Pharmacology and Therapeutics Flashcards
What are the efferent outputs from the CNS and give their main functions.
Describe the two pathways of the autonomic nervous system. Explain three functions.
Autonomic nervous system: exocrine glands, smooth muscle, cardiac muscle, metabolism, host defence
Somatic nervous system: skeletal muscle - diaphragm and respiratory muscle
Neuroendocrine system: growth, metabolism, reproduction, salt & water balance, host defence
Sympathetic: fight and flight
Parasympathetic: rest and digest
1 - sympathetic, 2 - parasympathetic
Eye: dilation of pupil, constriction of pupil and contraction of ciliary muscle
Salivary glands: thick, viscous secretion, copious, watery secretion
Tranches and bronchioles: dilation, constriction
Skin: piloerection, increased sweating (cholinergic)
Heart: increase rate and contractility, decrease
Liver: glycogenolysis, gluconeogenesis
Gastrointestinal: decrease motility and tone, sphincter contraction, increase motility, tone and secretions
Adipose: lipolysis
Blood vessels: dilation in skeletal muscle and constriction to skin, mucous membranes and splanchnic area
Kidney: increased renin secretion
Ureter and bladder: relax detrusor muscle, constriction of trigone and sphincter, contract detrusor and relax
Pupillary constriction
Cephalic (secretions) and gastric (motility/ secretions) phases of gastric secretion, vagus nerve
Basal control of heart rate - inhibition neurone
Explain the neurotransmitters involved in the autonomic and somatic nervous systems
Parasympathetic: cranial/sacral - long pre-ganglionic fibre and short post-ganglionic fibre.
Acetycholine at both synapses.
Discrete/localised (little divergence, 1:1 pre vs post, mostly one function at a time)
Sympathetic: thoracic/lumbar - short pre-ganglionic fibre
ACh at first, NA at second
Also ACh to adrenal medulla and then A and NA via bloodstream
One exception ACh and ACh for sweat glands
Coordinated response (very divergent up to 1:20)
In somatic, only one fibre releasing ACh to skeletal muscle
Explain the receptors involved in the pathways.
Acetylcholine
First = nicotinic, second = muscarinic
Nicotinic stimulated by nicotine/ acetylcholine and is type 1 - ionotropic (fast transmission) - ligand gated ion channels
5 subunits alpha, beta, gamma, delta, e
Subunit combo determines ligand binding properties of receptors (two main types of nicotinic - ganglionic and muscle)
Muscle - 2 alpha, beta, delta, e
Ganglion - 2 alpha, 3 beta
Effects of ACh relatively weak, needed high conc. of ACh
Throughout ANS so manipulating receptor can affect whole ANS.
Muscarinic
Post ganglion is parasympathetic
Stimulated by muscarinic/ acetylcholine
Type 2 - G-protein coupled
Subtypes of muscarinic cholinoceptors
M1 - neural (CNS), stomach, salivary glands (forebrain - learning and memory)
M2 - cardiac (brain - inhibitory autoreceptors)
M3 - exocrine and smooth muscle, salivary glands, bronchial/visceral smooth muscle, sweat glands, eye(hypothalamus - food intake)
M4 - periphery: prejunctional nerve endings (inhibitory) - x
M5 - striatal dopamine release - x
M1, M3, M5, Gq, increase IP3 and DAG -> PLC increase
M2, M4, GI, cAMP decrease
Adrenoceptors Post-ganglionic sympathetic fibres (sweat glands, muscarinic) Stimulated by NA/A Type 2 - G-protein coupled Subtypes - a1, a2, b1, b2
Describe the enteric nervous system.
This can affect gut function without communicating with brain, brain can still exert an influence
Sensory neurone connected to mucosal chemoreceptors and stretch receptors detect chemical substances in the gut lumber or tension in gut wall caused by food.
Info relayed to submucosal and myenteric plexus via interneurones.
Motor neurones release acetylcholine/substance P to contract smooth muscle or nitric oxide/vasoactive intestinal peptide to relax
What do we need to consider when describing the effect of all drugs?
What is the drug target? Adrenoceptors/muscarinic/nicotinic
Where is the drug target?
Side effects due to targets in other tissues
What is the end result of the interaction?
Side effect/ desired effect
Usually exogenous drugs but can apply to endogenous agents too.
Explain the biosynthesis and metabolism of acetylcholine, noradrenaline and adrenaline.
In general:
1) precursor from diet transported by blood to nerves
2) enzymatically converted to neurotransmitter
3) neurotransmitter packaged into vesicles
4) action potential causes Ca2+ influx which drives exocytosis.
5) neurotransmitter released into synapse
6) neurotransmitter binds and activates receptor then unbind
7) enzymatic metabolism -> clearance as degradation products
Acetylcholine
1) Acetyl CoA and choline bind to form ACh + CoA using choline acetyl transferase
2) Ca2+…
….
7) acetylcholinesterase breaks down into choline and acetate
Quick response but this is also lost quickly
Noradrenaline
1) Tyrosine into DOPA by tyrosine hydroxylase
2) DOPA to dopamine by DOPA decarboxylase
3) dopamine to noradrenaline by dopamine beta hydroxylase
4) Ca2+…
6) NA binds to adrenoreceptor
7) Break down NA in two pathways - Uptake 1: noradrenaline into neurone and converted into metabolites by monoamine oxidase A (MAO-A), uptake 2: degradation by COMT outside neurone. Not metabolised in synapse, proteins pick up on one side of membrane and flip onto another membrane.
Noradrenaline stays slightly longer and has a longer lasting effect.
Give the following definitions of:
Pharmacokinetics
Pharmacodynamics
Drug
Explain the different drug target sites.
Pharmacokinetics: the effect of the body on the drug
Pharmacodynamics: the effect of the drug on the body.
