptor antagonists reduce myocardial oxygen demand in angina?
Decrease HR
Decrease systolic BP
Decrease cardiac contractile activity
Reduce the oxygen demand whilst maintaining the same degree of effort
At low doses what effects do b1-selective agents have on HR and contractile activity?
At low doses, b1-selective agents, metoprolol, reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle
What are the adverse effects of b1-selective antagonists in angina treatment?
Fatigue Insomnia Dizziness Sexual dysfunction Bronchospasm Bradycardia Heart block Hypotension Decreased myocardial contractility
What patients should avoid b1-selective antagonists as angina treatment?
Patients with bradycardia (heat beat of less than 55 beats/min)
Patients with bronchospasm
Patients with hypotension (systolic pressure less than 90mmHg)
Patients with AV block
Patients with severe congestive heart failure
Outline the production and route of aqueous humour?
Produced by blood vessels in ciliary body via the actions of carbonic anhydrase
Flows into posterior chamber, through pupil to anterior chamber
Drains into trabecular network and into veins and canal of Schlemm
Production indirectly related to blood pressure and blood flow in ciliary body
What adrenoceptor antagonists can be used to treat glaucoma?
Beta antagonists
Non-selective (block B1 and B2)
Carteolol hydrochloride, levobunolol hydrochloride, timolol maleate
NB. Selective b1 antagonists betaxolol hydrochloride also shown to be effective
How do b-adrenoceptor antagonists treat glaucoma?
Reduce rate or aqueous humor formation by blocking receptors on ciliary body
What can b-adrenoceptor antagonists be used to treat?
Glaucoma Angina Arrhythmias Hypertension Heart failure Anxiety Migraine prophylaxis Benign essential tremor
Why are beta blockers useful in anxiety?
Control somatic symptoms associated with sympathetic overreactivity e.g. palpitations and tremor
What type of receptor is found at neuromuscular junctions?
nAChR (different from ganglionic nAChR)
Needs 2 molecules of ACh to stimulate it
Bonds to alpha Rs
List NM blocking drugs and their type
COMPETITIVE ANTAGONISTS (non-depolarising) Tubocurarine Galamine Pancuronium Alcuronium Atracurium Vecuronium
AGONISTS (depolarising)
Suxamethonium
What are the main sites/processes of NM blocking drug action?
Central processes
Conduction of nerve AP in motor neurone
ACh release
Depolarisation of motor end-plate AP initiation
Propagation of AP along muscle fibre and muscle contraction
True or false; tubocurarine and atracurium act postsynaptically?
True
True or false; suxamethonium acts presynaptically?
False (postsynaptically)
What NM drug acts on the central processes? How does it work?
Spasmolytics (diazepam, baclofen)
Act in SC
Reduce AP generation-> reduced muscle tension
What NM drug acts on the conduction of nerve AP in motor neurone? How does it work?
Local anaesthetics
Reduce AP propagation-> weakness of skeletal muscle
What NM drug acts on the ACh? How does it work?
Hemicholinium
Ca2+ entry blockers
Neurotoxins
Ultimately lead to depletion of ACh
Reduces exocytotic release of Ca
Inhibits release of ACh
What NM drug acts on the depolarisation of motor end-plate AP initiation? How does it work?
Tubocurarine
Suxamethonium
Affect nAChRs on post syn membrane
What NM drug acts on the propagation of AP along muscle fibre and muscle contraction? How does it work?
Spasmolytics (dantrolene)
Affects muscle fibres rather than CNS
NM drugs that act post-synaptically have a number of common features despite being non-depolarising antagonists or polarising agonists. These include…
They don’t affect consciousness
They don’t affect pain sensation
Always assist respiration
Suxamethonium:
MOA and pharmacokinetics
Depolarising NM blocker (agonist)
MODE OF ACTION
Extends EP depolarisation-> depolarisation block (phase 1)
Fasciculations-> flaccid paralysis
PHARMACOKINETICS
IV admin
Paralysis 5 min (short)
Metabolised by pseudo-cholinesterase in liver and plasma
What is suxamethonium used for?
Endotracheal intubation
Muscle relaxant for ECT (electroconvulsive therapy)
What are the unwanted effects of suxamethonium?
Post-operative muscle pains
Bradycardia (direct muscarinic action on heart)
Hyperkalaemia (soft tissue injury or burns-> ventricular arrhythymias or cardiac arrest)
Increased intra-ocular pressure (by action of extraocular skeletal muscles- avoid for eye injuries and glaucoma)
Tubocurarine: MOA
Naturally occurring quaternary ammonium compound (alkaloid) but now synthetic drugs available
Competitive nAChR antagonist
70-80% block necessary
What are the effects of tubocurarine?
Flaccid paralysis
Extrinsic eye muscles (double vision)-> small muscles of face, limbs, pharynx-> respiratory muscle-> RECOVERY
Why is it useful to relax skeletal muscles during surgical operations?
Less anaesthetic
Permit artificial ventilation
How can the actions of non-depolarising blockers be reversed?
Anticholinesterases
Neostigmine (and atropine)
What are the pharmacokinetics of tubocurarine?
IV admin (highly charged) Doesn't cross BBB or placenta Paralysis lasts 40-60min Not metabolised 70% excreted in urine 30% in bile (careful if renal or hepatic function impaired)
What are the unwanted effects of tubocurarine?
Hypotension (ganglion blockade-> decreased TPR, histamine released from mast cells)
Tachycardia (may-> arrhythmias)- reflex and blockade of vagal ganglia
Bronchospasm (histamine release)
Excessive secretions (bronchial and salivary)
Apnoea (always assist respiration)
The clinical use of neuromuscular blocking drugs will most likely involve interference with which of following physiological processes?
A: Kidney function B: Consciousness C: Body temperature regulation D: Pain sensation E: Respiration
E. Respiration
Which of the following effects would be observed with a non-depolarising neuromuscular block?
A: Initial muscle fasciculations B: Irreversible nAChR blockade C: The block would be enhanced by anti-cholinesterase drugs D: A flaccid paralysis E: Increased arterial pressure
D. Flaccid paralysis
What is phase 4 of the cardiac AP? (Bit under threshold)
Spontaneous depolarization (pacemaker potential) that triggers the AP
What is If?
Hyperpolarization-activated cycle nucleotide-gated (HCN) channels
What is Ica (T or L)?
Transient T or L type Ca channel
L= long lasting
What is Ik?
Potassium K channels
What mechanisms regulate heart rate?
If
Ica
Ik
What is the effect of the sympathetic system on cAMP, If and ICa?
Increase cAMP
Increase If
Increase Ica
What is the effect of the parasympathetic system on cAMP and Ik?
Decrease cAMP
Increase Ik
Outline cardiac Ca release following an AP
AP excitation (via If) from the SAN induces membrane depolarization -> Ca channel gates open-> small release of Ca into cytoplasm (T)
Small Ca current-> release of Ca from SR (Ca-induced Ca release) through RyR2 (L)
What percentage of the free Ca in a cardiac twitch is through L type channels?
20-25%
What percentage of Ca necessary for cardiac contraction is released through the RyRs?
75-80%
What effect does blood amount have on the heart?
Determines contractility
What is the primary determinant of myocardial oxygen demand?
Myocyte contraction
How does increased HR lead to an increased force of contraction?
Increased HR-> more contractions-> increased afterload or contractility (greater force of contraction)
How does increased preload affect contraction?
Small increase in force of contraction
What is the myocardial oxygen supply?
Increased coronary blood flow
Increased arterial O2 content
How does work affect the myocardial oxygen demand?
Increased heart rate, preload, afterload and contractility
List examples of drugs that reduce HR and how
B blockers= decrease If and Ica
Ca antagonists= decrease Ica
Ivabradine= decrease If
How do drugs reduce heart rate (overall)?
Prolong rate at which depolarisation occurs
E.g. Ca antagonists reduce ability of tissue to depol
List examples of drugs that decrease contractility
B blockers = decrease contracility
Ca antagonists= decrease ICa
What receptor to Ca antagonists act on?
DHPR (dihydropiridine receptors)
-> decrease Ca entry into cell
What are the classes of calcium antagonists?
Rate slowing (cardiac and smooth muscle actions)
Non-rate slowing (smooth muscle actions- more potent)
List examples of rate slowing calcium antagonists
Phenylalkylamines (e.g. Verapamil)
Benzothiazepines (e.g. Diltiazem)
List examples of non-rate slowing calcium antagonists
Dihydropyridines (e.g. amlodipine)
What heart condition can be caused by profound vasodilation (by Ca antagonists)?
Reflex tachycardia
How can drugs increase myocardial oxygen supply?
Hyperpolarised coronary vessel (due to organic nitrates and K channel openers)
- > impaired ability to contract
- > coronary blood flow
- > improved delivery to the heart
What effect do organic nitrates and K channel openers have on coronary blood flow?
Increase coronary blood flow (increases preload and afterload)
What effect does increasing coronary blood flow have on preload and afterload?
Increases both
What effect does vasodilation have on afterload?
Decreases
What effect does venodilation have on preload?
Decreases
K channel openers affect which of the following?
Coronary blood flow Arterial O2 content Heart rate Preload Afterload Contractility
Coronary blood flow
Preload
Afterload
Nitrates affect which of the following?
Coronary blood flow Arterial O2 content Heart rate Preload Afterload Contractility
Coronary blood flow
Preload
Afterload
Ivabradine affects which of the following?
Coronary blood flow Arterial O2 content Heart rate Preload Afterload Contractility
Heart rate
Beta blockers affect which of the following?
Coronary blood flow Arterial O2 content Heart rate Preload Afterload Contractility
Heart rate
Contractility
CCBs affect which of the following?
Coronary blood flow Arterial O2 content Heart rate Preload Afterload Contractility
Heart rate
Contractility
What is angina?
Myocardial ischaemia
What can be used to treat angina?
Beta blocker or calcium antagonist as background anti-angina treatment
Ivabradine is a newer treatment
Nitrate as symptomatic treatment (short acting)
Other agents e.g. K channel opener if intolerant to other drugs
What are the side effects of beta blockers?
Worsening of cardiac failure (C.O. reduction)
Bradycardia (heart block)(due to less conduction through AV node)
Bronchoconstriction (blockade of β2 in airways)
Hypoglycaemia (in diabetics on insulin)(decreased glycogenolysis/ gluconeogenesis)
Cold extremities and worsening of peripheral arterial disease (blockade of β2 in skeletal muscle vessels)
MAYBE.... Fatigue Impotence Depression CNS effects (lipophilic agents) e.g. nightmares
What causes the side effects of beta blockers?
Unwanted effects can be due to actions on B1 (and sometimes B2 Rs due to partial selectivity)
What are the side effects of Verapamil (Ca channel blocker)?
Bradycardia and AV block (Ca channel block)
Constipation (gut Ca channels in 25% patients)
What are the side effects of Dihydropyridines?
10-20% patients
Ankle oedema (vasodilation means more pressure on capillary vessels)
Headache/flushing (vasodilation)
Palpitations (vasodilation/reflex adrenergic activation)
What are the side effects of K channel openers and nitrates?
Ankle oedema (vasodilation means more pressure on capillary vessels)
Headache/flushing (vasodilation)
What are the aims of treatment for arrhthymias/dysrhythmias?
Reduce sudden death
Prevent stroke
Alleviate symptoms
How can you classify arrhythmias?
By site of origin
Supraventricular arrhythmias (e.g. amiodarone, verapamil)
Ventricular arrhythmias (e.g. flecainide, lidocaine)
Complex (supraventricular + ventricular arrhythmias) (e.g. disopyramide)
What is the Vaughan-Williams classification of anti-arrhythmic drugs?
Class I-IV (divided by mechanism of action)
Little clinical significance
1= Sodium channel blockade 2= Beta adrenergic blockade 3= Prolongation of repolarisation (membrane stabilisation) 4= Calcium channel blockade
What is adenosine used for?
Anti-arrhythmic
Used IV to terminate supraventricular tachyarrhythmias (SVT)
Short-lived actions (20-30s) so safer than verapamil
What is verapamil used for? How does it work?
Anti-arrhythmic
Reduction of ventricular responsiveness to atrial arrhythmias
Depresses SA automaticity and subsequent AVN conduction
What is amiodarone used for? How does it work?
Anti-arrhythmic
Superventricular and ventricular tachyarrhythmias
Complex action probably involving multiple ion channel blocks (prolongs AP-> prolongs hyperpolarisation-> reduces likelihood of reentry rhythms)
What are the adverse effects of amiodarone?
Accumulates in body (half life 10-100 days)
Photosensitive skin rashes
Hypo- or hyper-thyroidism
Pulmonary fibrosis
How does digoxin work?
Anti-arrhythmic
Cardiac glycosides
Binds to K binding site
- > interferes with Na and K exchange (inhibits Na-K-ATPase)
- > less Na outside the cell so less Na/Ca exchange
- > more Ca remains inside cardiac muscle
- > more Ca stored in SR and then released
- > increased contractility (POSITIVE INOTROPIC EFFECT)
-> central vagal stimulation causes increased refractory period and reduced rate of conduction through the AV node (STIMULATE VAGAL TONE TO SLOW HR DOWN)
What is digoxin used for?
Atrial fibrillation and flutter
Via vagal stimulation reduces the conduction of electrical impulses within the AV node (fewer impulses reach the ventricles and ventricular rate falls)
What are the adverse effects of digoxin?
Dyshrythmias (AV conduction block, ectopic pacemaker activity)
Hypokalamia
Why does hypokalamia lower the threshold for digoxin toxicity?
Digoxin binds to k binding site (directly competing with K) so if you have very low K then less competition for this target (so increased effects of digoxin)
How do endothelial cells impact smooth muscle?
Endothelial cells produce a raft of substances that can impact smooth muscle tone
Variscosities alongside nerve release NT (NA) when nerve is activated
What do the drugs affecting vascular resistance usually target?
Arterioles due to their contribution to bp
What determines vascular tone of an arteriole?
Arteriolar smooth muscle normally displays a state of partial constriction
What is the formula for BP?
BP= CO x TPR
What is hypertension defined as?
Consistently above 140/90mmHg
What does hypertension increase the risk of?
Strokes
Heart failure
MI
Chronic kidney disease
What drugs impact vascular tone?
ACE inhibitor (ACEi)
Angiotensin receptor blocker (ARB)
Calcium channel blocker (CCB)
Thiazide-like diuretic
What is the order drugs are given for hypertension?
STEP 1
ACEi or ARB for <55y olds
CCB or thiazide-type diuretic for >55y olds and all Afro-Caribbeans
STEP 2
CCB or thiazide-like diuretic AND ACEi or ARB
(For Afro-Caribbeans prefer ARBs to ACEis)
STEP 3
ACEi/ARB with CCB and thiazide diuretic
STEP 4 (resistant hypertension) Low-dose spironolactone B blocker or a blocker
How does the RAAS system change in hypertension?
Decreased Na reabsorption
Decreased renal perfusion pressure
Increased sympathetic NS
Outline the RAA system
Angiotensinogen is converted to angiotensin I (by renin from kidney)
AT1 converted to AT2 (by angiotensin converting enzyme ACE)
AT2
- > SNS activation/thirst
- > vasoconstriction
- > salt and water retention
- > aldosterone secretion
–
Bradykinin converted to inactive metabolites by ACE
Where does ACEi act?
On ACE
i.e. stops AT1-> AT2 and bradykinin->inactive metabolites
Where does ARB act?
Prevents AT2’s actions
i. e. stops;
- > SNS activation/thirst
- > vasoconstriction
- > salt and water retention
- > aldosterone secretion
How does ACEi work?
Inhibits the somatic form of ACE
Prevents conversion of AT1 to AT2
What are ACEi used to treat?
Hypertension Heart failure Post-myocardial infarction Diabetic nephropathy Progressive renal insufficiency Patients at high risk of cardiovascular disease
Example of ACEi?
Enalapril
How do ACEi treat hypertension?
TPR x CO= BP
(Increased TPR-> increased BP
Increased venous return-> increased cardiac contractility (Starling’s law) and CO)
So preventing vasoconstriction and salt and water retention-> lowered venous return and lowered TPR-> lowered BP
How do ACEi treat heart failure?
In heart failure
- Increased vasoconstriction-> increased afterload and cardiac work
- Increased venous return-> fluid retention and congestion (-> oedema)
Prevent this with ACEi which -> decreased vasoconstriction and salt/water retention
Overall, how do ACEis treat heart failure and hypertension?
Decreased vasoconstriction (decreases TPR) and decrease salt/water retention (decreases CO)
Example of ARB?
Iosartan
How do ARBs work?
Antagonists of type 1 (AT1) Rs for Ang II-> prevents renal and vascular actions of Ang II
How can ARBs be used to treat heart failure and hypertension?
Prevent vasoconstriction, salt/water retention and aldosterone secretion
What are the side effects of ACEi?
Generally well tolerated (less than ARB)
Cough (linked to bradykinin)
Hypotension
Hyperkalaemia (can have K supplements or K sparing diuretics)
Fetal injury
Renal failure in patients with renal artery stenosis
What are the side effects of ARB?
Generally well tolerated (more than ACEi)
Urticaria/angioedema
Hypotension
Hyperkalaemia (can have K supplements or K sparing diuretics)
Fetal injury
Renal failure in patients with renal artery stenosis
Why can ACEi lead to hyperkalaemia?
Prevent aldosterone from being produced
Leads to build up of K in blood
How does smooth muscle contract?
Membrane depol -> VGCCs open
Ca enters and binds to calmodulin (CaM)
Ca-CaM binds to and activates myosin light chain kinase (MLCK)
MLCK mediated phosphorylation-> smooth muscle contraction
How do CCBs work?
Block calcium channels
Dihydropyridines (DHPs) e.g. amlodipine= more selective for blood vessels, doesn’t cause negative inotropy
Non-DHPS (rate-limiting) e.g. varapamil= large inotropic effect
Why are DHPs (a type of CCB) used to treat hypertension?
Dihydropyridines inhibit Ca entry into vascular smooth muscle cells
Decreased TPR-> decreased BP
NB. Vasodilation can -> reflex tachycardia and increased inotropy thus increased myocardial O2 demand
Why can alpha blockers be used as anti-hypertensives?
Antagonise a1 adrenoceptor antagonists
Low side effects
Reduce BP
Give examples of alpha blockers used in hypertension?
Phentolamine
Prazosin
Outline the ‘reward’ pathways in the brain activated by drugs of abuse
Mesolimbic DA system
Drugs hijack the body’s natural reward pathway (which is set of DA producing neurones from ventral tegmental area to nucleus accumbens)
Why are drugs abused?
DA release causes feelings of reward
Generally drugs are more powerful than natural process
(Rewarding stimulus on VTA-> NAcc DA release)
What are the main routes of administration in drugs of abuse?
Snort= intra-nasal Eat= oral solid or liquid Smoke= inhalational Inject= intra-venous
How do the different routes of administration in drugs of abuse alter absorption?
Snort= mucous membranes of nasal sinuses (slow absorption)
Eat= GI tract (v. slow absorption)
Smoke= small airways and alveoli (rapid absorption- slightly faster than injecting)
-NB. Alveoli= very little barrier to drug
Inject= veins (rapid absorption)
In all systems- drug has to get into venous system then back to heart and then ejected to brain
Outline classifications of drugs of abuse
Narcotics/painkillers (e.g. opiates)
Depressants (downers e.g. alcohol, benzodiazepines, barbiturates)
Stimulates (uppers e.g. cocaine, amphetamine, caffeine, nicotine, metamphetamine)
Miscellaneous (e.g. cannabis, ecstasy)
How does the route of administration affect onset of euphoria?
In ascending order for onset of euphoria
Oral < intranasal < intravenous < inhalational
What are the types of cannabis/marijuana?
Hashish/resin= trichomes (glandular hairs)
Hash oil- solvent extraction
How has marijuana dosing changed over time?
Concentration of THC has been increasing because of farming etc.
Now more potent forms of cannabis
Massive increase in dose now (skunkweed/netherweed) than was administered in past (reefer)
Dose related= very important, more powerful effect
What is the difference in the pharmacokinetics of cannabis orally and by inhalation?
Oral= 5-15%
- Delayed onset/slow absorption
- First pass metabolism
Inhalation= 25-35%
Percentage shows bioavailability (i.e. how much actually gets into bloodstream)
Outline the pharmacokinetics of cannabis
Very lipid soluble (slowly accumulate in poorly perfused fatty tissues-> fatty conjugates)
LIVER= Substantial proportion of the deposit in fat seems to consist of fatty acid conjugates of 11-OH-THC (very potent)
GIT= 65%
URINE= 25%
What is the problem with the metabolism of cannabis?
Major metabolite from cannabis broken down in liver-> 11-hydroxy-THC
VERY POTENT
Also, GIT 65%= enterohepatic recycling
How does enterohepatic recycling affect cannabis?
