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