Drug: a chemical substance that interacts with the biological system to produce a physiological effect.
All drug target sites are proteins.
1) receptors
Proteins within cell membranes (usually - steroids inside cell nucleus)
Activated by neurotransmitter or hormone
Defined by agonists (acetylcholine) stimulate and antagonists (atropine - muscarinic .i.e. selective muscarinic) inhibit
4 types of receptors - chemo, thermo, photo, mechano, 3 general categories defined by structure and transduction systems - ion channel, G-protein, activated enzyme
2) ion channels
Selective pores in cell membranes allow transfer of ions down electrochemical gradients (gating mechanism)
2 types:
(I) voltage-sensitive .e.g. VSCC - voltage sensitive calcium channel, smooth muscle - change in membrane potential (depolarise)
(II) receptor-linked .e.g. nAChR - nicotinic acetylcholine receptor (nicotinic receptor in cell membrane, acetylcholine binds, receptor conformation opens calcium channel, influx of Na+ into cell)
Drugs: local anaesthetics - acts on VSNaC blocking flow of Na+ into cells, reduce a.p. To sensory cortex, calcium channel blockers
3) Transport systems
Transport against concentration gradients (glucose, ions and neurotransmitters) - noradrenaline is synapse back into presynaptic terminal
Specificity for certain species
Na+/K+ ATPase, NA uptake 1
Drugs: tricyclics anti-depressants (TCAs) - lipid soluble into brain, bind to NA uptake system and slow it down therefore NA spends longer in synaptic cleft, boost activity of 3 NA), cardiac glycosides - cardiac stimulant - bind Na+/K+ transporter in heart and slows down therefore small increase in intracellular Na+ so less Ca2+ leave cell, increase build up of Ca2+ intracellularly -> increase contractility.
4) Enzymes
Catalytic proteins, increase rate of reactions
Drug interactions:
(I) enzyme inhibitors - anticholinesterases (neostigmine) - increase synaptic acetylcholine levels
(II) false substrates e.g. methyldopa - for high b.p., enzyme nerve terminals take up methydopa -> methyldopamine -> methylnoradrenaline -> less effect in post synaptic receptors -> relaxation of vascular urge -> decrease b.p.
(III) products e.g. chloral hydrate -> trichloroethanol in liver through enzymatic activity, hypnotic drug used to treat insomnia
unwanted effects .e.g. paracetamol - overload enzymes in liver therefore metabolised by different enzymes which form reactive metabolites which can damage liver and kidney
Non-specific drug action - non-interacting proteins
Physiochemical properties:
Antacids - Mg/Al salts/oxides - basic, pH change
Osmotic purgatives - draw water into gut, increase volume, soften stools
Plasma protein binding (PPB) - pharmacokinetics, drug bound to plasma protein = inactive, free = active
Describe the different processes involved in drug-receptor interactions.
Agonist - ACh, nicotine
Antagonist - atropine, hexamethonium
Antagonists have affinity but no efficacy.
2 types:
1) competitive
Same site as agonist
Surmountable
Shifts D-R curve to right
Atropine (muscarinic), propranolol (beta blocker - B1 + B2 (non selective) antihypertensive, anxiety)
2) irreversible
Binds tightly or at different side - covalent bonds at sane site, can’t be displaced
Insurmountable - longer duration of action
Hexamethonium - block ion channel of nicotinic receptor
Potency (powerfullness) of a drug depends on:
1) affinity - binding property to receptor, electrostatic dories, hydrophobic, van der Waals, H-bonding between agonist and receptor
Ability of drug to bind to receptor and form drug receptor complex.
Stronger affinity, stronger binding and longer lasting.
2) efficacy - intrinsic activity - generating a response -> conformational change of receptor
Activate response and produce a response
Full agonist - full response
Partial agonist - antagonist activity when full agonist administered
Selectivity - distinguish and preferentiallly produce a articulations effect on a particular molecular target
Overlap of receptors = side effects
Structure-activity relationship
Lock and key: key turns lock and generates a response.
Agonists to antagonists: make small changes to agonists to make into antagonists.
Pharmacokinetics: change in drug can cause big change in pharmacokinetics .e.g. duration of action
Explain the types of drug antagonism.
1) Receptor blockade
Antagonism at same receptor: competitive, irreversible
Use-dependency of ion channel blockers .e.g. local anaesthetics
LA, more effective in ion channel if tissue more active
2) Physiological antagonism
Different receptors -> opposite effects in same tissue
E.g. NA and histamine on b.p. Vasculature in smooth muscle - NA - constriction, histamine - vasodilation
3) Chemical antagonism
Interaction of drugs in solution
Dimercaprol -> heavy metal complexes (cheating agent) - complex with lead reducing toxicity and excreted by kidney
4) Pharmacokinetic antagonism
Antagonists decreases the conc of active drug at site of action
Decrease absorption, increase metabolism, increase excretion
E.g. barbiturates - CNS depressant, used in treating epilepsy
Explain drug tolerance.
Gradual reduction in responsiveness to drug with repeated administration e.g.benzodiazepines- anxiolytic drug
1) pharmacokinetic factors
Increase rate of metabolism
Barbiturates, alcohol (increase in alcohol dehydrogenase)
2) loss of receptors
By membrane endocytosis - loss of receptors on cell surface, pinch receptors of through vesicles made from own cell membrane and take inside cell therefore agonist can’t see receptor and response of cell decreases.