Potent metabolite (11-OH-THC) from broken down cannabis-> metabolite largely excreted by bile-> very lipid soluble drug so excreted into intestines and then reabsorbed back into gut-> continuous effects
Why is the plasma cannabinoid concentration and degree of intoxication poorly correlated?
Poor correlation because potent metabolite (11-OH-THC) and enterohepatic recycling not taken into account
How long after smoking a cannabis cigarette will the effects persist in the body? 5 hours 12 hours 7 days 30 days 10 years
30 days
When can cannabinoids be measured in the blood?
Cannabinoids measured in blood up to 30 days later
Peak levels in fat after 5 days
Redistributed back in blood
Where are CB1 and CD2 receptors and what are they for?
GPCRs in the brain that respond to cannabinoids (and endogenous anandamide)
CB1 receptors in the hippocampus/cerebellum/cerebral cortex/basal ganglia (lots in the brain)
CB2 receptors on immune cells
How does cannabis lead to euphoria?
Process of disinhibition of DA-producing neurons
Cannabinoid Rs on GABA interneurones
Lots of GABA interneurons to suppress the neuronal system (suppresses reward system until euphoria switched on)
So cannabis switches of the inhibition-> increased firing rate of DA- producing neurons-> more DA
What is the anterior cingulate cortex (ACC) involved in?
Performance monitoring with behavioural adjustment in order to avoid losses
i.e. used in changing environments as we constantly need to adapt our behaviour by focusing on goal-relevant info and selecting the most appropriate behaviour
How is the anterior cingulate cortex affected in cannabis users?
Hypoactivity (so reduced monitoring)
Can impair ACC and can induce Schizophrenia trait in theory
What are effects of THC and THC with cannabidiol?
THC and cannabidiol= elation, giggling etc.
THC alone= really unpleasant, depressing, paranoid-> psychosis
(Seems to be THC that causes the problem, cannabidiol seems to have protective effects)
How does cannabis affect food intake?
Positive effect on orexigenic neurones in lateral hypothalamus
- Indirectly switches off inhibition of GABA to increase MCH which increases neuronal activity
- Directly switches on orexin neurones-> increased orexin production-> act to increase appetite
(Doesn’t affect leptin signals to the brain)
How does cannabis act as an immunosuppressant?
Large scale depressant effects
Disrupts B and T cell function
Decrease NK and macrophage activity
Profound immunosuppressant effect
Not an issue if not chronic
What parts of the brain are affected by cannabis?
Food intake= hypothalamus
Memory loss= limbic regions (amnesic effects, reduced BDNF)
Psychomotor performance= cerebral cortex
Also, psychosis and schizophrenia
What are the peripheral effects caused by cannabis?
Immunosuppressant
Tachycardia/vasodilation (used in treatment)
Medulla- low CB1 receptor expressor
Why is it important that the medulla has low CB1 receptor expression?
Can’t overdose
Doesn’t affect cardio/resp control centres in medulla
Why do eyes appear pink after smoking cannabis?
Conjunctivae
When is cannabis used medically?
MS/STROKE/PAIN= regulatory (increased regulation of CB receptors)
FERTILITY= pathology (increased regulation of CB receptors)
OBESITY= Endocannabinoids and CB1 receptors are up-regulated in the liver and adipose tissue so in theory should help with obesity (but -> suicide)
How is cannabis eliminated?
11-hydroxy-THC
65% via gut (enterohepatic cycling)
25% urine
What is rimonabant?
Used for autoimpairment
Inhibits Gi/o
What are dronabinol and sativex used for?
Autoprotection
What plant does cocaine come from?
Erythroxylum coca
Leaves= 0.6-1.8%
What are the pharmacokinetics/dosing of cocaine?
Paste mushed up= 80% cocaine (organic solvent)
Cocaine HCL= dissolve in acidic solution (IV, oral, intranasal)- NB. can’t be smoked
Crack= precipitate with alkaline alkaline solution (e.g. baking soda) (INHALATION)
Freebase= dissolve in non-polar solvent (e.g. ammonia and ether) (INHALATION)
How does speed of euphoria onset change with way cocaine is administered?
Smoked/IV, snort, oral
Oral (ionized in GIT so not quickly absorbed)= slowly absorption, prolonged action
How is cocaine metabolised?
Metabolised very quickly
Broken down-> inactive metabolites (75-90% - ecgonine methyl ester, benzoylecgonine)
Half life 20-90 mins depending on administration
How do the cocaine pharmacokinetics contribute to the addictive potential of the drug?
Very euphoric very suddenly (quick onset so associated with drug taking-> addiction)
But doesn’t take long
How is cocaine used as a local anaesthetic?
Therapeutic effect
Blocks predominantly sodium channels-> no nerve conduction locally
How does cocaine work?
Inhibits reuptake
Blocking the transporter-> increase life of NT in synapse
Not very selective so increases NA/Ad, 5-HT and DA
Does cocaine influence dopamine affinity/efficacy for the DA receptor?
Ability of NT/chem to bind to receptor (affinity) and activate the receptor (efficacy)
SO doesn’t affect NT binding
How does cocaine cause euphoria?
Very powerful euphoric affect
Blocks DA re-uptake (binds to DA transporter)
So DA stays in synapse
When does cocaine cause mild and sever symptoms?
Dose and chronicity affect what effects exist
MILD= positive/reinforcing SEVERE= negative/stereotypic
How can cocaine cause myocardial infarctions?
Cocaine stimulates the sympathetic nervous system by inhibiting catecholamine reuptake at sympathetic nerve terminals, stimulating central sympathetic outflow, and increasing the sensitivity of adrenergic nerve endings to NA
Cocaine also acts like a class I antiarrhythmic agent (local anesthetic) by blocking sodium and potassium channels, which depresses cardiovascular parameters
Of these 2 primary, opposing actions, enhanced sympathetic activity predominates at low cocaine doses, whereas the local anesthetic actions are more prominent at higher doses
In addition, cocaine stimulates the release of endothelin-1, a potent vasoconstrictor, from endothelial cells and inhibits nitric oxide production, the principal vasodilator produced by endothelial cells
Cocaine promotes thrombosis by activating platelets, increasing platelet aggregation
How is cocaine eliminated?
Ecgonine methyl ester, benzoylecgonine
Urine (75-90%)
What systems does cocaine affect?
Transporter inhibitor= euphoria (CNS effects) and CVS problems
What is nicotine?
Nicotine is a potent parasympathomimetic alkaloid
Present in particulate matter in cigarettes (smoking= 5% particulates and 95% volatile)
Particulates= tar droplets with alkaloid-> deep in lungs and then absorbed by blood
What are the pharmacokinetics/dosing of nicotine?
Most replacement mechanisms try to maintain nicotine levels
Nicotine spray – 1mg (20-50%)
Nicotine Gum – 2-4mg (50-70%)
Cigarettes – 9-17mg (20%)
Nicotine Patch – 15-22mg/day (70%)
Why is there no buccal absorption of nicotine?
Cigarette smoke is acidic i.e. no buccal absorption
(50% does get to lungs but very ionised so not great at getting into lungs and bloodstream except in lower/deeper lung)
Absorption in alveoli independent of pH
What is the pKa of nicotine?
7.9
How is nicotine metabolised?
Hepatic CYP2A6-> (70-80%)-> cotinine
Less addictive than cocaine but similar metabolism
Vast majority (75-80%) quickly metabolised in liver-> inert metabolite
Longer half life (t1/2-4 h) than cocaine but still short (so less addictive)
What are the pharmacodynamics of nicotine? (What does it bind to?)
Bind to nicotinic AchR
Ion-channel linked R
Increases channel opening
Increases ion flux
Mediates autonomic function-> impact parasymp and symp actions
How does nicotine cause euphoria?
Nicotine binds to nAChR and directly stimulates neurone at level of VTA
Firing rate of neurone increases
More DA produced
What are cardiovascular effects of nicotine?
Increase sympathetic stimulation (CNS and adrenals)
Increase HR and SV
NA induced vasoconstriction (of coronary arterioles and skin arterioles)
Vasodilation of skeletal muscle arterioles (due to symp system)= increased lipolysis/FFA/VLDL, decreased HDL, increased TXA2, decreased NO
What are the metabolic effects of nicotine?
Increased metabolic rate
Appetite suppressed by nicotine and increased metabolic rate -> suppresses weight gain
What are the neurodegenerative effects of nicotine?
Seems to have therapeutic value in development of PD and AD
PD= increased brain CYPs-> neurotoxins
(Chronic cig smokers-> increased cytochrome p450-> increased ability to metabolise neurotoxins-> less neurotoxin degradation of DAergic toxins-> less PD)
AD= decreased B-amyloid toxicity and APP (amyloid precursor protein)
(Chronic cig smokers-> decreased B amyloid toxicity and APP-> decreased AD risk)
How long is the onset of euphoria with nicotine?
Seconds
How does caffeine cause euphoria?
Oral and small doses so minor euphoria
Adenosine receptor antagonist
Adenosine activates A1 receptor-> negative effect on DA R function and DA secretion by mesolimbic pathway
So caffeine does opposite= increases DA release
Can chocolate be considered a drug of abuse?
Is naturally rewarding but doesn’t directly addictive doesn’t affect DA
Outline the epidemiology of alcohol?
Western Europe= bad for alcohol consumption especially Ireland
How do you calculate the absolute amount of alcohol?
% ABV x 0.78= g alcohol/100ml
ABV= alcohol by volume
How do you calculate units of alcohol?
1000
1 unit= 10ml or 8g of absolute alcohol
What is the recommended amount of alcohol per week?
Up to 14 units a week
for males and females
Should be spread throughout the week and with ‘drink free’ days
What is binge drinking?
> 8 units in one sitting
What is the legal driving limit?
0.08
Blood levels= 0.01% = 10mg/100ml blood
How is alcohol administered?
Oral alc-> 20% absorbed from stomach and 80% from small intestine
How does having a full stomach affect the speed of onset with alcohol?
Speed of onset= depends on gastric emptying (directly proportional)
Alc needs to get to small intestine
Stomach doesn’t empty if you’ve eaten a meal (slowly releases to SI)
So drinking on full stomach means alc stays in stomach more
Explain the metabolism of alcohol
90% metabolised
10% not metabolised= some of it can be breather out (use breathalyser)
85% occurs in liver
(Alcohol->acetaldehyde)
How does alcohol get converted to acetaldehyde?
75% alcohol dehydrogenase
25% mixed function oxidase (upregulates in chronic alc drinking-> tolerance [reversible])
How does alcohol tolerance build up?
Mixed function oxidase (which is involved in converting alcohol to acetaldehyde) upregulates in chronic alc drinking-> tolerance
Reversible
What is acetaldehyde?
Produced in first stage of alcohol metabolism (metabolite of alcohol)
Toxic
How much metabolised alcohol is metabolised in the liver?
85%
First pass hepatic metabolism
What percentage of metabolised alcohol is metabolised in the GIT?
15%
Alcohol -> alcohol dehydrogenase-> acetaldehyde
Why are blood alcohol levels higher in women?
Women are fatter than men, have less body water (50%) and less ADH
Men have more body water (59%) and less adipose tissue
Alcohol is water soluble
Why can disulfiram be effective as alcohol aversion therapy?
Prevents aldehyde dehydrogenase (which convert acetaldehyde to acetic acid)
Causes build up of acetaldehyde-> lots of negative effects of alcohol-> makes drinking more unpleasant
What causes ‘asian flush’?
Genetic polymorphism (particularly prevalent in asians/middle easterns)
People can’t build up acetaldehyde
Causes build up of acetaldehyde-> lots of negative effects of alcohol
What are the pharmacodynamics of alcohol?
Low pharmacological potency (‘alcohol as a key fits into a lot of locks’)
Very high levels to induce effects (poor affinity and efficacy)
What are the effects of alcohol on the CNS?
Acute effects
Primary= depressant
(CNS agitation may occur)
Disinhibition-> excitation but only at low dose
Degree of CNS excitability depends on environment and personality
Why are there acute CNS effects due to alcohol?
Increased pre- vs post-synaptic allopregnenolone (steroid)
Allosteric modulation (decreased NMDA Rs)
Neurotransmitters (deceased Ca channels)
How can alcohol cause euphoria?
Works similarly to opiates and cannabis
Switches off GABA (disinhibition)
Alcohol uses u receptor
Not as powerful as heroin (less selective)
What parts of the brain does alcohol affect? What does this cause?
Corpus Collosum= Passes info from the left brain (rules, logic)
to the right brain (impulse, feelings) and vice versa
Hypothalamus= Controls appetite, emotions, temperature, and pain sensation
Reticular Activating System= Consciousness
Hippocampus= Memory
Cerebellum= Movement and coordination
Basal Ganglia= Perception of time
How does alcohol cause cutaneous vasodilation?
Cutaneous vasodilation (acts on arterioles via acetaldehye)
Decreases Ca entry
Increases prostaglandins
Explains facial flush
How does alcohol cause the heart to speed up?
Speeds heart up
Mostly centrally mediated
Alc impairs the relationship between brain and baroreceptor (NORMALLY= stimulates parasympathetic and inhibits sympathetic from increasing heart rate)
Alc changes this, lose inhibition of sympathetic-> allows high firing from symp nerve-> increased HR
How does alcohol affect the cardiovascular system?
Cutaneous vasodilation
Tachycardia
How does alcohol affect the endocrine system?
ACUTE= Diuresis (polyuria)
CHRONIC= increased ACTH secretion and decreased testosterone secretion
Why does alcohol cause (diuresis) polyuria?
Posterior pituitary effects
Probably acetaldehyde not alcohol
Prevents VP secretion from post pit (depressant effect)
Less water retention-> more urine production
What are the chronic CNS effects of alcohol?
COMMON
Dementia= cortical atrophy/ volume cerebral white matter
Ataxia= cerebellar cortex degeneration
LEADS ON TO…
WENICKE-KORSAKOFF SYNDROME (due to thiamine deficiency)
= Chronic alcoholics get too much caloric intake from alc
So low thiamine for a length of time-> impaired brain metabolism
NB. Wernicke’s encephalopathy – (affects 3rd ventricle and aqueduct, initialyy reversible)
Korsakoff’s psychosis-(affects dorsomedial thalamus, irreversible hippocampal damge)
What are the chronic effects of alcohol on the liver?
Lipids build up in liver
- NAD+ mostly lost
- Triacylglycerol builds up in liver
Generation of free radicals
Blood and hepatic cytokine changes (e.g. increased IL-6 and TNF-a)
Why do lipids build up in the liver?
1)
Alcoholics use large amount of NAD+ to metabolise alc
NAD+ normally= to convert glucose to pyruvate and pyruvate to acetyl coa and acetyl co into citric acid cycle and fatty acid cycle
So diverting NAD+ (in alcoholic) means…
- Pyruvate-> lactate
- Acetyl coA-> ketones
- Lipids building up in liver
2)
Triacylglycerol builds up in liver because glycerol and fatty acids in blood can’t go to hepatocyte mitochondria
Why does chronic alcohol lead to free radical generation in hepatitis?
Generation of free radicals
Predominantly mixed function oxidase enzymes-> generates oxygen free radicals
Becomes big problem chronically (elevated in liver)-> generate inflam stimulus-> hepatitis (reversible if stop drinking)
Prolonged inflam-> cytokine release-> structural changes in liver
CIRRHOSIS NOT REVERSIBLE (if inflam is prolonged long enough)
What happens to the liver in cirrhosis?
Liver cells can’t regenerate
Not reversible
At some point, liver can’t manage the metabolic demands of the body
Hepatocyte regeneration decreased
Fibroblasts increases (supportive framework)
Active lier tissue decreases
What are the beneficial CVS effects of low dose alcohol?
Low dose alcohol is positive (probably protective against some cardiac disease)
Decreased mortality from coronary artery disease (men 2-4 units/day)
Increase HDLs
Increase tPA levels
Decreased platelet aggregation
What are the beneficial GIT effects of low dose alcohol?
Alcohol is absorbed from stomach
Chronic alcoholic= constantly have acetaldehyde in stomach
Damages stomach mucosa and possibly causes cancer
What are the chronic effects on the endocrine system of alcohol?
Increased ACTH secretion (high cortisol, like Cushing’s effects)
Decreased testosterone secretion (-> feminisation)
What are the constituents of blood?
45% blood cells (99% erythrocytes)
55% blood plasma
What blood constituents are involved in clotting?
BLOOD CELLS
Platelets
PLASMA CLOTTING FACTORS
Procoagulants= prothrombin, factors V, VII-XIII
Fibrinogen
Anticoagulants= plasminogen, TFPI, proteins C&S, antithrombin
What is TFPI?
Tissue factor pathway inhibitor
What do procoagulants lead to?
Physiologically= Clotting Pathologically= Thrombophilia
What do anticoagulants lead to?
Physiologically= Haemophilia Pathologically= Bleeding
What is haemostasis?
Essential physiological process- blood coagulation prevents excessive blood loss
What is thrombosis?
Pathophysiological process where blood coagulates within blood vessel and obstructs blood flow
Red thrombi can embolise
What is the difference between red and white thrombi?
RED= venous thromboses= high fibrin components (clot becomes life-threatening if it dislodges from the vessel-> embolises)
WHITE= arterial thromboses= high platelet components
What is atherosclerosis?
Pathophysiological process- thrombus forms within atherosclerotic plaque
Plaque can rupture-> thrombus released into lumen (ischaemia)
Arterial thromboses (white thrombi)
What is Virchow’s triad?
Rate of blood flow
Consistency of blood
Blood vessel wall integrity
How does rate of blood flow contribute to coagulation?
Blood flow is slow/stagnating -> no replenishment of anticoagulant factors and balance adjusted in favour of coagulation
How does consistency of blood contribute to coagulation?
Natural imbalance between procoagulation and anticoagulation factors e.g. Factor V leiden
How does blood vessel wall integrity contribute to coagulation?
Damaged endothelia-> blood exposed to procoagulation factors
How does Virchow’s triad go from physiology to thrombogenic?
Physiological:
Anti-coagulants= pro-coagulants
Thrombogenic:
Increased pro-coagulants
Decreased anti-coagulants
What is the cell-based theory of coagulation?
- INITIATION
Anticoagulants-> small scale production of thrombin - AMPLIFICATION
Antiplatelets-> large scale thrombin production on the surface of platelets - PROPAGATIONS
Thrombolytics-> thrombin mediated generation of fibrin strands
What causes the coagulation process?
Virchow’s triad
Cell-based theory of coagulation
List some important anti-coagulants
Antithrombin
Vitamin K
Factors II and X
What happens in the initiation of thrombosin production?
Small-scale thrombin production
- TISSUE FACTOR (TF)
TF bearing cells activate factors X and V forming-> prothrombinase complex - PROTHROMBINASE COMPLEX
This activates factor II (prothrombin) creating factor IIa (thrombin) - ANTI-THROMBIN (AT-III)
AT-III inactivates fIIa and fXa
What are other names for factors IIa and II?
IIa= thrombin II= prothrombin
How can anticoagulants be used to stop the initiation of thrombin production?
Inhibit factor IIa
- Dabigatran (oral) - factor IIa inhibitor
Inhibit factor Xa
- Rivaroxaban (oral) - factor Xa inhibitor
Increase activity of AT-III
- Heparin (IV, SC) - activates AT-III (decrease fIIa & decrease fXa)
- Low-molecular weight heparins (LMWHs, e.g.Dalteparin) - activate AT-III (decrease fXa)
Reduce levels of other factors
- Warfarin (oral) - vitamin K antagonist
- Vitamin K - required for generation of factors II, VII, IX and X
What is dabigatran used for?
Factor IIa inhibitor
Anticoagulant to reduce thrombin production initiation
What is rivaroxaban used for?
Factor Xa inhibitor
Anticoagulant to reduce thrombin production initiation
What is heparin used for?
Activates AT-III (decreases fIIa and fXa)
Anticoagulant to reduce thrombin production initiation
What are low molecular weight heparins (e.g. dalteparin) used for?
Activates AT-III (decreases fXa)
What is warfarin used for?
To reduce the levels of other factors
Vitamin K antagonist
(Vit K required for generation of factors II, VII, IX and X)
What are the indications for when you use anticoagulants to stop initiation of thrombin production?
Main indications for diseases that involve venous thrombosis (red thrombi)
Deep vein thrombosis and pulmonary embolism
Thrombosis during surgery
Atrial fibrillation - prophylaxis of stroke
How can anti-platelets be used to prevent amplification of platelets?
PLATELET ACTIVATION AND AGGREGATION
Thrombin
- Factor IIa -> activates platelets
Activated platelet
- Changes shape
- Becomes ‘sticky’ and attaches other platelets
How can you prevent platelet activation?
PREVENT PLATELET ACTIVATION/AGGREGATION
Clopidogrel (oral) - ADP (P2Y12) receptor antagonist
INHIBIT PRODUCTION OF TXA2
Aspirin (oral) - irreversible COX-1 Inhibitor
(NB: High doses no more effective BUT more side-effects)
PREVENT PLATELET AGGREGATION
Abciximab (IV, SC)- monoclonal ab
(Limited use AND only by specialists)
What is clopidogrel used for?
ADP (P2Y12) R antagonist
Inhibits platelet activation/aggregation
What is aspirin used for?
Inhibit production of TXA2
Aspirin irreversibly Inhibits platelet activation/aggregation
What is abciximab used for?
Inhibits platelet aggregation by inhibiting GPIIb/IIa receptor
What are the indications for when you stop platelet activation?
Arterial thrombosis
Acute coronary syndromes - myocardial infarction
Atrial fibrillation - prophylaxis of stroke
What happens in the propagation of the thrombolytics?
Generation of fibrin strands
- Activated platelets
- Large-scale thrombin production - Thrombin
- Factor IIa-> binds to fibrinogen and converts to fibrin strands
What is the mechanism of thrombolytics?
Anticoagulants and anti-platelets - DO NOT remove pre-formed clots
- Convert plasminogen plasmin
- Plasmin - protease degrades fibrin
- Alteplase (IV) - recombinant tissue type plasminogen activator (rt-PA)
How are platelets activated?
Thrombin - binds to protease-activated receptor (PAR) on platelet surface.
PAR activation rise in intracellular Ca2+
Ca2+ rise exocytosis of adenosine diphosphate (ADP) from dense granules
ADP RECEPTORS
ADP activates P2Y12 receptors platelet activation/ aggregation
CYCLO-OXYGENASE
PAR activation liberates arachidonic acid (AA)
Cyclo-oxygenase (COX) generates thromboxane A2 (TXA2) from AA
GLYCOPROTEIN IIb/IIIa RECEPTOR (GPIIb/IIIa)
TXA2 activation expression of GPIIb/IIIa integrin receptor on platelet surface
GPIIb/IIIa - involved in platelet aggregation
What indications do you use thrombolytics for?
Arterial and venous thrombosis
- Stroke= first-line treatment
- ST-elevated MI
What causes DVT? How can it develop into a PE?
‘Red’ thrombus-> deep vein of the leg (e.g poplietal vein)
Caused by:
- Decreased rate of blood flow
- Damage to endothelium
Thrombus detachment-> pulmonary embolism
What is the management strategy for DVT?
Restore balance between coagulants and anti-coagulants
Decreased levels of anti-coagulant factors
= Anticoagulants
What is an NSTEMI?
Non-ST elevated myocardial infarction (MI)
An acute coronary syndrome
What causes an NSTEMI? How can it be treated?
‘White’ thrombus -> partially occluded coronary artery
Caused by:
- Damage to endothelium
- Atheroma formation
- Platelet aggregation
Need to:
- Reduce lipid accumulation
- Reduce platelet aggregation
- Dissolve thrombus
Management:
a) Prevent further arterial occlusion
Decrease platelet activation/aggregation
= Anti-platelets (1 and 2)
b) Dissolve clot
= Thrombolytics (3)
What diseases are associated with thrombosis?
ARTERIAL
Brain= stroke
Heart= acute coronary syndromes (-> atrial fibrillation)
Arteries= aortic aneurysm, peripheral arterial disease
VENOUS
Deep vein thrombosis
Pulmonary embolism
How do you treat a stroke (associated with arterial thrombosis)?
Anti-platelets
Thrombolytics
How do you treat an acute coronary syndromes (associated with arterial thrombosis)?
Anti-platelets
Thrombolytics
How do you treat atrial fibrillation (associated with arterial thrombosis)?
Anti-platelets
Anticoagulants
How do you treat aortic aneurysms/peripheral arterial disease (associated with arterial thrombosis)?
Anti-platelets
How do you treat DVT (associated with venous thrombosis)?
Anticoagulants
How do you treat PEs (associated with venous thrombosis)?
Anticoagulants
Thrombolytics
Differentiate between the terms haemostasis and thrombosis
Haemostasis is a physiological process preventing blood loss whereas thrombosis is a pathophysiological process
Explain the process of coagulation and identify the actions of drugs that affect production or activation of clotting factors
The cell based theory of coagulation consists of three stages
Anticoagulants inhibit stage 1 and affect the activity/ production of clotting factors
Explain the process of platelet activation and identify the action of specific antiplatelet drugs
Platelets are activated by thrombin, which causes Ca2+ rise, ADP release and GPIIb/IIIa receptor expression
Anti-platelet drugs fall into 3 main categories:
COX inhibitors
P2Y12 receptor antagonists
GPIIb/IIIa receptor antagonists
What are the 3 main categories of anti-platelet drugs?
COX inhibitors
P2Y12 receptor antagonists
GPIIb/IIIa receptor antagonists
Explain the actions of fibrin and identify the role of thrombolytic drugs
Fibrin is produced from fibrinogen and stabilises blood clots
Plasmin can degrade fibrin strands and thrombolytic drugs activate plasmin
Understand which of these classes of drugs can be used in specific clinical situations
Anticoagulants: deep vein thrombosis, pulmonary embolism, during surgical procedures, atrial fibrillation
Antiplatelets: acute coronary syndromes (STEMI & NSTEMI), atrial fibrillation
Thrombolytics: STEMI, stroke
What kind of lipoproteins are the main drivers of atherosclerosis?
LDL
What are the main differences between LDL and HDL in circulating in solution?
LDLs have apoprotein b which allows them to circulate in an aqueous environment
(HDL- apoprotein A1)
What is the exogenous pathway of lipid metabolism?
Dietary triglycerides and cholesterol-> intestine
Chylomicron out of intestine-> (via LP lipase)-> FFA and chylomicron remnant
–
FFA-> skeletal muscle and adipose tissue
Chylomicron remnant-> remnant receptor in liver or to form atheroma
What is the endogenous pathway of lipid metabolism?
Liver is key organ
From liver= Large VLDL, small VLDL, IDL, LDL (also can be formed from the larger version)
LDL receptor on liver
What do chylomicrons do?
Whilst chylomicrons transport triglyceride from the gut to the liver
What is VLDL?
VLDL is the analogous particle that transports triglycerides from the liver to the rest of the body
What is reverse cholesterol transport?
As cholesterol cannot be broken down within the body, it is eliminated intact
Transported via HDL from peripheral tissues to liver
Why is HDL protective from atherosclerosis?
HDL acts as a vehicle for the transport of cholesterol for elimination (peripheral tissues-> liver)
HDL as a protective factor against the development of atherosclerosis
How is inflammation involved in atherosclerosis?
Monocyte goes into subendothelial space and converted into foam cells
Foam cells are loaded with cholesterol and cholesterol esters
Inflam process-> atherosclerosis
Outline endothelial dysfunction in atherosclerosis?
Endothelial dysfunction in atherosclerosis is characterised by a series of early changes
Changes:
- Greater permeability of the endothelium
- > Up-regulation of endothelial adhesion molecules
- > Leukocyte adhesion
- > Migration of leukocytes into the artery wall
-> Lesion formation
What is the fatty streak in atherosclerosis?
Fatty steak= earliest recognisable lesion of atherosclerosis
Caused by the aggregation of lipid-rich foam cells, derived from macrophages and T lymphocytes (within the intima)
Common, may increase in size, remain static or ever disappear
What later lesions occur after fatty streaks in atherosclerosis? How are they formed?
Smooth muscle cells
Steps= smooth muscle migration, T cell activation, foam cell formation and platelet adherence and aggregation
How is a complicated atherosclerotic plaque?
Plaque= advance stage in atherosclerotic process
Results from death and rupture of the lipid-laden foam cells in the fatty streak
Migration of vascular smooth muscle cells (VSMCs) to the intima and laying down of collagen fibres results in the formation of a protective fibrous cap over the lipid core
The fibrous cap separates the highly thrombogenic lipid-rich core from circulating platelets and other coagulation factors
Lesions expand at the shoulders by continued leukocyte adhesion
What characterises stable atherosclerotic plaques?
Stable atherosclerotic plaques are characterised by a necrotic lipid core covered by a thick VSM-rich fibrous cap
What are the types of atherosclerotic lesions?
Coronary artery at lesion-prone location
Type II lesion
Type III (preatheroma)
Type IV (atheroma)
Typve V (fibroatheroma)
Type VI (complicated lesion)
What happens to remnant lipoproteins?
Remnants= VLDL, chylomicron remnant, IDL)
Contribute to atherosclerosis (not LDL alone)
Remnant lipoproteins
- > remnants
- > modified remnants
- > MCP-1, macrophage, foam cells
Macrophage-> cytokines-> adhesion molecules
What are vulnerable atherosclerotic plaques characterised by?
Characterised by a thin fibrous caps, a core rich in lipid and macrophages, and less evidence of smooth muscle proliferation
What are vulnerable plaques prone to?
Rupture and ulceration
Followed by rapid development of thrombi
(NB. Size of plaque doesn’t appear to predict whether a plaque is prone to rupture)
Where does plaque rupture usually occur? What is it associated with?
Rupture usually occurs at sites of thinning (particularly at shoulder area of plaque) and is associated with regions with relatively few smooth muscle cells but abundant macrophages and T cells
Associated with greater influx and activation of macrophages, accompanied by release of matrix metalloproteinases involved with the breakdown of collagen
What modifies LDL cholesterol?
Modified by other risk factors
- Low HDL cholesterol
- Smoking
- Hypertension
- Diabetes
What is a 10% increase in LDL cholesterol associated with?
An approximate 20% increase in risk for CHD
What happens when HDL is low? What causes it to be low?
The lower the HDL cholesterol level, the higher the risk for atherosclerosis and CHD
HDL cholesterol tends to be low when triglycerides are high
HDL cholesterol is lowered by smoking, obesity and physical inactivity
What are examples of of lipid-lowering therapies?
Inhibitors of HMG CoA reductase (statins) Fibrates Bile acid sequestrants (resins) Nicotinic acid and its derivatives Probucol
What are bile acid sequestrants? SEs?
Potent cholesterol-lowering agents
NB. compliance can be a problem as patients may object to the taste and texture, and common adverse events are gastrointestinal bloating, nausea and constipation
What is nicotinic acid used for? SEs?
B-complex vitamin= with lipid-lowering properties
Very effective at increasing HDL cholesterol levels and is indicated for all dyslipidaemias except congenital lipoprotein lipase deficiency
Limited by the incidence of adverse events, which include flushing, skin problems, gastrointestinal distress, liver toxicity, hyperglycaemia and hyperuricaemia
What are fibrates? SEs?
Effective triglyceride-lowering drugs (effective for patients with type III hyperlipoproteinaemia)
Main mechanism= activation of PPAR (peroxisome proliferator activated) alpha receptors
In some patients they modestly lower LDL cholesterol and raise HDL cholesterol
However, in the majority of patients they are only moderately successful in reducing LDL cholesterol
What is probucol?
Prescribed for the treatment of high cholesterol levels
Only a modest LDL cholesterol-lowering effect, and there is no evidence that it reduces CHD risk
What is the mechanism of action of statins?
Affects cholesterol synthesis pathway
Inhibit HMG-CoA reductase
Increase number of LDL receptors on hepatocytes
Leads to reduced elevated LDL (reduced LDL-C particles)
List examples of statins and their % change on LDL and HDLs?
Simvastatin= LDL -32%, HDL +8%
Fluvastatin= LDL -22%, HDL +2%
Atorvastatin= LDL -38%, HDL +6%
Rosuvastatin= LDL -52%, HDL +14%
Pravastatin= LDL -32%, HDL +3%
Who are statins effective for?
Patients with establishes CVD (secondary prevention)
Benefits of primary prevention unknown
What do PPARs do?
Peroxisome proliferator activates receptors
Alpha in liver
Gamma in adipose tissue
Affecting them-> decreased plasma fatty acids and triglycerides
What is ezetimibe?
Inhibits cholesterol absorption from SI (CETP inhibitor)
Absorbed then activated as glucuronide
Added to simvastatin
What is CETP?
Cholesterol ester transfer protein
Involved in reverse cholesterol transport
What are the problems with cept inhibitors?
Adverse effects of torcetrapib “off target”
? due to activation of aldosterone synthesis leading to raised BP
Other “rapibs” do not have same effect
What is PCSK9?
Secreted inhibitor of the LDLR
Potential candidates for PCSK9 inhibitory therapy= familial hypercholesterolemia
Approved in UK and USA
What are the clinical uses of NSAIDs?
Analgesic (for mild-to-moderate pain)
E.g. toothache, headache, backache postop pain, dysmenorrhea
Antipyretic (reduction of fever)
E.g. influenza
Anti-inflammatory
E.g. Rheumatoid arthritis, osteoarthritis, musculo-skeletal inflam, soft tissue injuries, gout
How do NSAIDs affect prostanoids?
Inhibit synthesis of prostanoids
How do NSAIDs inhibit prostanoid synthesis?
Inhibit cyclo-oxygenases (COXS 1 and 2)
Prevent formation of prostaglanding H2 from arachidonic acid from phospholipid membranes
Means they aren't converted (with specific synthases) into: Prostacyclin Prostaglandin L2 Prostaglandin E2 Prostaglandin F2 Prostaglandin D2 Thromboxane A2
What are prostanoids?
E.g.s= Prostacyclin Prostaglandin L2 Prostaglandin E2 Prostaglandin F2 Prostaglandin D2 Thromboxane A2
Lipid mediators derived from arachidonic acid
Widely distributed
Not stored pre-formed
Receptor-mediated
What are the main isoforms of COX? How does this affect drugs?
2 main isoforms
Most NSAIDs reversibly inhibit both isoforms to varying degrees (e.g. ibuprofen)
Some selectively inhibit one (e.g. coxib family like celecoxib reversibly inhibits COX-2)
What are the known receptors of prostanoids?
10 known
DP1, DP2, EP1, EP2, EP3, EP4, FP, IP1,IP2, TP
All GPCRs but have effects independent of G proteins
What does PGE2 normally do?
Can activate 4 receptors
cAMP-dependent and independent downstream mechanisms
Gastroprotection
Renal salt and water homeostasis
Bronchodilation
Vasoregulation (dilation and constriction depending on receptor activated)
Unwanted actions
What are the unwanted effects of PGE2?
Increased pain perception Thermoregulation Acute inflammatory response Immune responses Tumorigenesis Inhibition of apoptosis
How do PGE2 analogues lower the pain threshold? How can you prevent this?
Stimulation of PG receptors sensitizes the nociceptors which cause pain both acutely and chronically
Co-injection of a COX-2 inhibitor prevents or reduces the duration of prolonged pain
How do prostanoids lower the pain threshold?
Mechanisms are not entirely clear
Possibly:
EP1 receptors
EP4 receptors (in periphery and spine)
Endocannabinoids (neuromodulators in thalamus, spine and periphery)
Not mutually exclusive
Why is PGE2 pyrogenic?
PGE2 stimulates hypothalamic neurones initiating a rise in body temperature
PGE2 in CSF-> increase temp
What is the role of PGE2 in inflammation?
PGE2 binds to EP3 Rs on mast cell-> Gi signalling via PLC (IP3) and PI3K (PIP3)
Histamine released (degranulation) -> increased vascular permeability
IL-6 from nucleus-> increased leukocyte recruitment
What are the desirable physiological actions of PGE2 and prostanoids?
Gastroprotection
Renal salt and water homeostasis
Bronchodilation
Vasoregulation (dilation and constriction depending on receptor activated)
What is the role of PGE2 in gastric cytoprotection?
PGE2 downregulates HCl secretion
PGE2 stimulus mucus and bicarbonate secretion
Why do NSAIDs increase the risk of ulceration?
PGE2 normally gastric cytoprotective
NSAIDs inhibit PGE2
NB. Celecoxib- few ulcers than conventional NSAIDs
How does PGE2 regulate salt and water homeostasis?
COX-1 and COX-2 found in kidney
COX-1= collecting duct
COX-2= macula densa and proximal ascening limb
COX-1 and COX-2=
How does PGE2 regulate salt and water homeostasis?
COX-1 and COX-2 found in kidney
PGE2 increases renal blood flow
Can cause renal toxicity:
Constriction of afferent renal arteriole
Reduction in renal artery flow
Reduced glomerular filtration rate
Where are COX-1 and 2 found in kidney?
COX-1= collecting duct
COX-2= macula densa and proximal ascening limb
COX-1 and COX-2= glomerulus
Why should NSAIDs not be taken by asthmatics?
Causes bronchodilation
COX-inhibition favours production of leukotrienes (bronchoconstrictors)
PGE2 seems to be protective normally
How do we know that prostanoids involved in vasoregulation?
Serious unwanted CV effects from NSAIDs (prostanoid action removed)
What are the unwanted CV effects of NSAIDs?
Vasoconstriction
Salt and water retention
Reduced effect of antihypertensives
Hypertension
Myocardial infarction
Stroke
Are the CV effects of COX-2 inhibitors or conventional NSAIDs worse?
COX-2 inhibitors
Why do COX-2 inhibitors have CV effects?
Affect vascular enothelial and smooth muscle cells-> enhanced probability of coronary atherothrombosis
Affect cardiomyocytes-> increased risk of heart failure
affect kidney-> increased LT CV risk and increased risk of heart failure
True or false; all NSAIDs increase risk of GI bleeds and CVS events?
True
How does NSAID use vary with analagesis use and anti-inflammatory use?
ANALGESIC USE
Usually occasional
Relatively low risk of side effects
ANTI-INFLAM USE
Often sustained
Higher doses
Relatively high risk of side effects
How can you limit the GI effects of NSAIDS?
COX-2 selective NSAIDs (but cardio=worse)
Topical application
Minimise NSAID use in patients with history of GI ulceration
Treat H pylori if present
Administer with omeprazole or other proton pump inhibitor
Minimise NSAID use in patients with other risk factors and reduce risk factors where possible e.g. alcohol consumption, anticoagulant or glucocorticoid steroid use
How does aspirin work?
Selective for COX-1
Binds irreversibly
Has anti-inflammatory, analgesis and anti-pyretic actions
reduces platelet aggregation
How do prostanoids affect platelet aggregation?
Platelets-> thromboxane A2 = promotes platelet aggregation
Endothelial cells-> prostacylcin (PGI2)= inhibits platelet aggregation
How does aspirin affect platelet aggregation?
COX-1 makes thromboxane A2 so inhibition of this by aspirin-> reduced platelet aggregation
No nucleus: no resynthesis of COX-1
NB. PGI2 (inhibits platelet aggregation) synthesised by COX-1 and 2
Nucelated: replenished COX-1 and COX-2
Anti-platelet actions of aspirin are due to….
Very high degree of COX-1 inhibition which effectively suppresses TxA2 production by platelets
Covalent binding which permanently inhibits platelet COX-1
Relatively low capacity to inhibit COX-2
Need low dose to allow endothelial resynthesis of COX-2
What are the major SEs of aspirin? Why are they more likely than with other NSAIDs?
Gastric irritation and ulceration
Bronchospasm in sensitive asthmatics
Prolonged bleeding times
Nephrotoxicity
Side effects are more likely with aspirin than other NSAIDS because it inhibits COX covalently and irreversibly, rather than its selectively for COX-1
Why is paracetamol not an NSAID?
Doesn’t have anti-inflam effect
Is a good analgesic (mild-to-mod) and anti-pyretic
NB. legislation exists
Why can paracetamol cause irreversible liver failure?
If glutathione is depleted-> the metabolite oxidises thiol groups of key hepatic enzymes-> cell death
What is the antidote for paracetamol poisoning?