Receptor down regulation
Eg. B-adrenoreceptors
3) change in receptors
Receptor desensitisation -> conformational change so reduce response, nAChR at NMJ = continual stimulation, change conformation, bind to ACh but won’t allow receptor response - no efficacy
4) exhaustion of mediator stores
Amphetamine: central stimulant drug which causes euphoria, highly lipid soluble, gains access to brain and binds to uptake transporter of noradrenaline neurones and taken up by nerve terminals, bind to vesicles and release NA
Repeat - reduce response, run out endogenous stores of NA, wait for de novo synthesis
5) physiological adaption
Homeostatic responses - maintain within reality range
Tolerance to drug side effects - antihypertensive drugs - b.p. Increase little bit again
Explain the receptor families.
4 types based on molecular structure and signal transduction systems.
Type 1: Ion channel-linked receptor Fast response (ms) GABAA (main GABA receptor which mediates inhibitory action of GABA in brain - linked to chloride channels, hyperpolarises - slows down a.p.), nAChR (nicotinic cation channel: Na+) Separate domain for agonist binding - 4/5 segments make up receptor
Type 2:
G-protein-coupled receptors
Slower response (secs)
Metabotropic receptors - acts via a secondary messenger
B1-adrenoceptors (heart)
External binding domain and intracellular G-protein coupling domain, no subunits, 7 transmembrane segments.
Type 3:
Kinase-linked type
Insulin/growth factor (mins)
Catalytic domain - tyrosine kinase phosphorylation.
Type 4:
Intracellular steroid type receptors (nuclear)
Steroids/ thyroid hormones (hr) - slower because needs to get inside, interact with DNA, transcription and translation.
Regulate DNA transcription
Binding domain in nucleus, unfolds receptor after binding to expose DNA binding domain.
State the pharmacokinetics of a drug and the different routes of administration.
Administration (ADME) Absorption Distribution Metabolism Excretion Removal Important to know to determine dose of drug available to tissues.
DIIIIIS Dermal - P Intramuscular - P Intraperitoneal - P Intravenous - P Inhalation - P Ingestion - E Subcutaneous - P
Systemic (entire organism) vs local (restricted to one area of organism)
Salbutamol - target lungs
Asprin - headache, ankle pain, gut to bloodstream
Betnovate - steroid skin on skin (local)
Cannabis - get to brain (systemic)
Antacid - neutralise stomach acid (local)
Nicotine - diffuse across skin into bloodstream to brain (systemic)
Enteral (GI administration) and parenteral (outside GI tract)
Explain absorption, distribution and excretion.
Drug molecules move around the body by:
Bulk flow transfer - bloodstream
Diffusion also transfer - molecule by molecule over short distances
Drugs have to transverse both aqueous (blood, lymphoma, ECF, ICF) and lipid (membrane - epithelium/endothelium - capillary wall if target outside cell) environments
Non-polar substance can freely dissolve in non-polar solvents
Most drugs are either weak acids or weak bases so drugs exits in ionised (polar) and non-ionised (non-polar) forms - ratio depends on pH
E.g. aspirin = weak acid (proton donor) and morphine =weak base
Henderson-Hasselbalch equation used to know how much of the drug is ionised/ unionised. The pKa of drug does not change but pH of body compartments change
Acids: if pH below pKa = unionised, opposite for bases
Positive value = more unionised than ionised
how much drug can enter tissues, can be localised in certain compartments
Drugs cross barriers by:
1) simple diffusion down electrochemical gradient
2) diffusion across aqueous pores (least relevant because drugs need to be very small)
3) carrier mediated transport - using active transport
4) pinocytosis
Factors influencing drug distribution:
1) regional blood flow
The more blood flow to a particular tissue, the more drug reaching it
Girly metabolically active tissues -> denser capillary networks .e.g. guts during digestion
Liver, kidneys, muscles (during exercise = more), brain, heart
2) extracellular binding (plasma-protein binding)
Multiple drugs binding to plasma protein, can displace the other - can increase free drug
If bound to plasma protein, doesn’t leave
Warfarin heavily bound, can’t access tissues, acidic drugs are heavily bound
3) capillary permeability (tissue alterations- renal, hepatic, brain/CNS, placental)
Continuos capillary = h20 filled gap junctions
Blood brain barrier - tight junctions
Fenestrated
Discontinuous
4) localisation in tissues
When given in high amounts, large proportion of drug housed in adipose tissue e.g. general anaesthetic: can feel drowsy afterwards, small leakage from adipose
When low, doesn’t matter because little blood supply
Excretion
There are two major routes of drug excretion:
1) Kidney - responsible for elimination of most drugs via urine
Glomerular filtration -> active secretion (dependent on transport proteins) of basic/acidic dugs into proximal tubule -> passive reabsorption (dependent on urine pH and extent of drug metabolism) of lipid soluble drugs.
Drugs made more water soluble to be excreted.
2) Liver - some drugs are concentrated in the bile (usually large molecular weight conjugated) -> faeces
Active transport systems pick up water soluble metabolites into bile (bile acids and glucuronides). Drugs access hepatocytes through discontinuous capillaries and hepatocytes make water soluble conjugates.
Enterohepatic cycling
Drug/metabolite is excreted into gut via bile. Conjugate broken down and free drug released, lip soluble diffuses and reabsorbed, taken to the liver via hepatic portal vein and excreted again - leads to drug persistence
Explain the pharmacokinetic terms used to predict the time course of drug action.
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
Biological half-life (linked to metabolism/ excretion)
Time taken for the conc 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.
What is meant by cholinomimetics? Give the differences between muscarinic and nicotinic effects.
Drug mimics acetylcholine in nervous system.
Muscarinic effects are those that can be replicated by muscarine and can be abolished by low does of the antagonist atropine.
Muscarinic actions correspond to those of parasympathetic stimulation.
After atropine blockade of muscarinic actions, larger doses of acetylcholine can induce effects similar to those caused by nicotine (high acetylcholine conc needed to stimulate nicotinic receptors)
Explain the effect on each muscarinic cholinergic target site.