Add compound with -SH groups (usually IV acetylcysteine, sometimes oral methionine)
Needs to be administered early
Aspirin is unique amongst NSAIDS because: It has no effect on COX-1 It has no effect on COX-2 It binds covalently to COX enzymes It binds covalently to TP receptors It causes gastric ulceration
ANSWER= It binds covalently to COX enzymes
It has no effect on COX-1
(It effectively inhibits COX-1)
It has no effect on COX-2
(It has some effect on COX-2)
It binds covalently to TP receptors
(Untrue)
It causes gastric ulceration
(True but not unique to aspirin)
Inhibition of which enzyme will reduce platelet aggregation with fewest side effects? COX-1 COX-2 Prostacyclin synthase Prostaglandin E synthase Thromboxane A2 synthase
ANSWER= Thromboxane A2 synthase (causes platelet aggregation but not much else)
COX-1
(No- rate limiting for multiple prostanoids)
COX-2
(No- rate limiting for multiple prostanoids)
Prostacyclin synthase
(No- prostacyclin reduces platelet aggregation)
Prostaglandin E synthase
(No- multiple complex effects)
Assertion: Inhibition of PGI2 synthesis by low dose aspirin decreases the risk of stroke
Because : Decreased PGI2 reduces platelet aggregation
Assertion true, reason true and explains assertion
Assertion true, reason true but does not explain assertion
Assertion true, reason false
Assertion false, reason true
Assertion false, reason false
ANSWER= Assertion false, reason false
Synthesis of PGI2 (prostacyclin) is inhibited by low dose aspirin, but it is not this action which decreases the risk of stroke, because PGI2 actually reduces platelet aggregation. It’s the inhibition of thromboxane synthesis
Define: nausea
Subjective unpleasant sensation in throat and stomach: often precedes vomiting
Often preceded by salivation, sweating and increased HR
Define: vomiting
Forceful propulsion of stomach contents out of the mouth
Often preceded by salivation, sweating and increased HR
Outline the vomiting pathway
Deep breath is taken, glottis is closed and larynx is raised to open the upper oesophageal sphincter
Soft palate is elevated to close off posterior nares
Diaphragm is contracted sharply downward-> creates negative pressure in thorax-> facilitates opening of oesophagus and distal oesophageal sphincter
Simultaneously with downward movement of the diaphragm - muscles of adbominal walls are vigorously contracted-> squeezes stomach and elevates intragastric pressure
With pylorus closed and oesophagus relatively open-> route of exit cleared
What is the consequence of acute nausea?
Interferes with mental and physical activity
What is the consequence of chronic nausea?
Very debilitating
What is the consequence of severe vomiting?
Dehydration
Loss of gastric hydrogen and chloride ions may lead to hypochloraemic metabolic alkalosis (raised blood pH)
Contributes to a reduction in renal bicarbonate excretion and an increased in bicarbonate reabsorption accompanied by increased sodium reabsorption in exchange for potassium, leading to the hypokalaemia
What components are involved in pathways of nausea/vomiting?
CNS= cortex, thalamus, hypothalamus, meninges
Vestibular system= H1 R?, M1 R
GI tract and heart= mechanoR, chemoR, 5-HT R
Chemoreceptor trigger zone (area postrema)= chemoR, D2 R, NK1 R, (5HT3 R)
Vomiting center (nucleus of tractus solitarius)= H1 R, M1 R, NK1 R, (5-HT3 R)
Outline the pathway in nausea/vomiting
CNS and vestibular system
-> Chemoreceptor trigger zone (area postrema)
CN IX or X (from GI tract and heart to vomiting centre in medulla oblongata)
-> Parasympathetic and motor efferent activity
What pathways feed into the vomiting centre?
Cortex (via intracerebral projections)
Vestibular system (via projections from vestibular nuclei)
- Direct to vomiting centre
- Via chemoreceptor trigger zone (then to vom centre via intracerebral projections)
Peripheral pathways
- Direct to vomiting venter (via vagus, splanchnic and glosspharyngeal nerves, sympathetic ganglia)
- Via chemoreceptor trigger zone (via vagus and splanchnic nerves and then to vom centre via intracerebral projections)
What is promethazine?
A phenothiazine derivative
Mixed receptor antagonist
Used as an anti-emetic
What is the mode of action of promethazine?
Competitive antagonist at histaminergic (type H1), cholinergic (muscarinic, M) and dopaminergic (type D2) receptors
Order of potency of antagonistic activity: H1> M > D2 receptors
Acts centrally (vestibular nucleus, CTZ, vomiting centre) to block activation of vomiting centre
What does promethazine act on?
Achm and H1 in vestibular system
D2 in chemoreceptor trigger zone
Achm in vomiting centre
How can promethazine be used as an anti-emetic?
Used prophylactically for motion sickness (some benefit taken after onset of nausea and vomiting)
Disorders of the labyrinth e.g. Meniere’s disease
Hyperemesis gravidarum
Pre-and post-op (sedative and anti-muscarinic action also useful)
NB. Other uses= relief of allergic symptoms, anaphylactic emergency, night sedation/insomnia
What is Meniere’s disease?
Inner ear-> balance problems
What is hyperemesis gravidarum?
Pregnancy complications
Lead to severe sickness
What is the pharmacokinetics of promethazine?
Administer orally
Onset of action 1-2 hours
Maximum effect circa 4 hours
Duration of action 24 hours
What are the unwanted effects of promethazine?
Dizziness Tinnitus Fatigue Sedation (‘do not drive or operate machinery') Excitation in excess Antimuscarinc side-effects
What is metoclopramide (domperidone)?
D2 R antagonist
Closely related to phenothiazine group
Outline the mode of action of metoclopramide: domperidone
Order of antagonistic potency:
D2 > H1 > Muscarinic Rs
Acts centrally, especially at CTZ (D2 receptors)
Prokinetic effects in the GI tract
What are the prokinetic effects in the GI tract caused by metoclopramide:domperidone?
Increases smooth muscle motility (from oesophagus to small intestine
Accelerated gastric emptying
Accelerates transit of intestinal contents (from duodenum to ileo-coecal valve)
What is metoclopramide: domperidone used for?
To treat nausea and vomiting associated with:
- Uraemia (severe renal failure)
- Radiation sickness
- GI disorders
- Cancer chemotherapy (high doses) e.g. cisplatin (intractable vomiting)
- Parkinson’s disease treatments which stimulate dopaminergic transmission in CTZ e.g. L-DOPA, DA agonists
(Stays mainly in periphery but little action on trigger zone)
Not effective against motion sickness
What are the pharmacokinetic consideration of metoclopramide: domperidone?
May be administered orally; rapidly absorbed; extensive first pass metabolism (may also be given i.v.)
Metoclopramide crosses BBB
Crosses placenta
NEED TO TAKE CARE WITH BIOAVAILABILITY OF CO-ADMINISTERED DRUGS
How can digoxin and nutrient supply be affected by metoclopramide: domperidone?
Affects the bioavailability of co-administered drugs
Absorption and hence effectiveness of digoxin may be reduced (due to the prokinetic effects with the increased transit in the early GIT this can effect other drug absorption)
Nutrient supply may be compromised- especially important in conditions such as diabetes mellitus
Outline the unwanted effects of meotclopramide:domperidone?
In CNS (Metoclopramide only due to CNS blockade of DA Rs; Domperidone does not cross main BBB)
Drowsiness
Dizziness
Anxiety
Extrapyramidal reactions (children more susceptible than adults- Parkinsonian-like syndrome)
In the endocrine system (stimulates PL release)
Hyperprolactinaemia
Galactorrhoea
Disorders of menstruation
What are the pharmacokinetic considerations of metoclopramide: domperidone?
When administered orally – rapidly absorbed but effective concentration entering the body is decreased by extensive 1st pass metabolism
May be given intravenously
Crosses the BBB (Metoclopramide)
Crosses the placenta
What is the mode of action for hyoscine?
Muscarinic receptor antagonist
Order of antagonistic potency: Muscarinic >D2 = H1 receptors
Acts centrally, especially in the vestibular nuclei and CTZ to block activation of vomiting centre
How can hyoscine be used as an anti-emetic?
Prevention of motion sickness
Has little effects once nausea/ emesis is established
In operative pre-medication
Where does hyoscine act on the nausea pathway?
Achm in vestibular system
D2 (central) in chemoreceptor trigger zone
Achm in vomiting centre
What are the unwanted effects of hyoscine?
Typical anti-muscarinic SEs: Drowsiness Dry mouth Cycloplegia Mydriasis
What is cycloplegia?
Paralysis of the ciliary muscle of the eye resulting in a loss of accommodation
What is mydriasis?
Dilation of the pupil of the eye
What are the pharmacokinetic considerations of hyoscine?
Can be administered orally (peak effect in 1-2 hours), intravenous, transdermally
What is the mode of action of ondansetron?
Acts to block transmission in visceral afferents and CTZ
How is ondansetron used as an anti-emetic?
Main use in preventing anticancer drug-induced vomiting, especially cisplatin
Radiotherapy-induced sickness
Post-operative nausea and vomiting
What is ondansetron?
Serotonin R (5-HT3) antagonists
Where does ondansetron act in the nausea pathway?
D2 (central) in chemoreceptor trigger zone
5HT3 receptors in GI tract
What are the pharmacokinetic considerations of ondansetron?
Administer orally
Well absorbed
Excreted in urine
What are the unwanted effects of ondansetron?
Headache
Sensation of flushing and warmth
Increased large bowel transit time (constipation)
Why/when is ondansetron used in combination with corticosteroids?
Use alone- efficacy may wear off
Corticosteroids, such as dexamethasone, may be used in combination with 5-HT3 receptor antagonists for high or moderately high emetogenic chemotherapy (without= low)
Improved efficacy of combined therapy may be due to anti-inflammatory properties of corticosteroids
How are cannabinoids used as anti-emetics?
THC isolated from Marijuana or the synthetic agent Nabilone
Effective at treating emesis from anti-cancer drugs which other antiemetic’s are not very effective against e.g. Cisplatin
Act at a number of cites within CNS via the CB1 Rs (located pre-synaptically and decrease the release of NTs associated with triggering the vomiting process)
Also inhibit prostaglandin synthesis which has been implicated in emesis from anti-cancer drugs
What are the major forms of IBD?
Ulcerative colitis
Crohn’s disease
(Distinction incomplete in 10% patients- indeterminate colitis)
What are the risk factors for IBD?
Genetic predisposition (163 loci- particularly Caucasian europeans)
Environmental factors= smoking (especially CD), diet/obesity, gut microbioma
Obesity (CD not UC)
How do gut flora and autoimmune diseases relate?
Defective interaction between mucosal immune system and gut flora
10x more gut bacteria than host cells
Complex interplay between host and microbes-> disrupted innate immunity and impaired clearance-> prof-inflammatory compensatory responses-> granuloma formation and physical damage
Outline the autoimmune background to Crohn’s disease
Th1-mediated e.g. IFNγ, TNFα, IL-17, IL-23
Florid T cell expansion
Defective T cell apoptosis
Outline the autoimmune background to UC
Th2-mediated e.g. IL-5, IL-13
Limited clonal expansion
Normal T cell apoptosis
What gut layers are affected in CD?
All layers
What gut layers are affected in UC?
Mucosa/submucosa
What regions are affected in CD?
Any part of GI
Patchy inflamed areas
What regions are affected in UC?
Rectum, spreading proximally
Continuous inflamed areas
Are abcesses/ fissures/ fistulae more common in CD or UC?
Common in CD
Uncommon in UC
Can surgery cure CD or UC?
Not always CD
Can cure UC
What are the clinical features of IBD?
Apthous ulcers
Anaemia, uveitis, fevers, sweats, jaundice
Primary sclerosing cholangitis
Abdominal pain
Right iliac fossa mass/pain
Arthritis, arthraligia
Weight loss
Skin rash (pyoderma, erythema nodosum)
Diarrhoea, blood mucus
What can be used as IBD therapies?
SUPPORTIVE (for acutely sick patient)
Fluids (electrolyte replacement)
Blood transfusion/oral iron
Nutritional support
SYMPTOMATIC: ACTIVE DISEASE
Glucocorticoids e.g. prednisolone
Aminosalicylates e.g. mesalazine
Immunosuppressives e.g. azathiprine
SYMPTOMATIC: PREVENTION OF REMISSION
Glucocorticoids
Aminosalicylates
Immunosuppressives
POTETIALLY CURATIVE
Microbiome manipulation
Biologic therapies
Why are aminosalicylates used in UC and CD?
Anti-inflammatory
UC
First line in inducing and maintaining remission
Good evidence base
CD
Literature unclear
Ineffective in inducing remission
Less clear cut than utility in UC
What are aminosalicylates?
Anti-inflammatory
Mesalazine or 5-ASA (amionsalicyclic acid)
Olsalazine (2 linked 5-ASA molecules)
How do aminosalicylates work as anti-inflammatory drugs?
Inhibition of IL-1, TNF-𝛼, and platelet activating factor (PAF)
Decreased antibody secretion
Non-specific cytokine inhibition
Reduce cell migration (macrophages)
Localised inhibition of immune responses
Why do you need to 5-ASA with other drugs?
5-ASA derivatives activated by gut flora
Depends where they are absorbed
Olsalazine metabolised by colonic flora and absorpsed by colon
What is better topically- 5-ASA or steroids in IBD?
Topical 5-ASA beter than topical steroids in inducing UC remission
Combined oral and topical 5-ASA better at inducing remission in UC than oral 5-ASA alone
Outline the use of glucocorticoids in IBD
UC
Use of glucocorticoids in decline
Can be used topically (enema) or IV if very severe
Aminosalicylates are better
CD
GCs remain drugs of choice for inducing remission
Likely to get SEs if used to maintain remission
Give examples of glucocorticoids
Prednisolone
Fluticasone
Budesonide
Why are glucocorticoids used in IBD?
Powerful anti-inflammatory and immunosuppressive drugs
Derived from the hormone cortisol
Activate IC glucocorticoid Rs which can then act as positive or negative transcription factors
When given systemically- chronic GCs-> many unwanted effected
What are the strategies to minimise unwanted effects of GCs?
Administer topically- fluid or foam enemas or suppositories
Use a low dose in combination with another drug
Use an oral or topically administered drug with high hepatic first pass metabolism e.g. Budesonide so little escapes into the systemic circulation
Are GCs or budesonides better at inducing remission in active CD?
Standard oral glucocorticoids better than budesonide at inducing remission in active CD
Should GCs be used to treat UC or CD?
Case by case basis
Avoid in UC
Used in CD - Budesonide preferred if disease is mild
What immunosuppressive agents are used to treat IBD?
Azathioprine and 6-mercaptopurine
- No advantage over placebo in active CD
- Some success in UC
Methotrexate
- Has demonstrable efficacy in some IBD patients
Cyclosporin
- Useful in severe UC only
What is azathioprine?
Immunosuppressive pro-drug (purine antagonist)
Activated by gut flora to 6-mercaptopurine
Mainly used to maintain remission in CD
May allow reduction in glucocorticoids
Slow onset- 3 to 4 months treatment for clinical benefit
What does 6-MP do?
Formed by azathioprine (prodrug) breaking down
Interferes with DNA synthesis and cell replication
It impairs:
- Cell- and antibody-mediated immune responses
- Lymphocyte proliferation
- Mononuclear cell infiltration
- Synthesis of antibodies
It enhances:
- T cell apoptosis
What are the unwanted effects of 6-MP?
Nearly 10% patients have to stop treatment because of SEs
Pancreatitis
Bone marrow suppression
Hepatotoxicity
Increased risk (4 fold) of lymphoma and skin cancer
What is 6-MeMP?
Hepatotoxic
Inactive form of of 6-MP (with TPMT)
What converts 6-MP to 6-TU (inactive)?
XO (xanthine oxidase)
Allopurinol inhibits XO
Outline the pathway from azathioprine to its derivatives?
Azathioprine-> 6-MP-> 6-TIMP
-> w/ TPMT-> 6-MeMP (inhibition of de novo puring synthesis)
OR
-> w/ IMPD/GMPS/kinases -> 6-TGN (incorporation into DNA)
What does 6-TGN do?
Beneficial but also causes myelosuppression
What is methotrexate used for in IBD?
Acts as folate antagonist
Reduces synthesis of thymidine and other purines
Not widely used as monotherapy due to SEs
Demonstrable effect in CD (inducing and maintaining remission)
What biologic therapies are used in IBD?
Potentially curative
Anti-TNFα e.g. Infliximab
Anti-α-4-integrin e.g. Natalizumab
Are probiotics useful in IBD?
No evidence for probiotics in CD
Some evidence for probiotics for maintenance of remission in UC (as effective as 5-ASA in inducing and sustaining remission in UC)
What is FMT in IBD?
Faecal microbiota replacement
Insufficient evidence
Why is Rifaximin used as antibiotic treatment in IBD?
To manipulate the microbiome
Interferes with bacterial transcription by binding to RNA polymerase
Induces and sustains remission in moderate CD
May be beneficial in UC
- REDUCES INFLAMMATORY MEDIATOR mRNA IN UC
What biological therapies are approved for use in IBD?
Anti- TNFα antibodies
E.g. Infliximab (iv)
Other antibodies effective but have more SEs
Is anti-tumour necrosis factor alpha used to treat IBD?
Successfully in treatment of CD (potentially curative)
Some evidence of effectiveness in UC
How do anti-TNFα antibodies in IBD work?
Anti-TNFα reduces activation of TNF α receptors in the gut
Reduces downstream inflammatory events
Also binds to membrane associated TNFα
Induces cytolysis of cells expressing TNFα
Promotes apoptosis of activated T cells
What is the pharmacokinetics of infliximab?
Infliximab given IV
Very long half-life (9.5 days)
Benefits can last for 30 weeks after a single infusion
Most patients relapse after 8 – 12 weeks
Therefore repeat infusion every 8 weeks
What are the problems of infliximab?
Up to 50% responders lose response within 3 years due to production of anti-drug antibodies and increased drug clearance
Attempts being made to optimise dosing regimens
What are the adverse effects of infliximab?
TUBERCULOSIS
4x to 5x increase in incidence
Also risk of reactivating dormant TB
SEPTICAEMIA
Increased risk
HEART FAILURE
Worsening
DEMYELINATING DISEASE
Increased risk
MALIGNANCY
Increased risk
Can be immunogenic- azothiaprine reduces risk, but raises TB / maligancy risk
When should infliximab be used?
Early use better than last resort
Combined infliximab and azathioprine therapy may be more effective than antibody alone
In IBD, budesonide causes fewer unwanted systemic effects than prednisolone because:
a. It can be administered topically
b. It can be co-administered with another drug
c. It has a higher potency at therapeutic doses
d. It has a lower potency at therapeutic doses
e. It is metabolised and inactivated locally
e. It is metabolised and inactivated locally
- -
a. It can be administered topically (True but not unique to budesonide)
b. It can be co-administered with another drug (True but not unique to budesonide)
c. It has a higher potency at therapeutic doses (Potencies are similar)
d. It has a lower potency at therapeutic doses (Potencies are similar)
The mechanism of action of Azathioprine in IBD:
a. Interferes with purine biosynthesis
b. Is a direct reduction of protein synthesis in the GI tract
c. Is blocked by co-administration with allopurinol
d. Means that it increases side-effects caused by infliximab
e. Needs activation of the drug by metabolism to 5-ASA
a. Interferes with purine biosynthesis
- -
b. Is a direct reduction of protein synthesis in the GI tract (it will reduce protein synthesis indirectly)
c. Is blocked by co-administration with allopurinol (untrue- allopurinol inhibits metabolism)
d. Means that it increases side-effects caused by infliximab (untrue- it reduces SEs of infliximab)
e. Needs activation of the drug by metabolism to 5-ASA (untrue- it needs activation to 6-mercaptopurine)
What kinds of therapy is used for treating gastric and dodenal ulcers?
TRIPLE THERAPY
Antibiotics
Inhibitors of gastric acid secretion
Cytoprotective drugs
Antacids
What is peptic ulcer disease?
Area of damage to the inner lining of the stomach (gastric ulcer) or upper part of duodenum (duodenal ulcer)
Imbalance of factors which protect or damage GI barrier
When is pain felt in a gastric ulcer?
Pain at mealtimes, when gastric acid is secreted
When is pain felt in a duodenal ulcer?
Pain relieved by a meal as pyloric sphincter closes- pain 2-3h after a meal
What is more common- duodenal or gastric ulcers?
Duodenal:gastric
4:1
What is important to protect the GI mucosal barrier?
The integrity of the gastrointestinal mucosal barrier is important in maintaining a disease free state
What is the use of protective factors in the gut?
Lubricate ingested food and protect the stomach and duodenum from attack by acid and enzymes
Mucous from gastric mucosa creates GI mucosal barrier
HCO3- ions trapped in mucous generate a pH6-7 at mucosal surface
Locally produced prostaglandins stimulate mucous and bicarbonate production (paracrine action) and inhibit gastric acid secretion
What factors that convert food into chyme can damage the mucosal barrier?
PARIETAL CELLS Acid secretion (isotonic solution of HCl, pH<1) from parietal cells of the oxyntic glands in the gastric mucosa
CHIEF CELLS
pepsinogens from the chief cells which can erode the mucous layer
What colour do you stain parietal (oxyntic) cells?
Pink
What factors may cause damage to mucosal GI barrier?
Increased acid and/or decreased bicarbonate production
Decreased thickness of mucosal layer
Increase in pepsin type I (breaks down proteins into smaller peptides)
Decreased mucosal blood flow
Infections with Helicobacter pylori
What are the risk factors for peptic ulcers?
Genetic predisposition
Stress
Diet, alcohol, smoking
What are the aims of treatment of peptic ulcers?
Eliminate cause of mucosal damage
Promote ulcer healing
Why are antibiotics good drugs for treating peptic ulcers?
Eradicate H. pylori
Why are inhibitors of gastric acid secretion good drugs for treating peptic ulcers?
Prevent gastric acid production
Why are cytoprotective drugs good drugs for treating peptic ulcers?
Promote healing
Why are antacids good drugs for treating peptic ulcers?
Neutralise gastric acid
What is H. pylori?
Gram-negative bacterium
Inflammation in the stomach (gastritis) and ulceration of the stomach or duodenum (peptic ulcer disease) is the result of an infection of the stomach caused by the bacterium
How can you see if H. pylori is present in the stomach?
Patients swallow urea labelled with an uncommon isotope
In the subsequent 10–30 minutes, the detection of isotope-labelled carbon dioxide in exhaled breath indicates that the urea was split
Urea split if urease (the enzyme that H. pylori uses to metabolize urea) is present in the stomach which means H. pylori bacteria are present
Why is antibiotic therapy useful in peptic ulcers?
50-80% worldwide are chronically infected
10-20% go on to develop peptic ulcer disease or neoplasia
Most people with duodenal ulcers and gastric ulcers are infected
What do we know about methods of transmission of peptic ulcers?
Transmitted by saliva
In poor countries= overcrowding, contact with animals and contaminated faeces-> poor hygiene associated with greater transmission (SOCIOECONOMIC CONDITIONS)
What is included in “triple therapy” in peptic ulcer treatment?
- Antibiotics (not just single)
- Drugs which reduce gastric acid secretion
- Drugs which promote healing
What are examples of gastric acid secretion inhibitors?
Proton pump inhibitors
Histamine type 2 (H2) receptor antagonists
Anti-muscarinics
What is SIH?
Somatostatin inhibiting hormone
Inhibits release of gastrin from G cells and Histamine from H cells
What stimuli act on the parietal cells?
ACh from the vagal nerve
Gastrin -> releases histamine from the H cells which act on the parietal cells
Prostaglandins E2 and I2 are local hormones (inhibit acid production and promotes a good blood supply)
How does gastrin act on parietal cells?
Stimulatory hormone produced in the antrum in response to food and vagal PNS-> then releases histamine from the H cells which act on the parietal cells
Gastrin also indirectly increases pepsinogen secretion, stimulates blood flow and increases gastric motility
What is the role of secretin in peptic ulcers?
Regulates water homeostasis and the pH of the duodenum
What is omeprazole?
Proton pump inhibitor
Inhibits the basal and stimulated gastric acid secretion from the parietal cells by 90%
How does omeprazole work?
Irreversible inhibitors of the H+/K+ ATPase
Inactive at neutral pH
As it is a weak base it accumulates in the cannaliculi of parietal cells
Why is omeprazole’s action prolonged?
As it is a weak base it accumulates in the cannaliculi of parietal cells
This concentrates its action there and prolongs its duration of action (2-3 days) and minimizes its effect on ion pumps elsewhere in the body
Define: oesophagitis
Inflammation of the lining of the oesophagus
Most cases are due to reflux of stomach acid which irritates the inside lining of the oesophagus
What are the uses of proton pump inhibitors?
Peptic ulcers which are resistant to H2 antagonists
Component of triple therapy
Gasteoesophageal reflux disease (GORD), oesophagitis
Prophylaxis of peptic ulcers in the intensive care setting, and among high-risk patients prescribed aspirin, NSAIDs, as antiplatelets and anticoagulants
What are the pharmacokinetics of proton pump inhibitors?
Orally active
Administered as an enteric coated slow-release formulation
What are the unwanted effects of proton pump inhibitors?
Rare (short term use)
Long-term and/or high-dose administration associated with several potential SEs e.g. enteric infections (C. diff), community acquired pneumonia, and hip fracture
What drugs act on the histamine type 2 (H2) receptor antagonist?
Cimetidine, ranitidine
What are cimetidine/ ranitidine?
Inhibits gastric acid secretion from the parietal cells by 60%
Less effective at healing ulcers than PPIs
How do cimetidine/ranitidine work?
Competitive antagonism of H2 histamine receptors
What are the pharmacokinetics of cimetidine/ ranitidine?
Orally administered, well absorbed
Ranitidine is longer acting than cimetidine
What are the unwanted effects of cimetidine/ ranitidine?
Rare (dizziness, headache)
Fewer side effects with Ranitidine (Zantac, available OTC)
Relapses likely after withdrawal of treatment, >90% recurrence within 1 year after initial healing
Are antimuscarinics useful anti-ulcer drugs?
Little use alone
More effective combination therapies
Give examples of cyto-protective drugs
Drugs that enhance mucosal protection mechanisms and/ or build a physical barrier over the ulcer
Sucralfate
Bismuth chelate
Misoprostol
What is sucralfate?
Cyto-protective drug
Polymer containing aluminium hydroxide and sucrose octa-sulphate
How does sucralfate act?
Acquires a strong -vecharge in an acid environment
Binds to positively charged groups in large molecules (proteins, glycoproteins) resulting in gel-like complexes
-> coat and protect the ulcer, limit H+ diffusion and pepsin degradation of mucus
Increase prostaglandins, mucous and HCO3- secretion and reduces the number of H. pylori
What are the unwanted effects of sucralfate?
Most of the orally administered Sucralfate remains in the GIT
May cause constipation or reduced absorption of some other drugs e.g. antibiotics and digoxin
What is bismuth chelate (pepto-bismol)?
Acts like sucralfate
Used in triple therapy (where resistance to drugs has been shown)
Has anti-inflammatory actions in the stomach
Weak anti-biotic and antacid properties
What is misoprostol?
Stable prostaglandin analogue
Orally active
Co-prescribed with chronically used oral NSAIDs
How does misoprostol act?
Mimics the action of locally produced PG to maintain the gastroduodenal mucosal barrier
Why is misoprostol used with NSAIDs?
Misoprostol= stable prostaglandin analogue
NSAIDs block the COX enzyme required for PG synthesis from arachidonic acid
Therefore, there is a reduction in the natural factors that inhibit gastric acid secretion and stimulate mucus and HCO3- production
What are the unwanted effects of misoprostol?
Diarrhoea, abdominal cramps, uterine contractions (not to given during pregnancy)
What are antacids?
Mainly salts of Na+, Al3+ and Mg2+
May be effective in reducing duodenal ulcer recurrence rates
What speed of effects do the following have?
Sodium bicarbonate
Aluminium hydroxide
Magnesium trisilicate
Sodium bicarbonate has rapid effects
Aluminium hydroxide and magnesium trisilicate have slower actions
How do antacids work?
Neutralise acid, raises gastric pH, reduces pepsin activity
How are antacids administered?
Taken orally- primarily used for non-ulcer dyspepsia (OTC)
What are the problems associated with triple combination therapy?
Compliance
Resistance to antibiotics (may be superseded by vaccination)
Adverse response to alcohol (metronidazole interferes with alcohol metabolism)
Give examples of triple combination
1
Metronidazole/amoxycillin
Clarithromycin
PPI
2
H2 R antagonist
Clarithromycin
Bismuth
What is GORD/GERD?
Stomach and duodenal contents reflux into the oesophagus (oesophagitis)
OCCASIONAL
Occasional and uncomplicated GERD
Heart burn, may treat by self medication with antacids and H2 antagonists (OTC)
CHRONIC
Chronically may progress to pre-malignant mucosal cells and potentially oesophageal adenocarcinoma
How can GERD be treated?
PPIs (drug of choice) or H2 antagonists (less effective)
Combine with drugs that increase gastric motility and emptying of the stomach e.g. Dopamine D2 receptor antagonist (metoclopramide)
What is an adverse drug event?
Preventable or unpredicted medication event- with harm to patient
Why is methotrexate important in adverse drug events?
High doses for treatment of cancers
Low doses= rheumatoid arthritis
Adverse events happen when given too much or too frequently
What percentage of ADRs are preventable?
30-60%
Substantial morbidity and mortality
How are ADRs classified?
Onset
Severity
Type
What are the possible onsets for ADRs?
Acute= within 1 hour, e.g. anaphylaxis Sub-acute= 1 to 24 hours Latent= >2 days
What are the possible severities of ADRs?
Mild= requires no change in therapy Moderate= requires change in therapy, additional treatment, hospitalisation Severe= disabling or life-threatening
What can severe ADR cause?
Results in death Life-threatening Requires or prolongs hospitalisation Causes disability Causes congenital anomalies Requires intervention to prevent permanent injury
What is Type A ADR?
70% of adverse reactions
Extension of pharmacologic effect
Usually predictable and dose dependent
E.g. atenolol and heart block, anticholinergics and dry mouth, NSAIDs and peptic ulcer
What is the ADR profile of paracetamol?
Up to threshold= very safe drug
Then toxicity increases very rapidly and mainly effects live
What is the ADR profile of digoxin?
Toxicity at any dose, not a threshold
What is Type B ADR?
Idiosyncratic or immunologic reactions
Includes allergy and “pseudoallergy”
Rare (even very rare) and unpredictable
E.g., chloramphenicol and aplastic anemia, ACE inhibitors and angioedema
What is Type C ADR?
Associated with long-term use
Involves dose accumulation
E.g., methotrexate and liver fibrosis, antimalarials and ocular toxicity
What is Type D ADR?
Delayed effects (sometimes dose independent)
Carcinogenicity (e.g. immunosuppressants)
Teratogenicity (e.g. thalidomide)
What is Type E ADR?
Withdrawal reactions= Opiates, benzodiazepines, corticosteroids
Rebound reactions= Clonidine, beta-blockers, corticosteroids
“Adaptive” reactions= Neuroleptics (major tranquillisers)
Why is clonidine withdrawal so dangerous?
Rebound effect
Potent anti hypertensive
Makes you drowsy and tired
Miss dosses and bp suddenly increases (can lead to strokes or death)
Missing one dose now manageable
Before 170/10
During 145/90
After 220/130
What is the ABCDE classification of adverse drug reactions?
Augmented pharmacological effect Bizarre Chronic Delayed End-of-treatment
What are the kinds of allergy classes?
Type I-IV
What is Type I of allergic reactions?
Immediate, anaphylactic (IgE)
E.g. anaphylaxis with penicillins
What is Type II of allergic reactions?
Cytotoxic antibody (IgG, IgM) E.g. methyldopa and hemolytic anemia
What is Type III of allergic reactions?
Serum sickness (IgG, IgM)
antigen-antibody complex
E.g. procainamide-induced lupus
What is Type IV of allergic reactions?
Delayed hypersensitivity (T cell) E.g. contact dermatitis (more common)
What are pseudoallergies?
Similar presentation to a true allergy
Due to different causes
May be due to alterations in the metabolism of histamine
Can be the cause of some forms of food intolerance
How are Aspirin/NSAIDs and bronchospasm an example of pseudoallergies?
Happens mostly to asthmatics
Blocking COOX pathways which usually makes prostaglandins
AA converted to make leukotrienes= pro inflam-> bronchospasm
How is ACE inhibition and cough/angioedema an example of pseudoallergies?
ACE inhibitors stop breakdown of inflammatory peptides e.g. bradykinin particularly in lung
Accumulated can -> cough by acting on sensory nerves of lung
What are the common causes of ADRs?
Antibiotics Antineoplastics Anticoagulants Cardiovascular drugs Hypoglycemics Antihypertensives NSAID/Analgesics CNS drugs
Why are ADRs increasing in frequency?
Increasing polypharmacy
So more people having interactions
How are ADRs detected?
SUBJECTIVE REPORT
Patient complaint
OBJECTIVE REPORT Direct observation of event Abnormal findings Physical examination Laboratory test Diagnostic procedure
Why are rare events not usually detected before drug is marketed?
Need a lot of patients to see adverse reactions
What is the yellow card scheme?
Voluntary
Used by doctors, dentists, nurses, coroners and pharmacists
For established drugs= only report serious adverse reaction
For ‘black triangle’ drugs (newly licensed)= report any suspected adverse reactions
Why is it hard to calculate drug-drug interaction incidence?
True incidence difficult to determine
Data for drug-related hospital admissions do not separate out drug interactions (focus on ADRs)
Lack of availability of comprehensive databases
Difficulty in assessing OTC and herbal drug therapy use
Difficulty in determining contribution of drug interaction in complicated patients
What are the pharmacodynamic drug interactions?
Additive, synergistic, or antagonistic effects from co-administration of two or more drugs
Give an example of synergistic drug interactions
Antibiotics
Give an example of overlapping toxicities drug interactions
Overlapping toxicities - ethanol and benzodiazepines
Give an example of antagonistic drug interactions
Anticholinergic medications (amitriptyline and acetylcholinesterase inhibitors)
What are pharmacokinetic drug interactions?
Alteration in absorption
Protein binding effects
Changes in drug metabolism
Alteration in elimination
What is chelation?
Irreversible binding of drugs in the GI tract
So can’t be absorbed
E.g. Tetracyclines, quinolone antibiotics - ferrous sulfate (Fe+2), antacids (Al+3, Ca+2, Mg+2), dairy products (Ca+2)
How do protein binding interactions lead to competition in drug reactions?
Competition between drugs for protein or tissue binding sites
Increase in free (unbound) concentration may lead to enhanced pharmacological effect
Metabolism interactions
What happens in phase 1 and 2 in drug metabolism and elimination?
Phase 1= original drug altered but then cleared (-> liver/kidney or to phase 2)
Phase 2= altered once and then again before being excreted by kidney (-> kidney)
Also could be directly excreted unchanged by kidney
What happens to the drug before the kidney?
Converted from lipid to water soluble so easier to get rid of in the kidney
What happens in phase I drug metabolism?
Oxidation
Reduction
Hydrolysis
What happens in phase II drug metabolism?
Conjugation
Glucuronidation
Sulphation
Acetylation
What happens to drug metabolism with co-administration of other drugs?
Inhibited or enhanced
CYP 450 system= most extensively studied
CYP3A4, CYP2D6, CYP1A2, CYP2B6, CYP2C9, CYP2C19 and others
What are CYP 450 substrates metabolised by?
Single isozyme (predominantly) Multiple isozymes
What drugs have CYP 450 metabolised by a single isozyme?
Few examples of clinically used drugs
Examples of drugs used primarily in research on drug interactions
What drugs have CYP 450 metabolised by a multiple isozymes?
Most drugs metabolized by more than one isozyme
E.g. Imipramine: CYP2D6, CYP1A2, CYP3A4, CYP2C19
What happens if you co-administer a CYP 450 substrate with CYP 450 inhibitor?
If co-administered with CYP450 inhibitor, some isozymes may “pick up slack” for inhibited isozyme
I.e. block one subtype of enzyme others will kick in and start metabolising the drug
List examples of CYP 450 inhibitors
Cimetidine
Erythromycin and related antibiotics
Ketoconazole etc
Ciprofloxacin and related antibiotics
Ritonavir and other HIV drugs
Fluoxetine and other SSRIs
Grapefruit juice
List examples of CYP 450 inducers
Rifampicin Carbamazepine (Phenobarbitone) (Phenytoin) St John’s wort (hypericin)
Many inducers in plants and vegetables which may have affect on drug metabolism (not known in much detail)
What is the difference in time between inhibition and induction? Why?
Inhibition= very rapid (hours) Induction= hours/days becuase need time for transcription and translation
Where do drug elimination interactions usually happen?
Almost always in renal tubule
What kind of drug elimination interaction happens between probenecid and pencillin?
Good
What kind of drug elimination interaction happens between lithium and thiazides?
Bad
Outline the drug elimination interaction between lithium and thiazides
Thiazide reduces clearance so toxic accumulation in blood
Increasing secretion of sodium salt but lithium is retained
Why is levodopa & carbidopa a deliberate interaction?
Allows lower doses to be used because not broken down in periphery
Why is ACE inhibitors & thiazides a deliberate interaction?
Enhance each others antihypertensive effects
Why is penicillins &gentamicin a deliberate interaction?
Severe staphylococci infections prevented
Why is salbutamol & ipratropium a deliberate interaction?
Treatment of asthma and COPD
What are opiates?
An alkaloid derived from the poppy
Natural product
Papaver somniferum
Are opioids synthetic?
Can be natural, synthetic or semi-synthetic
What part of morphine contributes to analgesia? Why? How can it be made into an antagonist?
Tertiary form of nitrogen permits receptor anchoring (binds drug to R)
Can be made into antagonist if you extend side chain to 3+ carbons (determines if you can activate R)
(Quaternary nitrogen-> decreased analgesia because can’t get into CNS)
How is morphine altered to become codeine?
Add methyl to hydroxyl group at position 3
Required for binding
Codeine is a prodrug
Much less potent than morphine
How is morphine altered to become heroin? Why is this important?
Acetylated (oxidised) hydroxyl groups 3 and 6
Diacetyl morphine-> increases lipid solubility (penetrates tissues much better)
Converted to morphine in the tissue
What are the similarities between the structure of methadone and morphine?
Tertiary nitrogen remains
Phenyl group
Quaternary carbon
Look different but have same key features
What are the similarities between the structure of fentanyl and morphine?
Tertiary nitrogen remains
Phenyl group
NO quaternary carbon (tertiary)
Make it more powerful
Why is the oral route of morphine not very efficient?
Orally (but not well absorbed from stomach because remains mostly ionised= weak base)
Relatively well absorbed from SI
Heavily metabolised in liver (lots of first pass)
Only about 20% gets into blood
What is the pKa of most opioids?
> 8
Weak bases
How do you ensure high bioavailability of morphine?
Inject
IV
Still distributes to brain relatively slowly because not great lipid solubility
Which opioids are more/less lipid soluble?
MOST-> LEAST
Methadone/fentanyl
Heroin
Morphine
NB. More lipid soluble- more potent
What is morphine metabolised to? Why is this important?
Various metabolites
Including Morphine-6- glucuronide (10% - active metabolite)
Length of action prolonged by active metabolites
Why is fentanyl used as an analgesic and methadone used to help wean people off heroin?
Fentanyl is metabolised very quickly (fast onset, quickly cleared)
Methadone is slowly metabolised (prolonged effects, long acting)
How much codeine is metabolised to morphine?
5-10%
How is codeine metabolised?
CYP2D6 metabolism is slow but converts codeine to morphine i.e. codeine is a prodrug for morphine
What deactivates codeine?
CYP3A4
Why do some people not respond well to codeine?
2D6 polymorphism
What metabolises morphine?
Morphine is the major exception- metabolised by uridine 5 diphosphate glucoronosyltransferase
How do opioids work?
Act via specific opioid receptors (mu, delta, kappa)
What are examples of endogenous opioid peptides? What do they affect?
Endorphins= pain/mood/CVS Enkephalins= pain/mood/CVS Dynorphins/neoendorphins= appetite
What receptors do endorphins act on? Where are these?
Opioid
Mu or delta-> mu
Thalamus, amygdala, n.acc, PAG
What receptors do enkephalins act on? Where are these?
Opioid
Delta
N.acc, caerebral cortex, amygdala
What receptors do dynorphins act on? Where are these?
Opioid
Kappa
Appetite
What is the cellular mechanism of action of opioids?
Depressant
- > hyperpolarisation (increases K+ efflux )
- > diminishes inward Ca current
- > decrease adenylate cyclate activity
All work to decrease activity of cell
Why might opioids be taken?
Analgesia
Euphoria
Depression of cough centre (anti-tussive)
Depression of respiration (medulla)
Stimulation of chemoreceptor trigger zone (nausea/ vomiting)
Pupillary constriction
GI effects
How do opioids have an affect of analgesia?
Decrease pain perception
Increase pain tolerance
Maybe central pain perception
Where can opioids act on the pain pathway to prevent pain perception?
Pain perceived in PNS
Pain relayed to DH
Spinothalamic tracts relay up to brain
Thalamus= mu (sorting of signals) Cortex= mu, delta (adds emotional response)
Outline the pain tolerance pathway
Integrating centre (PAG)= mu, kappa
- Receives + from thalamus
- Receives +/- from cortex
Info relayed to NRM= delta
- Also info from NRPG (independent of thalamus, essentially reflex)= mu, delta
NRM inhibits DH (decreases sensation of pain)
Locus coeruleus also has negative effect (SNS suppresses sensation of pain- fight/flight)
Why is pain tolerance needed?
Recognise pain initially (to avoid damage)
But need to depress feelings of pain= tolerance
Too much pain is harmful
What information can the DH process?
Some is automatic= not processed, just direct inhibitory effect
But structures within SC can be involved in processing info= substantia gelatinosa
Further processes descending info
Where can opioids act?
NRPG
PAG
Periphery at site of tissue injury
Why do opioids cause euphoria?
Opiates act at mu receptors
Depress firing rate of GABA acting on VTA
Causes more DA release by NAcc-> euphoria
What leads to coughing? Why are opioids used as anti-tussives?