1) Eye
Contraction of the ciliary muscle: accommodation for near vision, allows lens to bulge and becomes more convex, more light bounces back.
Contraction of the sphincter papillae (circular muscle of iris): constricts pupil (mitosis) and improves drainage of intraocular fluid.
Lacrimation (tears)
2) Heart
ACh binds to M2 AChR in atria and SAN/AVN nodes, cAMP decrease, leads to:
(I) decreased Ca2+ -> decreased cardiac output, negative ionotropic effect
(II) increased K+ efflux -> decreased heart rate, negative chronotropic effect (bradycardia)
3) Vasculature
Most blood vessels do not have parasympathetic innervation, more of a secondary effect of NO. Acts on endothelial not directly on smooth muscle.
Acetylcholine acts on vascular endothelial cells to stimulate NO release via M3 AChR
NO induces vascular smooth muscle relaxation
Results in a decrease in TPR
Overall effect on cardiovascular system:
Decreased HR (bradycardia)
Decreased CO (decreased atrial contraction)
Vasodilation (stimulation of NO production)
All combined -> sharp drop of b.p.
3) Non-vascular smooth muscle Smooth muscle that does have parasympathetic innervation responds oppositely to vascular i.e. it contacts Lung: bronchoconstriction Gut: increased peristalsis (motility) Bladder: increased bladder emptying
4) Exocrine glands Salivation Increased bronchial secretions Increased gastro-intestinal secretions (e.g. HCl production) Increased sweating (SNS)
Summary: Decreased HR Decreased BP Increased sweating Difficulty breathing Bladder contraction GI pain Increased salivation and tears
Explain a glaucoma.
In closed angle glaucoma, iris can be folded/ruffled, reducing angle of drainage so rate of drainage reduced and production of fluid remains the same.
Intra-ocular pressure increases which can damage retina and optic nerve which may cause blindness. The function of the intra-ocular fluid is to bathe the lens and supply cornea with nutrients and O2. Ciliary body produces aqueous humour.
Cholinomimetic drugs stimulate muscarinic receptors in circular muscle of the iris and returns the iris to normal position (flattens it). Contraction of sphincter papillae opens pathway for aqueous humour, allowing drainage via the canals of Schlemm and reducing pressure.
B-receptor antagonist, decrease production of aqueous humour, stop ciliary epithelial cells from producing aqueous humour, bicarbonate ions,
Describe the two types of cholinomimetic drugs.
The two types are directly and indirectly acting drugs.
Directly acting drugs include typical agonists at the muscarinic receptors:
1) choline esters (bethanechol)
2) alkaloids (pilocarpine)
Structural similarities to acetylcholine, can act as muscarinic agonists.
1) minor modification of acetylcholine, produces an M3 AChR selective agonist.
Resistant to degradation - not broken down by acetylcholinesterase, orally active and with limited access to the brain - limits CNS side effects (Half life = 3-4hrs)
Mainly used to assist bladder emptying and to enhance gastric motility
Side effects: sweating, impaired vision, bradycardia, hypotension, respiratory difficulty (orally, systemic)
Cevimeline - newer, more selective to M3
2) From leaves on shrub Pilocarpus
Non-selective muscarinic agonist, good solubility - can be given locally e.g. eye drops and plasma half life 3-4 hrs.
Useful for treating glaucoma
Side effects: blurred vision (from bulging), sweating, GI disturbance and pain, hypotension, respiratory distress
Indirectly acting ones effect acetylcholinesterase in synaptic cleft, increase conc of endogenous acetylcholine.
Increase effect of normal parasympathetic nerve stimulation
Two types of cholinesterases differing in distribution, substrate specificity and function:
1) Acetylcholinesterase (true or specific cholinesterase)
Found in all cholinergic synapses (peripheral and central)
Very rapid action
Highly selective for acetylcholine
Hydroxyl group within enzyme splits acetate from choline by hydrolysis
2)Butyrylcholinesterase(pseudocholinesterase)
Found in plasma and most tissues, not synapses
Broad substrate specificity, also hydrolysed other esters e.g. suxamethonium
For low plasma acetylcholine (breaks down ACh in blood)
Shows genetic variation
Two types of anticholinesterases:
1) Reversible: physostigmine, neostigmine, donepezil (treat Alzheimer’s)
2) Irreverisble: ecothiopate, dyflos, sarin (used as nerve gases)
Effects of cholinesterase inhibitors: Low dose = enhanced muscarinic activity Moderate dose = further enhancement of muscarinic activitym increased transmissions at ALL autonomic ganglia (nAChRs) High dose (toxic) = depolarising block of nicotinic receptors at autonomic ganglia and NMJ -> respiratory depression (muscarinic and nicotinic at autonomic ganglia so not only parasympathetic)
1) compete with acetylcholine for active site on cholinesterase enzyme
Donate a carbamyl group to enzyme, blocking active site and preventing acetylcholine from binding
Carbamyl group removed by slow hydrolysis (mins rather than secs)
Increase duration of acetylcholine activity in synapse
Physostigmine
Tertiary amine from Calabar beans
Acts at postganglionic parasympathetic synapse (half life 30 mins), more sensitive to parasympathetic
Used in treatment of glaucoma, aiding intraocular fluid drainage
Used to treat atropine poisoning - surmounting atropine block
Lipid soluble
2) organophosphate compounds
Rapidly react with enzyme active site, leaving large blocking group
Stable and resistant to hydrolysis - recovery requires production of new enzymes (days/weeks)
Only ecothiopate in clinical use, others intesticides and nerve gases
Ecothiopate:
Potent inhibitor of acetylcholinesterase
Slow reactivation of the enzyme by hydrolysis takes several days
Used as eye drops to treat glaucoma - prolonged duration of action
Systemic side effects: sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty
Describe the effect of anticholinesterase drugs on the CNS.