Stimulation of mechano-or chemoreceptors (throat, resp passages or stretch Rs in lungs)= respond to irritants
Afferent impulses to cough centre (medulla)
OPIOIDS ACT ON- Ach/NK C-fibres relay to Vagus (stop info to cough centre)
Efferent impulses via parasympathetic and motor nerves to diaphragm, intercostal muscles and lung
OPIOIDS ACT ON - 5HT1A receptors (negative feedback receptors) (stop cough centre)
Increased contraction of diaphragmatic, abdominal and intercostal (ribs) muscles-> noisy expiration (cough)
OPIOIDS HAVE PERIPHERAL EFFECTS on mu-opioid receptors in airway vagal sensory neurons
AND OPIOIDS INHIBIT both eNANC nerve activity and cholinergic contraction of smooth muscles
Wy do opioids cause respiratory depression?
Most dangerous side effect
Interfere with central chemoreceptors (which respond to PaCO2)
- Disconnect resp control centre from amount of CO2 in blood
Act directly in medullary control centre
- Pre-Botzinger complex (part that deals with breathing rhythm)
- Opioids suppress this area
Why do opioids cause nausea/vomiting?
Activate mu receptors in chemoreceptor trigger zone-> medullary vomiting center-> vomiting reflex
Probably due to interference with GABA (switch off GABA-> feel nauseous)
Why do opioids cause miosis?
Pinpoint pupils (e.g. in heroin deaths/overdose)
Mu opioid receptors in Edinger-Westphal nucleus
Opioids activate parasympathetic nerve independent of what optic nerve is doing
Probably relates to GABA (switched off- parasymp nerve starts firing like crazy)
Why do opioids cause gastrointestinal disturbance?
Opioids have significant inhibitory effects on gut-> constipating
ENTERIC NS (controls gut function) Several opioid receptor types can be demonstrated on myenteric neurons
Both kappa and mu receptor agonists regulate cholinergic transmission in the myenteric plexus
Why do opioids cause urticaria?
Not well understood
In some people, opioids (with combination of the N-methyl group and the 6-hydroxyl group) cause histamine release
Affects mast cells near skin
PKA activates-> histamine release
(NB. not allergy but looks like it)
What determines opioid tolerance? How is it developed?
Not PK, this is issue tolerance
Opioids taken chronically will upregulate levels of arrestin in tissue
Arrestin promotes R internalisation (normal process to recycle Rs BUT upregulating-> too many Rs internalised)
Develop tolerance to opioids
What is opioid withdrawal associated with?
Psychological craving Physical withdrawal (resembling flu)
Depressant effects in opioid users-> cells upregulate adenylate cyclase to compensate
When withdraw drugs-> left with cells with too much adenylate cyclase (slowly returns to normal)
What happens in an opioid overdose?
Coma
Respiratory depression
Pin-point pupils
Hypotension
How can you treat an opioid overdose?
Naloxone (opioid antagonist) i.v.
What is the target organ of diuretics?
Kidney
In the PCT cell, outline ionic composition/channels?
Free movement of H2O and Na across apical membrane from lumen into cell
SODIUM
Need to constantly remove sodium from cell to maintain conc gradient
- Na/K exchange (Na out, K in)
WATER
Sodium removal also helps passage of water (back towards blood)
- And helped by oncotic pressure
PARACELLULAR= big gap junctions
Allow movement of H2O, Na, CL, HCO3-
CARBONIC ANHYDRASE
Enzyme to allow movement of bicarb ions from apical to basal sides of cell
- CA on outside of apical surface (ensures bicarb and H ions are converted to CO2 and H2O which can move into cell more easily by diffusion)
- Cytoplasmic CA converts it back to H and HCO3 (bicarb)
- Bicarb then cotransported with sodium back towards blood
AMINO ACIDS
Na/H transporter (Na in, H out)
Coupled with glucose/AA transport at apical membrane into cell
Exporting exogenous proteins also happens
How do drugs leave the kidney?
Transported across PCT cell
Lost in urine
How much of the filtered load is reabsorbed in the PCT?
Of the filtered load, up to 70% is reabsorbed in PCT
In the DESCENDING LIMB outline ionic composition/channels?
Water moves down osmotic gradient
Aquaporins present
In the ASCENDING LIMB outline ionic composition/channels?
Very little through paracellular route
Pretty much impermeable to water
Move NaCl from one side to other
- Na/2Cl/K transporter moves ions across cell into blood
- K also moves in opposite direction into lumen
Outline the countercurrent effect
PUMP NA FROM ACSCENDING TUBULE
Descending limb-
permeable to water
Ascending limb- impermeable to water
Na leaves the ascending limb and enters medullary interstitium
Fluid in ascending limb decreases in osmolarity
ADJUST OSMOLARITY OF DESCENDING TUBULE
More concentrated
medullary interstitium draws water from the permeable descending limb
Fluid in descending limb
increases in osmolarity
MORE FLUID FLOWS INTO TUBULE
More fluid enters and forces fluid from descending to
ascending limb
- This fluid
has increased in osmolarity due to increased Na+ conc
in the medulla
SECOND ROUND OF NA PUMPING
Ascending limb –
impermeable to water
Na+ leaves the ascending
limb and enters medullary
Interstitium
Fluid in ascending limb
decreases in osmolarity
Why is the countercurrent multiplier effect in the LOH important?
Drives the reabsorption of water (particularly in PCT)
Why loop diuretics are so powerful
In the DCT outline ionic composition/channels?
EARLY DCT
Predominant effect driven by NaCl cotransport protein
- Reabsorbed together and transferred across into the blood
LATE DCT
Aldosterone= steroid= most important in driving Na reuptake
- Binds to mineralocorticoid R-> moves to nucleus-> increases production of Na channels and Na/K/ATPase
AQP2 via VP determine water reabsorption
In the COLLECTING DUCT outline ionic composition/channels?
Aldosterone= steroid= most important in driving Na reuptake
- Binds to mineralocorticoid R-> moves to nucleus-> increases production of Na channels and Na/K/ATPase
AQP2 via VP determine water reabsorption
How do diuretics work?
Inhibit the reabsorption of Na+ and Cl-
i.e. increase excretion
(1 kind= increases the osmolarity of tubular fluid
i.e. decrease the osmotic gradient across the epithelia)
What are the 5 main diuretic classes (with eg)?
Osmotic diuretics e.g. mannitol
Carbonic anhydrase inhibitors e.g. acetazolamide
Loop diuretics e.g. frusemide (furosemide)
Thiazides e.g. bendrofluazide (bendroflumethiazide)
Potassium sparing diuretics e.g. amiloride, spironolactone.
Which diuretic classes are used clinically?
Loop diuretics
Thiazides
K sparing diuretics
How do osmotic diuretics e.g. mannitol work?
Pharmacologically inert= don’t affect kidney tubule cells
Just change osmolarity of filtrate
Filtered by glomerulus but not reabsorbed
No ACTION OF NA REABSORPTION
ACTION OF H2O REABSORPTION
- Increase osmolarity of tubular fluid
- Decrease H20 reabsorption where nephron is freely permeable to water i.e. PCT, desc loop and CT
Where do carbonic anhydrase inhibitors work?
Act proximally
Where do loop diuretics work?
LOH
Where do thiazides work?
DCT
Where do K sparing diuretics work?
Late DCT and collecting duct
How do carbonic anhydrase inhibitors e.g. acetazolamide work?
ACTION OF NA REASBORPTION
Inhibit Na and HCO3 reabsorption in PCT
Act on carbonic anhydrase (apical and cytoplasmic) -> more bicarb in filtrate (not transferred across cell)
-> affects some of the Na reuptake (Na retention in lumen increases-> more Na and therefore water lost in urine)
ACTION ON H2O REABSORPTION
Increased tubular fluid osmolarity and decreased osmolarity of medullary interstitium-> decreased H2O reabsorption in CT
OTHER
Increased bicarb delivery to DCT-> K loss
Ca and Mg affected-> loss of K recycling
NB. Earlier you act in kidney-> give kidney more time to adapt (better to use other diuretics)
How do loop diuretics e.g. frusemide work?
Act on ascending limb (very powerful because affect countercurrent multiplier)
Via affect Na/2Cl/K cotransport protein
Sodium chloride mostly reasborbed
Potassium recycling drives the positive lumen potential
BUT with loop diuretics-> reduce K movement by interfering with positive lumen potential-> less transfer of electrolyte
ACTION ON NA REABSORPTION
Inhibit Na and Cl reabsorption in ascending limb (30%)
ACTION OF H2O REABSORPTION
Increase tubular fluid osmolarity and decrease osmolarity of medullary interstitium-> decreased H2O reabsorption in CT
OTHER
Increased Na delivery to DCT-> K loss (due to increased Na/K exchange)= like thiazides
Ca and Mg affected-> loss of K recycling
How do thiazides e.g. bendroflumethiazide work?
Less powerful, act on DCT
Prevent NaCl reuptake-> more water being lost out of kidney
ACTION ON NA REABSORPTION
Inhibit Na and Cl reabsorption in early DCT=5-10%
ACTION ON H2O REABSORPTION
Increased tubular fluid osmolarity-> decreased H2O reabsorption in the collecting duct (promote fluid loss)
OTHER
Increased Na delivery to DCT-> K loss (due to increased Na/K exchange)= like loop diuretics
Lose Mg (like loop diuretics)
Increased Ca reabsorption (maybe, not understood)
What effect do diuretics have on renin secretion long term?
If chronically taking diuretics-> reduced sodium load passing through DCT in blood-> detected by macula densa cells-> stimulates renin production which counters the effects of diuretic (promotes Na and water reabsorption)
Particularly loop diuretics and thiazides
Which diuretic would have the most powerful effect on renin secretion?
Loop diuretics (and thiazides)
Loop diuretic sensitive transporter especially affected
How do potassium sparing diuretics e.g. spironolactone and amiloride work?
Act on collecting duct and late DCT (no longer need to worry about Na/K exchange)
ACTION ON NA REABSORPTION
Inhibit Na reabsorption (and concomitant K secretion) in early distal tubule (5%)
ACTION ON H2O REABSORPTION
Increase tubular fluid osmolarity-> decreased H2O reabsorption in collecting duct
OTHER
Decreased reabsorption of Na to distal tubule increases H retention (decreased Na exchange)
Mechanism depends on class
What are the classes of K sparing drugs?
Aldosterone receptor antagonists (mineralocorticoid receptor affected) e.g. spironolactone
Inhibitors of aldosterone-sensitive Na channels e.g. amiloride
What are the common side effects of diuretics?
Hypovolemia Metabolic alkalosis Hyperuricemia Metabolic acidosis Hyperkalemia Hypokalemia Hyponatremia
What side effects do loop diuretics cause?
30% loss-> Hypovolemia and hyponatremia
Cl loss-> Metabolic alkalosis
? -> Hyperuricemia
Na/K exchange-> Hypokalemia
What side effects do thiazides cause?
10% loss-> Hypovolemia and hyponatremia
Cl loss-> Metabolic alkalosis
? -> Hyperuricemia
Na/K exchange-> Hypokalemia
What side effects do carbonic anhydrase inhibitors cause?
HCO3- loss-> Metabolic acidosis
What side effects do potassium sparing diuretics cause?
Less Na/K exchange-> Hyperkalemia
Why do you get hyperuricemia with thiazides and loop diuretics?
High conc of diuretic competes with uric acid for transporter (organic anion basal transporter)
Uric acid levels in blood start to build up
What diuretics are used to treat hypertension?
Thiazide
= First line in most countries
= Good for salt sensitive hypertension
(Other drugs also used for hypertension)
How are thiazides used to treat hypertension?
Initial response (4-6 weeks)= loss in blood volume After 4-6 weeks= plasma volume restored, reduced TPR
TPR reduced by activated eNOS (endothelium), Ca channel antagonism and opening of K Ca channel (smooth muscle)
How do diuretics treat heart failure and oedema?
Heart failure activates SNS which is bad
Loop diuretics used-
30% Na load (better with K sparing diuretics)
Acute reduction in congestion (decreased ventricular filling pressures and improvment
Prompt diuretic effects (furosemide within 30 mins, peaks at 1.5 hours)
Resistance happens quickly (but great acutely)
Outline what happens at a GABAergic synapse
GABA synthesised from glutamate (converted by GAD)
GABA taken up into vesicles ready for arrival of AP down axon (mostly short axon interneurones)
Release mechanism= diffuses across cleft and reacts with recepto
Stimulates post-synaptic GABA A Rs (linked to chloride channel)
GABA stimulation means chloride enters-> potential drops down to -90mV (less likely to be activated)
GABA reuptake by selective carriers
Can be repackaged and used again or broken down by metabolic enzymes e.g. SSA
How does GABA go to succinic semialdehyde?
GABA transaminase (GABA-T)
Mitochondrial enzyme
How does succinic semialdehyde go to succinic acid?
Succinic semialdehyde dehydrogenase (SSDH)
Mitochondrial enzyme
What is sodium valproate used for?
EPILIM anti-convulsants used for epileptics
Inhibits GABA T and SSDH
What is vigabatrin used for?
SABRIL
Suicide inhibitor
Binds covalently to GABA-T
What happens when you inhibit GABA metabolism?
Large increase in brain GABA
What is the GABA-A receptor complex? How is binding enhanced?
Binding of GABA
Linkage of GABA R and BDZ
R proteins by GABA modulin-> opening of chloride channel (chloride ions enter postsynaptic cell)
Presence of benzodiazepine (BDZ) receptor enhances GABA action to increase affinity of GABA and GABA R
Barbiturates bind to a different place and enhance GABA binding (not reciprocal)
What is bicuculline?
Competes with GABA (competitive antagonist)
What is flumazenil?
Competive benzodiazepine receptor antagonist
What are the actions of BZs and BARBs on the GABAA R complex? What are the differences?
No activity alone (allosteric action)
Different binding sites and different mechanisms
BZs increase frequency of openings
BARBs increase duration of openings
BARBs less selective than BZs
Decreased excitatory transmission and has other membrane effects
What are the clinical uses of BZs and BARBs?
Anaesthetics (BARBs only, thipentone) Anticonvulsants (diazepam, clonazepam, phenobarbital) Anti-spastics (diazepam) Anxiolytics Sedatives and hypnotics
What is an anxiolytic?
Drug to remove anxiety without impairing mental or physical activity
Minor tranquilisers
What is a sedative?
Reduce mental and physical activity without producing loss of consciousness
What is a hypnotic?
Drug that induces sleep
What should anxiolytics, sedatives and hypnotics do?
Have wide margin of safety Not depression respiration Produce natural sleep (hypnotics) Not interact with other drugs Not produce 'hangovers' Not proudce dependence
Give an example of a sedative and hypnotic barbiturate
Amobarbital
Severe intractable insomnia
Half life= 20-25h
What are the unwanted effects of barbiturates?
Low safety margins= depress respiration, overdosing lethal
Alter natural sleep (reduce REM)-> hangovers and irritability
Enzyme inducers
Potentiate effect of other CNS depressants (e.g. alcohol)
Tolerance
Dependence-> withdrawal syndrome (insomnia, anxiety, tremor, convulsions, death)
Give examples of barbiturates
Phenobarbitone
Pentobarbitone
Thiopentone
What kind of drug is chloral hydrate (to tricholerthanol)?
Hypnotic
What do benzodiazepines do?
All act at GABA A receptors
All similar
Pharmacokinetics determine use
Outline the pharmacokinetics of benzodiazepines
Well absorbed P.O.
Peak plasma conc after 1h
IV used for status epilepticus
Bind plasma proteins strongly
Highly lipid soluble (so wide distribution)
Usually extensive metabolism (liver)
Excreted in urine, glucoronide conjugates
Action varies greatly
Short or long acting (slow metabolism and or active metabolites)
How are benzodiazepines metabolised?
LONG ACTING
Diazepam (32h)-> nordiazepam (60h)-> oxazepam (8h)-> glucoronide
Diazepam (32h)-> temazepam (8h)-> oxazepam (h)-> glucoronide
Chlordiazepxodie (12h)-> nnordiazepam (60h)-> oxazepam (8h)-> glucoronide
Nitrazepam (28h)-> glucuronide
SHORT ACTING
Temazepam (8h)-> oxazepam (h)-> glucoronide
Lorazepam (12h)-> glucuronide
SEE DIAGRAM!
What is diazepam?
Valium
Long-acting anxiolytic
What can oxazepam cause?
Hepatic impairment
Give examples of long-acting anxiolytics
Diazepam (valium)
Chlordiazepoxide (librium)
Nitrazepam (NB. has daytime anxiolytic effects)
Give examples of short-acting sedatives and hypnotics
Temazepam
Oxazepam
What are the advantages of benzodiazepines?
Wide margin of safety (overdose just causes prolonged sleep= rousable), flumazenil
Mild effect on REM sleep
Don’t induce liver enzymes
What are the unwanted effects of benzodiazepines?
Sedation, confusion, amnesia, ataxia (impaired manual skills)
Potentiate other CNS depressants (alcohol, barbs)
Tolerance (less than barbs, ‘tissue’ only)
Dependence (withdrawal syndrome, similar to barbs but less intense)
Withdraw slowly
Free plasma concentration increases e.g. by aspirin, heparin
What is zopiclone? How does it work?
Sedative Short acting (half life 5h) Acts at BZ receptors (cyclopyrrolone) Similar efficacy to BZs Minimal hangover effects but dependency still a problem
Give an example of antidepressant anxiolytics
SSRIs
Effective, delayed response, popular
Give examples of antiepileptic anxiolytics
Valproate
Tiagabine
Give examples of antipsychotic anxiolytics
Olanzapine
Quetiapine
Marked side-effects so not often used
What is propanolol?
Anxiolytic
Improves physical symptoms (tachycardia, B2 and tremor, B2)
What is buspirone?
5HT1A agonist (anxiolytic)
Fewer side effects (less sedation)
Slow onset of action (days and weeks)
Benzodiazepines are used to treat ‘panic attacks’ and other anxiety states. By what mechanism do they produce their anti-anxiety effects?
A: Inhibition of GABA breakdown
B: Activation of 5HT1A receptors
C: Enhancement of the action of GABA at GABA-A receptors
D: Inhibition of GABA reuptake
E: Enhancement of the action of GABA at GABA-B receptors
C: Enhancement of the action of GABA at GABA-A receptors
Which of the following drugs is commonly used in the treatment of insomnia?
A: Thiopental B: Phenytoin C: Baclofen D: Sodium valproate E: Temazepam
E: Temazepam
What is the nigrostriatal pathway?
Cell bodies originate in the substantia nigra zona compacta and project to the striatum
Control of movement
What is the mesolimbic pathway?
Cell bodies originate in the vetnral tegmental in the ventral tegmental area and project to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercule
Involved in emotion
What is the tuberoinfundibular system?
Short neurones running from the arcuate nucleus of the hypothalamus to the medial eminence and pituitary gland
Regulate hormone secretion
What dopamine receptors are in the D1 family?
D1 and D5
What dopamine receptors are in the D2 family?
D2, D3 and D4
How many case of PD are familial?
8% of all cases
What is PD believed to be caused by?
Combination of environmental, oxidative stress, altered protein metabolism and risk genes
What are the main signs of PD?
Rest tremor (shaking of limb when relaxed)
Rigidity (stiffness, limbs feel heavy and weak)
Bradykinesia (slowness of movement)
Postural abnormality (forward tilt of trunk)
What is the main problem with current PD drugs?
Treat the clinical symptoms don’t slow the degenerative process
What are the presenting symptoms of PD?
Pill-rolling rest tremor
Difficulty with fine movements e.g. micrographia
Poverty of blinking
Impassive face
Monotomy of speech and loss of volume of voice
Disorders of posture- flexion of the neck and trunk
Lack of arm swing
Loss of balance- lack of righting reflex, retropulsion
Short steps, shuffling gait
Unilateral onset
Spreads to both sides
Generally worsen
What are the non-motor symptoms of PD?
Depression Sleep disturbances Pain Taste and smell disturbances Cognitive decline and Demention
Autonomic - Constipation - Postural hypotension Urinary frequency and urgency Impotence Increased sweating
What areas of the brain are affected in PD?
Substantia nigra
Lewy bodies
Also, locus coruleus, dorsal vagus nucleus, nucleus basalis of Mynert
What are the stages of PD and what is affected in these stages?
STAGES 1-2
Dorsal motor nucleus of vagus
Raphe nucleus
Locus coeruleus
STAGE 3
Substantia nigra pars compacta
STAGE 4
Amygdala
Nucleus of Meynert
Hippocampus
STAGE 5-6 Cingulate cortex Temporal cortex Frontal cortex Parietal cortex Occipital cortex
NB. Stages 1-3 presymptomatic
What biochemical change happens in PD?
Marked reduction in caudate nucleus and putamen dopamine content
Symptoms appear when 80-85% of DAergic neurons are lost and 70% of striatal dopamine
Compensatory mechanisms mean symptoms take time to appear
What is the purpose of L-DOPA?
DOPA is precursor to dopamine (converted by dopa decarboxylase in brain)
Dopamine can’t cross BBB so give L-dopa
Why is L-DOPA given with another drug?
Needs to be given with peripheral DOPA decarboxylase inhibitor
Because otherwise L-DOPA metabolised to DA in periphery (SEs include nausea and vomiting)
What are the major preparations of L-DOPA
Sinamet (Carbidopa + L-DOPA)
Madopar (Benserazide + L-DOPA)
What does L-DOPA treat?
Hypokinesia, rigidity and tremor
Start with low dose and increase until max benefit without SEs
Effectiveness declines over time
What are the SEs of L-DOPA?
ACUTE
Nausea
Hypotension
Psychological effects= confusion, disorientation and nightmares
CHRONIC
Dyskinesias
“On-Off” effects
What can be used to treat nausea caused by L-DOPA?
Doperidone (peripheral acting antagonist)
What are dyskinesias that appear as chronic SEs of L-DOPA?
Abnormal movements of limbs and face
Can occur within 2 years of treatment
Disappear if reduce dose but clinical symptoms reappear
What are the chronic “on-off” effects of L-DOPA
Rapid fluctuations in clinical state
Off periods may last from minutes to hours
What do dopamine agonists do?
Act on D2 receptors
Give examples of dopamine agonists
Bromocriptine
Pergolide
Ropinerol
What are the benefits of using dopamine agonists to treat PD?
Smoother and more sustained response
Actions independent of dopaminergic neurons
Incidence of dyskinesias is less
Can be used in conjunction with L-DOPA
What are the adverse effects of dopamine agonists?
Common= confusion, dizziness, nausea and vomiting, hallucinations
Rare= constipation, headache, dyskinesias
Problems with heart valves
Addictive behaviours
What is Deprenyl (selegiline)?
MAO inhibitor (selective for MAO-B) Predominates in dopaminergic areas of CNS Doesn’t have peripheral SEs
What is Deprenyl used to treat?
PD
Cab be given alone in early stages
Given in combo with L-DOPA (so can reduce L-DOPA dose by 30-50%)
What are the SEs of Deprenyl?
Rare
Hypotension, nausea and vomiting, confusion and agitation
What is resagiline?
MAO inhibitor
Neuroprotective properties by inhibiting apoptosis
Promotes anti-apoptosis genes
May be useful in PD- clinical trials
What are COMT inhibitors?
Catechol-O-methyl transferase inhibitors
E.g. tolocapone (CNS and peripheral) and Entacapone (peripheral)
What does tolocapone do?
COMT inhibitor
CNS= Prevents breakdown of dopamine in the brain
PNS= Stops 3-OMD formation so increases penetration of L-DOPA across the BBB (reduce L-DOPA dosage)
What does entacapone do?
Peripheral COMT inhibitor
PNS= Stops 3-OMD formation so increases penetration of L-DOPA across the BBB (reduce L-DOPA dosage)
What is 3-OMD (in COMT inhibition)?
COMT in the periphery converts L-DOPA to 3-OMD
3-OMD and L-DOPA compete to be transported into the brain
More 3-OMD means less L-DOPA enters brain
So inhibiting this (with COMT inhibitors) is beneficial to increase L-DOPA reaching the brain
What are the SEs of COMT inhibitors?
Cardiovascular complications
What percentage of the general population are affected by Schizophrenia?
1%
What groups of symptoms is Schizophrenia comprised of?
Positive symptoms
Negative symptoms
Cognitive deficits
What are the positive symptoms in schizophrenia?
Hallucinations
Delusions
Disorganized thoughts
What are the negative symptoms in schizophrenia?
Reduced speech (alogia)
Lack of emotional and facial expressive (affective flattening)
Diminished ability to begin and sustain activities (avolition)
Decreased ability to find pleasure in everyday (anhedonia)
Social withdrawal (asociality)
What are the cognitive deficits in schizophrenia?
Memory
Attention
Planning
Decision making
What happens once someone has been diagnosed with schizophrenia?
10-20% resolved illness, never returns (with or without treatment)
30-35% illness recurs repeatedly with full recovery after each episode
30-35% illness recurs repeatedly with incomplete recovery and a persistent defective state develops (more pronounced with each successive relapse)
10-20% illness pursues a downhill course from start
What is the role of dopamine in schizophrenia?
Excessive dopamine transmission in the mesolimbic and striatal region leading to positive symptoms (mediated through D2 receptors)
Dopamine deficit in pre-frontal region (mediated by D1 receptors) leads to negative symptoms
What is the evidence that dopamine is involved in schizophrenia?
Dopamine agonists e.g bromocriptine, and amphetamine can induce various psychotic reactions
Typical anti-schizophrenic drugs are dopamine receptor antagonists and there is a strong correlation between antipsychotic potency and activity in blocking D2 receptors
What is the glutamate theory of schizophrenia?
NMDA receptor antagonists e.g. phencyclodine, ketamine etc. produce psychotic symptoms
Reduced glutamate concentrations and glutamate receptor densities in post-mortem schizophrenic brain
In mice with reduced NMDA receptor expression- mice show stereotypical behaviours like schizophrenia and respond to antipsychotic therapy
Glutamate and dopamine exert effects on GABAergic striatal neurons (then project to the thalamus and constitute a sensory ‘gate’)
Too little glutamate (excitatory) or too much dopamine (inhibitory), disables the gate, allowing uninhibited sensory input to reach the cortex
How do glutamate and dopamine relate to the ‘sensory gate’ in schizophrenia?
Glutamate (excitatory) and dopamine (inhibitory) exert effects respectively on GABAergic striatal neurons (then project to the thalamus and constitute a sensory ‘gate’)
Too little glutamate or too much dopamine disables the gate, allowing uninhibited sensory input to reach the cortex
What is the genetic basis of Schizophrenia?
Strong but incomplete hereditary tendency
Risk genes but no single gene responsible
Weak associations of polymorphisms
Neuregulin 1 seems most robust
8 other susceptibility genes (all associated with glutamate or dopamine transmission)
What is the mechanism of antipsychotics? What do they do?
Neuroleptic drugs are antagonists at dopamine ‘D2 like’ receptors
Block other receptors too e.g. 5HT
Treat positive symptoms not negative ones
Delayed effects
Initial increase in DA synthesis declines over time
What kinds of side effects can antipsychotics cause?
Exprapyramidal Sedation Weight gain Hyperglycaemia Anticholinergic Orthostatic hypotension
What are atypical antipsychotics?
Antipsychotics that are second generation compounds producing less extrapyramidal side effects
What can neuroleptics be used to?
Anti-psychotic
Anti-emetic
Outline the anti-emetic effect of neuroleptics
Blocking dopamine receptors in the chemoreceptor trigger zone
E.g. Phenothiazine= effective at controlling vomiting and nausea induced by drugs (e.g. chemotherapy) , renal failure
Many neuroleptics also have blocking action at histamine receptors so are effective at controlling motion sickness
What are the extrapyramidal SEs of antipsychotics?
Acute dystonia
Tardive dyskinesias
What are are SEs of antipsychotics?
Extrapyramidal (acute dystonia and tardive dyskinesias)
Endocrine effects (prolactin secretion)
Blocking alpha adrenoceptors= orthostatic hypotension
Blocking 5HT Rs= weight gain
Blocking cholinergic muscarinic receptors= anti-muscarinic side effects e.g blurring of vision, increased intra-ocular pressure, dry mouth, constipation, urinary retention
How do antipsychotics lead to breast swelling?
DA inhibits PL secretion via D2 receptors
Lowering D2 Rs means increased serum prolactin concentrations
Breast swelling in men and women and sometimes lactation in women
What is acute dystonia? How does it relate to antipsychotics?
Blockade of DA Rs in nigrostriatal system can induce PD-like side effects
Involuntary movements e.g. muscle spasm, protruding tongue, fixed upward gaze, neck spasm etc.
Often accompanied by Parkinson’s features
Occur in the first few weeks, often declining with ongoing therapy. Reversible on drug withdrawal or anti-cholinergics
What is tardive dyskinesia? How does it relate to antipsychotics?
Blockade of DA Rs in nigrostriatal system can induce PD-like side effects
Involuntary movements, often involving the face and tongue, but also limb and trunk
Occur in about 20% of patients after several months or years of therapy (hence ‘tardive’)
More associated with typical antipsychotics
Made worse by drug withdrawal or anti-cholinergics
May be related to proliferation in pre-synaptic DA D2 receptors or glutamate excitotoxic striatal neurodegeneration
What does general anaesthesia do?
Loss of consciousness (at low concentration)
Suppression of reflex responses (at high concentration)
Loss of consciousness Suppression of reflex responses Relief of pain (analgesia) Muscle relaxation Amnesia Relief of pain (analgesia) Muscle relaxation Amnesia
List types of general anesthetics
GASEOUS/INHALATION Nitrous oxide Diethyl ether Halothane Enflurance
INTRAVENOUS
Propofol
Etomidate
Structurally dissimilar
Outline the mechanism of action of general anaesthetics
Either reduced neuronal excitability or altered synaptic function
Different for IV and inhalation
What did Meyer and Overton show with anaesthetic? What were the problems with this?
More lipid soluble= better anaesthetic
Anaesthetic potency increases in direct proportion with oil:water partition coefficient
Problems:
At relevant anaesthetic concentrations, change in bilayer was minute
2. How would this change impact membrane proteins?
What are the targets of inhaled GAs?
ALTERED SYNAPTC FUNCTION
1) GABA Rs (halogenated compounds-> enhance depressive)
Via interaction with glycine receptors (homologous to GABA A Rs) and GABA A
a1 subunit-> suppression of reflex responses
2) NMDA-type glutamate Rs (NO and ketamine-> diminish excitatory)
Blocked (probably by competing with co-agonist glycine)
3) Neuronal nicotinic ACh receptor
Decreased activity with more halogenated compound
REDUCED NEURONAL EXCITATION
4) TREK (background leak) K channel
Enhanced-> increased hyperpolarisation of neurones for longer (harder to excite)
What are the targets of IV GAs?
Via GABA A receptors (enhancement-> depressant effects)
GABA RS
B3 subunit common on GABA A-> suppression of reflex responses
a3 subunit common on GABA A-> amnesia
How does neuroanatomy affect the loss of consciousness function of GAs?
Depress excitability of
thalamocortical neurons
Influences reticular
activating neurons
(RAS carries all the cortical varieties of consciousness)
- ACh released from cholinergic nerve terminals projecting from RAS to the thalamus and cortex
- Anaesthetics can directly hyperpolarize thalamocortical neurons by activating TREK channels or potentiating GABA A receptors
How does neuroanatomy affect the suppression of reflex responses by GAs?
Depression of reflex pathways in spinal cord
Possible because of high density of GABA Rs in the DH of the SC
How does neuroanatomy affect the amnesia of GAs?
A5 subunit of the GABAAR is rare but lots in hippocampus
GAs decrease synaptic transmission in hippocampus and amygdala
What is the difference in administration between inhalation and intravenous anaesthetic inhalation?
IV
Inject drug into blood
Then can freely access target tissue (brain)
How long it lasts is dependent on its metabolism by the liver
INHALED
Less well they dissolve in blood= quicker the onset of action
Drug diffuses from airway-> alveoli-> across into blood
Depends of blood:gas coefficient
What happens when an inhaled a drug has a high blood:gas coefficient?
High blood:gas coefficient (less lipid soluble) so higher percentage disappears into blood, slower process into brain (slower induction time)
Takes longer until equilibrium with the brain partial pressure of the gas
What happens when an inhaled a drug has a low blood:gas coefficient?
Low blood:gas coefficient (more lipid soluble) so lower percentage disappears into blood, faster process into brain (faster induction time)
Quicker to equilibrium with the brain partial pressure of the gas
What is the blood:gas coefficient?
The blood/gas partition coefficient describes how the gas will partition itself between the two phases (blood and brain) after equilibrium has been reached
True or false; a poorly soluble GA will have a slow onset of action?
False
Will be rapid
Inhalation vs intravenous GA?
IV (often first for induction)
Fast induction
Less coughing and excitatory phenomena
NB. Not in control, reliant on liver metabolism
INHALATION (often good to maintain depth and controlling)
Rapidly eliminated
Rapid control of depth of anaesthesia (brain and lungs very similar levels so quick to reverse)
NB. Airway irritation can lead to the cough reflex being initiated
What GAs are commonly used in GAs?
To lose consciousness and suppress reflexes:
Induction= propofol (IV)
Maintenance= enflurane (inhalation)
Alongside GAs, what drugs would you use in surgery?
Relief of pain (analgesia)= opioid (e.g. IV fentanyl)
Muscle relaxation = neuromuscular blocking drugs (e.g. suxamethonium
Amnesia= benzodiazepines (e.g. IV midazolam)
What is a local anaesthetic?
A drug which reversibly blocks neuronal conduction when applied locally
List examples of local anaesthetics
Procaine *Cocaine Tetraqcaine (amethocaine) Cinchocaine (dibucaine) *Lidocaine (lignocaine) Prilocaine Bupivacaine Benzocaine (doesn't have amine side chain)
What are the structural components of local anaesthetics?
Aromatic region (important for mechanism of action and metabolism)
Ester or amide bond
Basic amine side-chain
NB.
Ester= procaine, cocaine, tetraqcaine, cinchocaine
Amide= lidocaine, prilocaine, bupivacaine
How do local anaesthetics interact with sodium channels?
HYDROPHILLIC PATHWAY
LA (a weak base) is injected
Non-ionised form needed as it passes through connective tissue sheath and passes inside axon (e.g. nociceptive neuron)
Equilibrium established between ionised and non-ionised form
Cationic (ionised) form is needed as it has the LA activity by binding to inside of VSSC-> stereochemically blocks channel (reduces generation and propagation of APs)
Use-dependent because binding site is inside ion channel (needs to be open)
HYDROPHOBIC PATHWAY
Lipid soluble LAs e.g. benzocaine
Passes towards inside of axon (can drop into channel and ionize and block channel even if it isn’t being used)
What are the effects of LAs?
Prevent generation and conduction of APs
Do NOT influence resting membrane potential
May also influence channel gating and surface tension
Selectively block small diameter fibres and non-myelinated fibres
What is the pKa of LAs?
8-9
Weak bases
How can LAs be administered?
SURFACE
INFILTRATION ANAESTHESIA
IV REGIONAL ANAESTHESIA
NERVE BLOCK ANAESTHESIA
Outline surface LA administration
Mucosal surface (mouth, bronchial tree)
Spray (or powder)
High concentrations-> systemic toxicity
Outline infiltration anaesthesia
Directly into tissues-> sensory nerve terminals
Minor surgery
Adrenaline co-injection (NOT extremities)
Outline IV regional anaesthesia
IV distal to pressure cuff
Limb surgery
Systemic toxicity of premature cuff release
Outline nerve block anaesthesia
Close to nerve trunks e.g. dental nerves
Widely used- low doses, slow onset
Vasoconstrictor co-injection
Outline spinal anaesthesia
Sub-arachnoid space-> spinal roots
Abdominal, pelvic, lower limb surgery
Reduced BP-> prolonged headache
Glucose (increased specific gravity)
Outline epidural anaesthesia
Fatty tissue of epidural space-> spinal roots
Abdominal, pelvic, lower limb surgery and painless childbirth
Slower onset-> higher doses
More restricted action (less effect on BP)
Lidocaine Property= Absorption (mucous membranes)= Plasma protein binding= Metabolism= Plasma half life=
Property= amide Absorption (mucous membranes)= good Plasma protein binding= 70% Metabolism= hepatic N-dealkylation Plasma half life=2h
Cocaine Property= Absorption (mucous membranes)= Plasma protein binding= Metabolism= Plasma half life=
Property= good Absorption (mucous membranes)= good Plasma protein binding= 90% Metabolism= liver and plasma, non-specific esterases Plasma half life= 1h
What are the unwanted effects of lidocaine?
CNS (paradoxical)
Stimulation
Restlessness, confusion
Tremor
CVS (Na channel blockage)
Myocardial depression
Vasodilatation
Decreased BP
What are the unwanted effects of cocaine?
CNS (sympathetic actions)
Euphoria
Excitation
CVS (sympathetic actions)
Increased CO
Vasoconstriction
Increased BP
Lidocaine:
A: Inhibits reuptake of 5-hydroxytryptamine
B: Blocks voltage-gated K+ channels
C: Is a competitive muscarinic cholinoceptor antagonist
D: Is a weak base
E: Is a general anaesthetic
D: Is a weak base
Which ONE of the following statements about local anaesthetics is INCORRECT? They:
A: Cause blockade of voltage-sensitive sodium channels
B: Block rapidly firing neurones more readily than more slowly firing neurones
C: Enhance action potential propagation
D: Are largely ionised at physiological pH
E: Have their durations of action increased if injected with adrenaline
C: Enhance action potential propagation
What kind of disorder is depression?
Affective disorder (a type of psychosis)
What are the symptoms of depression?
EMOTIONAL( psychological) Misery, apathy, pessimism Low self-esteem Loss of motivation Anhedonia
BIOLOGICAL (somatic)
Slowing of thought AND action
Loss of libido
Loss of appetite, sleep disturbance
What is unipolar depression or depressive disorder?
Mood swings in same direction
Relatively late onset
Reactive depression
- stressful life events
- non-familial
Endogenous depression
- unrelated to external stresses
- familial pattern
Drug treatment same for endogenous and reactive
What is bipolar depression or manic depression?
Oscillating depression and mania
Less common, early adult onset
Strong hereditary tendency
Drug treatment (Lithium)
What is ECT?
Electroconvulsive therapy
Electroconvulsive therapy (ECT) is a procedure, done under general anaesthesia, in which small electric currents are passed through the brain, intentionally triggering a brief seizure
Seems to cause changes in brain chemistry that can quickly reverse symptoms of certain mental illnesses
What is the monoamine theory of depression?
Depression= functional deficit of central MA transmission Mania= functional excess
Main biochemical theory of depression
Down regulation of a2, B NA and 5HT receptors
HPA axis (increased CRH levels) Hippocampal neurodegeneration
What is the pharmacological evidence supporting the monoamine hypothesis of depression?
Tricyclic antidepressants-> block NA and 5HT reuptake-> improves mood
MAO inhibitors-> increase stores of NA and 5HT-> improves mood
Reserpine-> inhibits NA and 5HT storage-> lowers mood
a-methyltyrosin-> inhibits NA synthesis-> lowers mood (calms manic patients)
Methyldopa-> inhibits NA synthesis-> lowers mood
ECT-> increases CNS responses to NA and 5HT> improves mood
What is the mode of action of TCAs?
E.g. amitriptyline
Neuronal monoamine re-uptake inhibitors
- Enhance NA and 5HT in the brain
- Less effective on DA transport
Also other receptor actions
- a2
- mAchRs
- histamine
- 5-HT
Delayed down-regulation of B-adrenoceptors and 5HT Rs
What are the pharmacokinetics of TCAs?
Rapid oral absorption
Highly PPB (90 - 95%)
Hepatic metabolism (active metabolites -> renal excretion of glucuronide conjugates)
Plasma half life= 10-20 hrs
What are the unwanted effects of TCAs?
AT THERAPEUTIC DOSES (given o.d. once reaches baseline)
Atropine-like effects (amitriptyline)
Postural hypotension (vasomotor centre)
Sedation (H1 antagonism)
ACUTE TOXICITY
CNS= excitement, delirium, seizures -> coma, respiratory depression
CVS= cardiac dysrhythmias, ventricular, fibrillation and sudden death
NB. Risk of attempted suicide
What are the main drugs TCA interact with?
PPB= increased TCA effects (aspirin, phenytoin)
Hepatic microsomal enzymes= increased TCA effects (neuroleptics; oral contraceptives)
Potentiation of CNS depressants (alcohol)
Antihypertensive drugs (monitor closely)
What is the mode of action of MAOIs?
E.g. phenelzine
MAO-A: NA and 5HT
MAO-B: DA
Most are non-selective MAOIs
Irreversible inhibition so long duration of action
Rapid effects= increased cytoplasmic NA and 5HT
Delayed effects= clinical response, downregulation of B-adrenoceptors and 5HT2 receptors
Also inhibit other enzymes
Outline the pharmacokinetics of MAOIs
Rapid oral absorption
Short plasma half life (few hrs) but longer duration of action
Metabolised in liver-> excreted in urine
What are the unwanted effects of MAOIs?
Atropine-like effects (< TCAs)
Postural hypotension (common)
Sedation (seizures in overdose)
Weight gain (possibly excessive)
Hepatotoxicity (hydrazines- rare)
What are the drug interactions of MAOIs?
Very serious problem
‘Cheese reaction’= tyramine-containing foods and MAOI -> hypertensive crisis (throbbing headache, increased BP, intracranial haemorrhage
MAOIs and TCAs -> hypertensive episodes (avoid)
MAOIs and pethidine -> hyperpyrexia, restlessness, coma and hypotension
Moclobemide: reversible MAO-A inhibitor (RIMA) can reduce drug interactions but also decreases duration of action
Why is moclobemide useful?