Describe the treatment of organophosphate poisoning.
Non-polar anticholinesterases can cross blood-brain barrier.
Low doses: excitation with possibility of convulsions
High doses: unconsciousness, respiratory depression, death
Exposure to organophosphate can cause severe toxicity (increase muscarinic activity, CNS excitation, depolarising NM block)
Treatment: atropine intravenously, artificial respiration, pralidoxime intravenously ( can remove block within first few hours otherwise becomes irreversible)
Describe nicotinic receptor antagonists.
Also called ganglion blocking drugs
Can block receptor on ion channel or the ion channel itself
Can affect all ANS - parasympathetic and sympathetic but what it effects depends on which one is dominant at time drug is given.
Hexamethonium
Block ion channel
Use-dependent block - the more open the channels, the more effective the drug.
May be incomplete blockade because not completely blocked.
The more acetylcholine present, the more effective the drug as ion channel opens.
No affinity, just a blockade
Trimetaphan
Block receptor
The more acetylcholine, the more ineffective the drug
Has affinity
The above drugs are anti-hypertensives. Trimetaphan used during surgery - short acting
TPR and BP decreases
Blood vessels and kidneys
Other effects:
Smooth muscle: Pupil dilation (light sensitive), constipation, bladder dysfunction, decreasing GI tone, bronchodilaton
Exocrine secretions: decrease, difficulty sweating, reducing saliva, GI and trachea
Can cause paralysis in skeletal muscle.
Overall use of these drugs give too many unwanted side effects.
Describe muscarinic receptor antagonists.
Eye, salivary glands, trachea and bronchioles, heart, GI and ureter and bladder effects
CNS effects:
Atropine (less M1 selective)
Normal dose: little effect
Toxic dose: mild restlessness, agitation
Hyoscine (more M1 selective)
Normal dose: sedation, amnesia
Toxic dose: CNS depression or paradoxical CNS excitation (associated with pain)
(Greater permeation into CNS - penetrate deeper, influence at therapeutic dose)
Tropicamide used in the examination of the retina, pupil dilation - paralyses muscle in iris
Anaesthetic premedication
Dilates airway for anaesthetic to enter
Prevent secretion of saliva going back down the airway which can cause choking
Rate and contractility of heart decreases
Sedation
Neurological
Motion sickness caused by cholinergic sensory mismatch between info from eyes (abducens and oculomotor nuclei) and info from balanced from labyrinth linked to vomiting centre
Hyoscine patch: hyoscine diffuses across skin into bloodstream and blocks receptor at vomiting centre
Parkinson’s
Loss of dopaminergic neurones extending from substantia nigra to striatum
Muscarinic receptor suppresses D1 receptor. Therefore blocking M4R makes D1R more receptive to dopamine.
Respiratory
Asthma/obstructive airway disease - ipratropium bromide is structural analogue of atropine inhaled into lungs and less likely to cross lipid membrane so localised in lungs. Atropine would diffuse and cause side effects.
GI
Irritable bowel syndrome - M3 receptor antagonist
Unwanted effects
Hot as hell: decreased sweating, thermoregulation
Dry as a bone: decreased secretions
Blind as a bat: cyclopegia- paralyse lens, no ability to change focus
Mad as a hatter: CNS disturbance
Explain atropine poisoning.
Explain Botox
Treat with anti-cholinesterase e.g. physostigmine
More acetylcholine in synapse
SNARE complex usually formed in exocytosis of ACh, botulinum toxin blocks this SNARE complex. If too much used, ACh cannot exit to skeletal muscle, can’t move = paralyse skeletal muscle.
Used in Botox carefully, localising in tissue
Explain actions of adrenaline as adrenoceptor agonists.
Mimic the actions of NA/A by binding and stimulating adrenoceptors (GPCRs)
Selectivity for noradrenaline
A1, a2 > b1, b2
Selectivity for adrenaline
B1, b2 > a1, a2
Non-specific
Adrenaline: used in treatment for allergic reactions and anaphylactic shock because more selective to B2, histamine mediated bronchoconstriction targeted by dilation. Hypotension targeted, B1- tachycardia
Less stomach cramps by relaxing smooth muscle in GI
Asthma
Acute bronchospasm associated with chronic bronchitis or emphysema (b2 airway mediator release)
Cardiogenic shock - sudden inability of heart to pump sufficient oxygen-rich blood (b1 ionotropic effects)
Spinal anaesthesia - a1, vasoconstriction - increase TPR, increase BP
Local anaesthesia - vasoconstriction, prolonged action
Adrenaline unwanted actions
Secretions - reduced and thickened mucous (more immune function)
CNS - minimal
CVS effects - tachycardia, palpitations, arrhythmias
- cold extremities, hypertension (vasoconstriction)
-overdose - cerebral haemorrhage, pulmonary ordinance
GI - minimal
Skeletal muscle - tremor
Explain the actions of alpha selective adrenoceptor agonists.
Phenylephrine a1 >a2>b1/b2
Chemically related to adrenaline - more resistant to COMT but not MAO
Clinical uses
Used as a nasal decongestant because:
Vasoconstriction: less white cell infiltration, less fluid exacerbation, less build up of mucus
Also mydriatic - dilated pupils
Clonidine a2>a1>b1/2 - treat hypertension and migraine by vasodilation (brain is b2 controlled, increase blood flow)
Reduces sympathetic tone
-a2 adrenoceptor mediated presynaptic inhibition by NA release
-central action in brainstem within baroreceptor pathway to reduce sympathetic outflow
Glaucoma
A1- wil cause vasoconstriction, increase production of fluid (don’t want this)
A2 - decrease humour formation, interfere with B1 which is connected to aqueous humour production
Explain the actions of B-selective adrenoceptor agonists.