Rtyramine-containing foods and MAOI -> hypertensive crisis (throbbing headache, increased BP, intracranial haemorrhage
What is the mode of action for SSRIs?
E.g. fluoxetine
Selective 5-HT re-uptake inhibition
Less troublesome side-effects, safer in overdose
But less effective vs severe depression
Outline the pharmacokinetics of SSRIs
Oral administration
Plasma half life= 18-24 hrs
Delayed onset of action (2-4 weeks)
Fluoxetine competes with TCAs for hepatic enzymes (avoid co-administration)
What are the unwanted effects of SSRIs?
Nausea, diarrhoea, insomnia and loss of libido
Interact with MAOIs (avoid co-administration)
Increased suicidality (< 18 years old)
Fewer SEs than TCAs and MAOIs
What is the most commonly prescribed antidepressant drug?
Fluoxetine (‘Prozac’)= an SSRI
What is venlafaxine?
Dose-dependent reuptake inhibitor
5HT > NA > DA
2nd Line treatment for severe depression
What is mertazapine?
a2 receptor antagonist
Increases NA and 5HT release
Other R interactions (sedative)
Useful in SSRI-intolerant patients
What are the main drug types used to treat depression?
TCAs
MAOIs
SSRIs
Tricyclic antidepressant drugs (TCAs) work largely by:
A: Antagonism at 5HT receptors B: Inhibiting central DA reuptake C: Blocking VSCCs D: Inhibition of central NA & 5HT reuptake E: Enhancement of the action of GABA
D: Inhibition of central NA & 5HT reuptake
The ‘cheese reaction’ is most likely to be caused by:
A: Tricyclic antidepressants (TCAs) B: Selective serotonin reuptake inhibitors (SSRIs) C: Monoamine oxidase inhibitors (MAOIs) D: Reversible MAO-A inhibitors (RIMAs) E: α2-Adrenoceptor antagonists
C: Monoamine oxidase inhibitors (MAOIs)
Outline the epidemiology of Alzheimer’s disease
Main risk factor= age
Huge economic cost in the UK but low research investment
AD and dementia are leading cause of death in UK
Genetic basis= APP, PSEN, ApoE (hereditary= 8%)
What are the symptoms of AD?
Memory loss= especially recently acquired information
Disorientation and confusion= forgetting where they are
Language problems= stopping in the middle of a conversation
Personality changes= becoming confused, fearful, anxious
Poor judgement= such as when dealing with money
What is the normal physiological process of amyloid?
Amyloid precursor protein (APP) cleaved by alpha-secretase
sAPPa released but C83 fragment remains
C83 is digested by y-secretase
Products removed
What is the pathophysiological process of amyloid (amyloid hypothesis)?
APP cleaved by beta secretase
sAPPb released but C99 fragment remains
C99 digested by y-secretase releasing B-amyloid protein
AB forms toxic aggregates
What is the normal physiological tau process?
Soluble protein present in axons
Important for assembly and stability of microtubules (important for structure and function of neuronal cells)
What is the pathophysiological tau process (tau hypothesis) in AD?
Hyperphosphorylated tau is insoluble-> self-aggregates to form neurofibrillary tangles
These are neurotoxic and result in microtubule instability
What is the inflammation hypothesis of AD?
Involves microglia
Phenotype changes of specialised CNS immune cells (similar to macrophages)
Increased release of inflammatory mediators and cytotoxic proteins
Increased phagocytosis
Decreased levels of neuroptective proteins
Increased inflammatory load on NS
What are the main hypotheses for AD?
Amyloid hypothesis (cleavage by beta secretase)-> AB plaques Tau hypothesis (hyperphosphorylated)-> neurofibrillary tangles and neuronal instability Inflammation hypothesis (activity of microglial cells)-> inflammatory load on NS increased
What drug classes can be used to treat AD?
Anticholinesterases= donepezil, rivastigmine, galantamine
NMDA receptor blockers= memantine
Treat symptoms not pathophysiology
What anticholinesterases are used to treat AD?
DONEPEZIL
Reversible cholinesterase inhibitor
Long plasma half-life
RIVASTIGMINE
Pseudo-reversible AChE and BChE inhibitor
8 hour half-life
Reformulated as transdermal patch
GALANTAMINE
Reversible cholinesterase inhibitor
7-8 hour half-life
7 nAChR agonist
What NMDA receptor blocker is used to treat AD?
MEMANTINE
Use-dependent non-competitive NMDA receptor blocker with low channel affinity
Only licensed for moderate-severe AD
Long plasma half-life
What are the major AD treatment failures that have occurred?
y-secretase inhibitors
- Tarenflurbil (binds to APP molecule) and semagacestat (small y-secretase inhibitor) failed clinical trials
B-amyloid immunotherapy
- active= vaccines (in development)
- passive= antibodies e.g. solanezumab and bapineuzumab (humanised monoclonal antibodies)
Tau aggregation
- In clinical trials now= methylene blue (currently used for methaemoglobinaemia)
What are the main differences in the membranes of gram positive and negative bacteria and mycolic bacteria?
GP=prominent peptidoglycan cell wall
GN= outer membrane with lipolysaccharides
MB= outer mycolic acid layer
How are prokaryotic proteins synthesised?
NUCLEIC ACID SYNTHESIS
Dihydropterate (DHOp) produced from paraminobenzoate (PABA)
Converted into dihydrofolate (DHF)
Tetrahydrofolate (THF) produced from DHF by DHF reductase
THF is important in DNA synthesis
DNA REPLICATION DNA gyrase (topoisomerase-> releases tension)
PROTEIN SYNTHESIS
Ribosomes produce protein from RNA templates
Differ from eukaryotic ribosomes
How do eukaryotics and prokaryotic ribosomes differ?
P= 30s and 50s E= 40s and 60s
How can antibiotics inhibit protein synthesis?
NUCLEIC ACID SYNTHESIS
Sulphonamides inhibit DHOp synthase
Trimethoprim inhibits DHF reductase
DNA REPLICATION
Fluoroquinolones (e.g. Ciprofloxacin) inhibit DNA gyrase and topoisomerase IV
The rifamycins (e.g. Rifampicin) inhibits bacterial RNA polymerase
PROTEIN SYNTHESIS
Ribosomes can be inhibited (e.g. macrolides like erythromycin, aminoglycosides, chloramphenicol and tetracyclines)
How are bacterial walls synthesised?
PEPTIDOGLYCAN (PtG) SYNTHESIS
A pentapeptide is created on N-acetyl muramic acid (NAM)
N-acetyl glucosamine (NAG) associates with NAM forming PtG
PtG TRANSPORTATION
PtG is transported across the membrane by bactoprenol
PtG INCORPORATION
PtG is incorporated into the cell wall when transpeptidase enzyme cross-links PtG pentapeptides
How do bacterial wall inhibitors work?
PtG SYNTHESIS
Glycopeptides (e.g. Vancomycin) bind to the pentapeptide preventing PtG synthesis
PtG TRANSPORTATION
Bacitracin inhibits bactoprenol regeneration preventing PtG transportation
PtG INCORPORATION
B-lactams bind covalently to transpeptidase inhibiting PtG incorporation into cell wall
CELL WALL STABILITY
Lipopeptide - (e.g. daptomycin) disrupt Gram +ve cell walls
Polymyxins - binds to LPS and disrupts Gram -ve cell membranes
Give examples of beta lactam antibiotics
Carbapenems
Cephalosporins
Penicillins
A patient with a chest infection is prescribed a beta-lactam antibiotic. Which one of the following drug classes is a beta-lactam antibiotic? Carbapenems Glycopeptides Lipopeptides Macrolides Sulphonamides
Carbapenems
Considering the bacterial structure and the drug mechanism of action, which class of drug is less likely to be effective in the treatment of E Coli infections? Glycopeptides Macrolides Rifamycins Quinolones Sulphonamides
Glycopeptides
Because e. coli is GN
What are the main causes of antibiotic resistance?
Unnecessary prescription
(50% of antibiotic prescriptions not required)
Livestock farming
(30% of UK antibiotic use in livestock farming)
Lack of regulation
(OTC availability in Russia, China, India)
Lack of development
(No new antibiotic drug classes in years)
What are the types of antibiotic resistance?
Additional target
Different DHF reductase enzyme produced
Hyperproduction
Over-production of DHF reductase
Drug Permeation
Decreased drug influx, increased efflux systems
Enzyme alteration
Mutations in DNA gyrase enyme
Destruction enzymes
Production of beta-lactamase
How does ‘additional target’ antibiotic resistance work? Give an example
Bacteria produce another target that is unaffected by the drug
E.g. E. Coli produce different DHF reductase enzyme making them resistant to trimethoprim
How does ‘hyperproduction’ antibiotic resistance work? Give an example
Bacteria significantly increase levels of DHF reductase
E.g. E. Coli produce additional DHF reductase enzymes making trimethoprim less effective
How does ‘drug permeation’ antibiotic resistance work? Give an example
Alteration to the enzyme targeted by the drug
Enzyme still effective but drug now ineffective
E.g. S. Aureus= mutations in the ParC region of topoisomerase IV confers resistance to quinolones
How does ‘enzyme alteration’ antibiotic resistance work? Give an example
Reductions in aquaporins and increased efflux systems
E.g. Primarily of importance in GN bacteria
How does ‘destruction enzyme’ antibiotic resistance work? Give an example
B-lactamases hydrolyse C-N bond of the B-lactam ring
E.g. Penicillins G and V (GP) Flucloxacillin and Temocillin -> lactamase resistant Amoxicillin->broad spectrum GN activity Co-administered with Clavulanic acid
Why is amoxicillin sometimes given with clavulanic acid?
Stops it being beta lactam resistant
How can fungal infections be classified?
Can be classified in terms of tissue/organs
Superficial= outermost layers of skin Dermatophyte= skin, hair or nails Subcutaneous= innermost skin layers Systemic= primarily respiratory trac
What are the most common categories of anti-fungal drugs in the UK?
Azoles= fluconazole Polyenes= amphotericin
How do azoles work?
Anti-fungalsls (inhibits membrane sterol synthesis)
Inhibit cytochrome P450-dependent enzymes involved in membrane sterol synthesis
Fluconazole (oral) -> candidiasis and systemic infections
How do polyenes work?
Anti-fungals (form membrane channe
Interact with cell membrane sterols forming membrane channels
Amphotericin (IV) -> systemic infections
Following surgery for mitral valve prolapse a patient is placed on anticoagulant and antiplatelet therapy using warfarin and aspirin. Describe the mechanisms of actions of these two drugs (2 marks)
Warfarin- vitamin K antagonist
Aspirin- CO inhibitor
Regular blood monitoring was subsequently initiated with the aim to maintain the international normalised ratio (INR) between 3-3.5. Explain the potential complications of an INR below this range AND above this range (2 marks)
Below the range increases risk of thrombosis
Above the range increases risk of bleeding
Unfortunately, the patient develops infective endocarditis and is prescribed a penicillin, an aminoglycoside and a rifamycin antibiotic. Describe how these three drugs work (2 marks)
Pencilin- binds covalently to transpeptidase inhibiting PtG incorporation into cell wall
Rifamycin- inhibits bacterial RNA polymerase
Aminoglycoside- protein synthesis inhibitor
What are the main targets for antibiotics?
IC TARGETS Nucleic acids DNA gyrase RNA polymerase Bacterial ribosomes
CELL MEMBRANE TARGETS
Peptidoglycan (PtG) synthesis PtG incorporation
Membrane stability
Differentiate between the drugs used to treat fungal infections
Azoles= inhibit ergosterol production Polyenes= bind to ergosterol and create pores
Describe the structure of a virus
Envelope proteins
Lipid envelope
Capsid (protein shell surrounding the genetic material of the virus)
Genetic material (RNA and DNA)
Outline what causes viral hepatitis?
Liver hepatocytes
Hep B involves reverse transcriptase as a drug target
Hep C involves RNA polymerase as a drug target
Only chronic infection requires treatment
How is chronic hep B treated?
Tenofovir nucleotide analogue, given sometimes with Peginterferon alfa
How is chronic hep C treated?
Ribavirin and Peginterferon alfa
Ribavirin nucleoside analogue prevents viral RNA synthesis
Boceprevir protease inhibitor
Most effective against Hep C genotype 1
What do hep C treatments depend on?
Aim to cure the virus
Depends on:
HCV genotype (genetic structure of the virus)
Viral load
Past treatment experience
Degree of liver damage
Ability to tolerate the prescribed treatment
Need for liver transplant
Outline the HIV life cycle
ATTACHMENT AND ENTRY
Viral membrane proteins interact with leukocyte membrane receptors
- HIV Glycoprotein (GP)120 attaches to CD4 receptor
- GP120 also binds to either CCR5 or CXCR4
GP41 penetrates host cell membrane
Viral capsid endocytosis
REPLICATION AND INTEGRATION
Within cytoplasm- reverse transciptase enzyme converts viral RNA into DNA
DNA transported into nucleus and integrated into host DNA
ASSEMBLY AND RELEASE
Host cell’s ‘machinery’ utilised to produce viral RNA and essential proteins
Virus is assembled within cell -> mature virion is released
How do HIV entry inhibitors interfere with attachment and entry in the HIV life cycle?
ENFUVIRTIDE
Binds to HIV GP41 transmembrane glycoprotein
Subcutaneous- people don’t like it
MARAVIROC
Blocks CCR5 chemokine receptor
How do HIV replication inhibitors interfere with replication in the HIV life cycle?
Nucleoside RT inhibitors
Activated by 3 step phosphorylation process
E.g. Zidovudine
Nucleotide RT inhibitors
Fewer phosphorylation steps required
E.g. Tenofovir
Non-nucleoside RT inhibitors
No phosphorylation required
Not incorporated into viral DNA
E.g. Efavirenz
How do HIV integration inhibitors interfere with integration in the HIV life cycle?
Viral integrase inserts viral DNA into host DNA
Inhibited by integrase inhibitors e.g. raltegravir
How do HIV protease inhibitors interfere with assembly and release in the HIV life cycle?
HIV protease cleaves Gag precursor protein (which encodes all viral structural proteins)
Protease inhibitors (PI) Saquinavir (always given with ritonavir)
Why is ritonavir given with protease inhibitors e.g. saquinavir?
Low dose Ritonavir reduces PI metabolism ( co-administered as ‘booster’)
Outline the herpes simplex virus
VIROLOGY
Double-stranded DNA
Surrounded by tegument and enclosed in a lipid bilayer
TROPISM
HSV-1 -> cold-sores
HSV-2 -> genital herpes
How is herpes simplex virus treated?
Acylcovir
A nucleoside analogue
Outline the influenza virus
VIROLOGY
Multipartite single stranded RNA virus
Envelope protein neuraminidase -> release
TROPISM
Nose, throat and bronchi
How is influenza treated?
Doesn’t fully work
Neuraminidase inhibitor = oseltamivir
Distinguish between different types of virus and describe how they use the host cell to replicate
HIV= retrovirus, leukocytes
Hepatitis= DNA and RNA viruses, hepatocytes
Herpes Simplex= DNA virus
Influenza= RNA virus
Summarise the mechanisms of action of antiretroviral drugs
Entry inhibitors= Enfuvirtide and maraviroc
RT inhibitors= nucleoside analogues (Zidovudine) and non-nucleoside analogues (Efavirenz)
Integrase inhibitors= raltegravir
Protease inhibitors= saquinavir
Describe the actions of other (non-antiretroviral) antiviral drugs
Nucleotide analogues= ribavirin, acyclovir
Protease inhibitors= boceprevir
Neuraminidase inhibitors= oseltamivir
Outline general seizures
Begins simultaneously in both hemispheres of brain
Genetic disorder?
Types of general seizure include:
Tonic-clonic seizures
Absence seizures
Myoclonic seizures
What are the types of general seizure?
Tonic-clonic seizures
Absence seizures
Myoclonic seizures
Outline partial or focal seizures
Begins within a particular area of brain and may spread out
May be the result of an injury or insult to the brain
More common in adults
Types of seizure include:
Simple or complex partial
Temporal lobe epilepsy
What are the types of partial seizures?
Simple or complex partial
Temporal lobe epilepsy
How can you measure brain activity?
Electroencephalography (EEG)
Magnetoencephalography (MEG)
Functional magnetic resonance imaging (fMRI)
What are the brain firing patterns?
High to low Hz
Gamma: awareness- hyperactive Beta: awareness- thinking Alpha: awareness- relaxed Theta: drowsiness, meditation Delta: deep-sleep
What happens to brain firing patterns in seizures?
Irregular and asynchronous firing patterns due to neuronal over-activity
What happens in a glutamatergic synapse?
VGSC opens -> membrane depolarisation
VGKC opens -> membrane repolarisation
Ca2+ influx through VGCCs -> vesicle exocytosis
Synaptic vesicle associated (SV2A) protein allows vesicle attachment to presynaptic membrane
Glutamate activates excitatory post-synaptic receptors (e.g. NMDA, AMPA and kainate receptors)
What is carbamazepine?
Voltage-gated Na channel blocker
Used for partial seizures and tonic-clonic seizures
Stabilises inactive state of channel
Outline the phamacokinetics of carbamazepine
Induces the expression of hepatic enzymes
16-30 hour half-life
Dangerous in individuals with HLA-B*1502 allele
What is phenytoin?
Voltage-gated Na channel blockers
Indicated for most forms of epilepsy (not absence)
Class 1b channel blocker
Outline the pharmacokinetics of phenytoin
Fast onset (10mins) and long half-life (10-20 hours
What is retigabine?
VGKG enhancer
Potassium channel opener specific for KV7 alpha subunit Only licensed for adjunctive treatment Fast onset (30mins); 10h half-life
What is ethosuximide?
VGCC blocker
T-type Ca2+ channel antagonist
Mainly used for absence seizures
Long half-life (50 hours)
What is gabapentin?
VGCC blocker
Thought to inhibit a2d subunit
Indicated for partial seizures
What is levetiracetam?
Anti-convulsant
Affects glutamate exocytosis
Binds to synaptic vesicle associated protein (SV2A) preventing glutamate release
Monotherapy for focal seizures
Fast-onset (1 hour), half-life (10 hours)
What is topiramate?
Anti-convulsant
Inhibits GluK5 subunit of kainate receptor
Also affects VGSCs and GABA receptors
Indicated for most types of epilepsy
Fast-onset (1 hour), long half-life (20 hours)
What is perampanel?
Anti-convulsant
Selective inhibitor of AMPA receptor
Only licensed for as an adjunct for partial seizures
Fast-onset (1 hour), long half-life (24 hours)
Give an overview of drugs that interfere with glutamatergic synapse?
VGSC antagonist: e.g phenytoin, carbamazepine
VGKC enhancer: retigabine
VGCC antagonist: ethosuximide (T-type antagonist); gabapentin (2 blocker)
SV2A inhibitor: Llvetiracetam
Glutamate receptor antagonist: perampanel (GluA), topiramate (GluK)
What happens in a GABAergic synapse?
GABA can be released tonically and also following neuronal stimulation
GABA activates inhibitory post-synaptic GABAA receptors
GABAA receptors are chloride (Cl-) channels -> membrane hyperpolarisation
GABA is taken up by GAT
GABA is metabolised by GABA transaminase (GABA-T)
Outline clonazepam
Anticonvulsant
GABAAR drug
Benzodiazepine (BZD) indicated for ALL forms of epilepsy
Fast-onset (2h), long half-life (30h)
Outline phenobarbital
Anticonvulsant
GABAAR drug
Indicated for most forms of epilepsy except absence seizures
Acts as a sedative in adults and may cause behavioural disturbances in children
Interacts with numerous drugs
Very fast-onset (20mins), long half-life (60h)
Outline tiagabine
Anticonvulsant
Selective inhibitor of GAT-1 (GABA transporter)
Adjunctive treatment for partial seizures
Fast onset (45min), short half-life (6h)
Outline sodium valproate
Anticonvulsant
Indicated for ALL forms of epilepsy
Inhibits GABA transaminase
Fast onset (1h), half-life (12h)
Outline vigabatrin
Anticonvulsant
Irreversibly inhibits GABA transaminase enzyme
Monotherapy for infantile spasm or as an adjunct for partial seizures
What drugs are used for tonic-clonic seizures?
Valproate
What drugs are used for absence seizures?
Valproate
What drugs are used for myoclonic seizures?
Topiramite
Ethosuximide
Valproate
What drugs are used for partial or focal seizure seizures?
Carbamazepine
How can you treat epilepsy?
Glutamate inhibition= VGSCs, VGKCs, VGCCs, SVA2 and GluRs
GABA enhancement= GABARs, GABA transporter and GABA transaminase