Isoprenaline b1=b2>a1/2
Chemically related to adrenaline - more resistant to MAO and uptake 1
Clinical
Cardiogenic shock
Acute heart failure
Myocardial infarction
B2-stimulation in vascular smooth muscle (vasodilation) in skeletal muscle results in fall in venous blood pressure which triggers a reflex tachycardia via the stimulation of baroreceptors
Dobutamine b1>b2>a1/2 Clinical use Cardiogenic shock Lacks isoprenaline’s reflex tachycardia Plasma half life 2 minutes (rapidly metabolised by COMT)
Salbutamol (ventolin) b2>b1>a1/2
Synthetic catecholamine derivative with relative resistance to MAO and COMT
Blue inhaler
Longer in system
Clinical uses
Treatment of asthma
-b2-relaxation of bronchial smooth muscle inhibition of release of bronchoconstrictor substances from mast cells
Treatment of threatened premature labour
-b2-relaxation of uterine smooth muscle
Side effects - reflex tachycardia, tremor, blood sugar dysregulation
What are the main processes involved in drug metabolism. What are the two phases.
Drugs need to be lipophilic so they can access tissues - therapeutic effect
Drugs need to be water soluble to be retained in the blood and delivered to excretion sites.
Body alters the drug to make it less lipid soluble and easier to excrete. The process of metabolism involves the conversion of drugs usually lipid soluble to metabolites (less lipid soluble and easier to excrete).
Two biochemical reactions:
Phase 1 - main aim is to introduce a reactive group to the drug (increase polarity)
Phase 2 - main aim is to add a water soluble conjugate to the reactive group, make water soluble.
Describe phase 1 metabolism.
Mostly in liver
- Most common =Oxidation (often start with hydroxylation - add hydroxyl group)
- Hydrolysis - unmasks reactive group, functional group serves as a point of attachment for phase II reactions)
- Reduction
3 outcomes of phase 1 metabolism:
1) active parent drug -> inert metabolite (no effect on body)
2) active parent drug -> active metabolite (prolongs effects) .e.g. cannabis
3) inactive parent drug -> active metabolite (prodrug) .e.g. codeine -> morphine
Describe phase 2 metabolism.
Most common: glucoronidation
Glucoronidation is low affinity/high capacity (large amount metabolised)- more likely to occur at high drug dosages.
Water soluble to be able to excrete
Aspirin -> salicylic acid
Sulfation: high affinity/low capacity (not a lot but very effective) - more likely to occur at low dosages
Paracetamol
Glutathione conjugation
Drug needs to be electrophilic to be conjugated or biotransformed to an electrophilic conjugate
When there’s enough glutathione stores, conjugate formation not a problem. In overdose, we use up stores therefore in the case of paracetamol, NAPQI (Electrophile) can cause damage to liver tissue instead of forming glutathione conjugate.
Problem: electrophilic are extremely reactive and glutathione stores overwhelmed.
Less common metabolism pathways compared to previous 3:
Acetylation - aromatic amine
Methylation
Amino acid conjugation - two reactions possible: 1) with carboxylate acid group of AA 2) with amino group of AA
Why is drug metabolism important?
The biological half-life of the chemical is decreased.
The 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.
The pharmacology/toxicology of the drug can be governed by its metabolism.
What are the adrenoceptor subtypes.
A1 - vasoconstriction, relaxation of GI
A2 - inhibition of transmitter (which inhibit sympathetic) release, contraction of vascular smooth muscle, CNS actions
B1 - increased cardiac rate and force, relaxation of GIT, renin release from kidney
B2 - bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis
B3 - lipolysis
Give examples of adrenoceptor antagonists.
Non-selective: a1+b1 = carvedilol A1+a2: phentolamine A1: prazosin (selective) B1+b2: propranolol B1: atenolol
Explain the uses of B-blockers in the treatment of hypertension.
B-blockers decrease heart rate and force of contraction therefore decrease cardiac output, reduce b.p
Renin and angiotensin II release decrease, angiotensin II is a potent vasoconstrictor and increase aldosterone production
Therefore aldosterone and blood volume (Na+ and water) decrease
Blockade of facilitatory effects of presynaptic B-adrenoceptors on noradrenaline release may also contribute to the antihypertensive effect (Not as effective as a2)
1) non-selective: equal affinity for B1 and B2 receptors (propranolol)
2) B1-selective: more selective for B1 (atenolol), MORE so may still activate B2
3) mixed blockers (B1, B2, a1): a1 blockade gives additional vasodilator properties (carvedilol)
4) Other: nebivolol = also potentiates NO (vasodilator), sotalol = inhibits K+ channels (interfere with cell hyperpolarisation)
Atenolol may be advantageous over propranolol because only B1 so asthmatics and diabetes less likely to respond to drugs.
Carvedilol advantageous over atenolol and propranolol because more powerful hypotensive effect on heart, kidney and block vasoconstriction decreasing TPR but does increase side effects.
Unwanted side effects
Bronchoconstriction - asthma/COPD
Cardiac failure - need some sympathetic drive to the heart for blood tissue demand
Hypoglycaemia - mask the symptoms of hypoglycaemia/ inhibit glycogen breakdown (B2 liberates blood glucose)
Fatigue - decrease cardiac output and decrease muscle perfusion (B2 dilates)
Cold extremities - loss of B-receptor mediated vasodilation in cutaneous vessels
Bad dreams
Explain the use of alpha-blockers in treating hypertension.
A1-receptors are Gq linked (PLC and Ca2+ influx), postsynpatic on vascular smooth muscle
A2-receptors are GI (inhibitory G protein) linked (decrease cAMP), presynaptic autoreceptors inhibiting NE release
Non selective a-blocker: phentolamine used to treat phaechromocytoma-induced hypertension (tumour in adrenal medulla)
Side effect is diarrhoea
A2 receptors and baroreceptors reduce the effectiveness of phentolamine - a-blockers dilate blood vessels, decreasing pressure,
1) block a2 - negative feedback therefore increases NE, competitive reaction between phentolamine on a1 and NE in synapse
baroceptor firing decreases -> sympathetic drive so CO and SV increases.
A1-specific: prazosin inhibit the vasoconstrictor activity of NE
Have modest b.p. Lowering effects
Only used as adjunctive treatment because not as powerful
Explain the effect of false transmitters on the treatment of hypertension.
1) Methyldopa converted to false transmitter (produced instead of NA)
2) Less active at beta/alpha 1 receptor (more selective to a2)
3) Not metabolised by MAO (no conc. gradient, not broken down therefore uptake lower)
4) More likely to accumulate and displace noradrenaline in the vesicles
More powerful hypotensive with vasoconstriction but can cause very low hypotension. Improved blood flow Antihypertensive especially: Renal - kidney disease CNS - cerebrovascular disease
Side effects with saliva production and blood vessels to skin
Explain the use of b-blockers in the treatment of arrhythmias.
Abnormal or irregular heart beat, main cause myocardial ischaemia
Increased sympathetic drive to heart precipitates arrhythmias (b1)
AV conductance dependent on sympathetic activity (b1)
B-blockers such as propranolol used to rest - restore normal rhythm to improve blood flow therefore cardiac output
Explain the use of B-blockers in the treatment of angina.
Stable: pain on exertion. Increased demand on the heart and is due to fixed narrowing of the coronary vessels .e.g. atheroma, still enough blood flow to meet demands at rest, not exercise
Unstable: 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
Variable: occurs at rest, caused by coronary artery spasm, associated with atheromatous disease
At low doses, B1 selective agents such as metoprolol reduce heart rate and myocardial contractile activity without affecting bronchial smooth muscle. Decreases effort your heart makes, easing angina pain.
Explain neuromuscular transmission.
A-motor neurone found in ventral horn e.g. sciatic nerve.
NAChR different to ganglionic nAChR so can develop drugs which have selectivity to neuromuscular function.
The end-plate potential is a gradient potential.
ACh binds onto a subunit, opening channel, influx of Na+
What are the sites of neuromuscular blocking drug action?
In order of transmission:
1) Central processes (a morose neurone generates a.p. In spinal cord) - spansmolytics (diazepam, baclofen) which cause relaxation of skeletal muscle, anti-spasticity
2) Conduction of nerve a.p. In motor neurone - local anaesthetics injected around terminals of sensory fibres, not effective near motor neurone.
3) ACh release - hemicholinium (prevents reuptake of choline), Ca2+ entry blockers, neurotoxins (decrease ACh release, bind to terminals and gains access inside nerve terminal and interact with intracellular proteins e.g. botox
4) depolarisation of motor end-plate, a.p. Initiation - tubocurarine, suxamethonium
5) propagation of a.p. Along muscle fibre and muscle contraction - spasmolytics (dantrolene) - acts inside skeletal muscle, decrease Ca2+ release from sarcoplasmic reticulum, relaxation of muscle.
Explain two types of neuromuscular blocking drugs.
Act post synaptically on skeletal muscle.
Two types:
1) non-depolarising (competitive antagonists)e.g. tubocurarine, atracurium
2) depolarising (agonists) e.g. suxamethonium (succinylcholine)
Similarities between ACh and drugs
They do not affect consciousness (not anaesthetic)
They do not affect pain sensation (no analgesics properties)
ALWAYS assist respiration until drug inactive or antagonised
1) structure more rigid, little rotation, bind + block receptor
2) more free rotation, bind + activate - efficacy
Explain depolarising neuromuscular blockers.
Suxamethonium
Mechanism of action: extended end plate depolarisation -> depolarisation block (phase 1)
Overstimulation of nicotinic receptors therefore receptor shut down
fasciculations -> flaccid paralysis, as drug diffuses into muscle, we see fasciculations (muscle twitching) then flaccid paralysis (shut down)
Pharmacokinetics
Route of administration: intravenous (highly charged)
Duration of paralysis 5 mins
Metabolised by pseudo-cholinesterase in live and plasma (short duration)
Uses
Endotracheal intubation - insertion of tube down trachea for general anaesthetics, investigating bronchoscope - suxamethonium allows relaxation of vocal cords to allow tube to be inserted
Muscle relaxation for ECT(electroconvulsive therapy) used to treat severe clinical depression. Drug used to relax skeletal muscles
Unwanted effects
Post-operative muscle pains
Bradycardia - direct muscarinic action on heart (atropine given as premed to prevent effect on heart)
Hyperkalaemia - avoid use in soft tissue injury or burns (damage after EN6, fibres, response of skeletal muscle is putting more nicotinic receptors on surface of fibre on end-plate region to amplify reduced input) -> ventricular arrhythmias/cardiac arrest
Explain non-depolarising neuromuscular blockers.
Tubocurarine (prototype)
Naturally occurring quaternary ammonium compound (alkaloid)
Mechanism of action: competitive nAChR antagonist, 70-80% block necessary for end plate potential to be insufficient to cause firing
ACh released but reduced binding to receptors
Effects
Flaccid paralysis
Respiratory recovery in order of:
1) respiratory muscles e.g. respiratory arrest
2) small muscles of face, limbs and pharynx e.g. trouble swallowing
3) extrinsic eye muscles e.g. double vision
Uses
Relaxation of skeletal muscles during surgical operations (=less anaesthetic)
Permit artificial ventilation
Actions of non-depolarising blockers can be reversed by anticholinesterases - raise endogenous acetylcholine, cometitive overcome block
Neostigmine (longer acting anticholinesterase) (+atropine - dampens down overstimulation of muscarinic receptors)
Pharmacokinetics
Route of administration - I.v. (Highly charged)
Does not cross BBB or placenta
Duration of paralysis: 1-2 hr (long)
Not metabolised
Excretion: 70% urine: 30% bile (if renal or hepatic function impaired - excreted more slowly, increased duration of action therefore increased duration of action)
In case of these conditions, different drug like atracurium used which is chemically unusable, hydrolysed in plasma into 2 inactive fragments (15 mins)
Unwanted effects
(Ganglion block; histamine release)
Hypotension
Ganglion blockade, higher dose can block (decrease TPR therefor bp)
Histamine release from mast cells (vasodilation, decrease bp)
Tachycardia (may cause arrhythmias), reflex in response to low b.p., blockade of vagal ganglia (parasympathetic)
Bronchospasm and excessive secretions (bronchial and salivary) due to histamine release
Apnoea (ALWAYS assist respiration)
Explain the mechanisms regulating heart rate, contractility and myocardial oxygen supply.
Heart rate
Channels: if, ica (l), ica (t), ik in SAN
If - hyperpolarization-activated cyclic nucleotide–gated (HCN) channels - switch on during hyperpolarisation, utilise cAMP and drive Na+ entry to initiate depolarisation
Ica (T or L) – Transient T-type Ca++ channel -as current increases, open or Long Lasting L-type Ca++ channel - first T, then L
IK – Potassium K+ channels - positive voltage, repolarisation
Phase 4 is the spontaneous depolarization (pacemaker potential) that triggers the action potential
Sympathetic - increase cAMP, increase If and Ica
Parasympathetic - decrease cAMP, increase Ik
Contractility
1) ap enters from adjacent cell
2) voltage-gated Ca2+ channeled open, Ca2+ enters cell
3) Ca2+ induces Ca2+ release through ryanodine receptor-channels (RyR), 25% Ca2+ from oudside, 75% from SR
4) local release causes Ca2+ spark
5) summed Ca2+ sparks create a Ca2+ signal
6) Ca2+ ions bind to troponin to initiate contraction
7) relaxation occurs when Ca2+ unbinds from troponin
8) Ca2+ is pumped back into the SR for storage
9) Ca2+ is exchanged with Na+
10) Na+ gradient is maintained by the Na+-K+-ATPase
Myocardial oxygen supply and demand
Myocardial oxygen supply
-Increase coronary blood flow
-arterial O2 content
Work —> myocardial oxygen demand
- increase in heart rate
- increase in preload - Starling’s law, more blood return, more SV
- increase in afterload - pressure in system, acts as resistance —> work harder
- increase in contractility
Describe the drugs affecting heart rate, contractility and myocardial oxygen supply.
Heart rate - for angina to decrease HR
- B-blockers - decrease If and Ica - SNS increase,B1 receptor, increase nodal activity, increase in If and Ca2+ influx
- calcium antagonists - decrease Ica - ca2+ influx increases
- ivabradine - decrease If - blocks If, decrease speed of depolarisation
Contractility
-B-blockers - decrease contractility - B1 receptor, less Ca2+ influx
-Calcium antagonists - decrease Ica
Two classes of calcium antagonists
• Rate slowing (Cardiac and smooth muscle actions) - large effect on HR
– Phenylalkylamines (e.g. Verapamil)
– Benzothiazepines (e.g. Diltiazem)
• Non-rate slowing (smooth muscle actions – more potent) - not much effect on heart but great impact on vasculature. Profound vasodilation can lead to reflex tachycardia - baroreceptors respond to vasodilation
Myocardial oxygen supply and demand
-organic nitrates and potassium channel openers = increase in coronary blood flow
Vasodilation decreases afterload; dilate veins too (venodilation) - decrease preload because more blood can stay in venous system and doesn’t need to rent to heart
– Dihydropyridines (e.g. amlodipine)
Drugs for treating stable angina - heart doesn’t receive enough oxygen = pain, usually due to atherosclerosis
Beta blocker/calcium channel blocker given as a first line treatment - reduce HR and contractility - decrease cardiac work but makes it harder to exercise
Can combine
If contradicted - long-acting nitrate, K+ openers
What are the side effects of drugs affecting heart rate, contractility and myocardial oxygen supply?
Beta blockers
Worsening heart failure - inability to match CO to tissue need
-CO reduction
-increased vascular resistance
Bradycardia
-heart block - decreased conduction through AV node
Non-selective e.g. pindolol
Equal affinity for B1 and B2 receptors
With intrinsic sympathetic activity - normal daily activities - some sympathetic activity, not in exercise
Mixed B-a blockers
A1 blockade gives additional vasodilator properties
E.g. carvediol - b1, b2, a1
Trachea and bronchioles - constriction - asthmatics
Liver - decreases glycogenolysis and gluconeogenesis - masks hyperglycameia - diabetics
Cold extremities/ worsening peripheral artery disease because of loss of B2 receptor mediated cutaneous vasodilation in extremities - harder for blood to enter extremities
Not tested in exam, not enough evidence
Fatigue, Impotence (sexual dysfunction), Depression
Calcium channel blockers - “safer drugs”
Verapamil
• Bradycardia and AV block (Ca2+ channel block) • Constipation (Gut Ca2+ channels) – 25 % patients
Dihydropyridines – 10-20% patients
• Ankle Oedema – vasodilation means more pressure on capillary vessels - gravity to feet
• Headache / Flushing (blood flow peripherally to face) – vasodilation -in brain
• Palpitations - reflex, barorecptors sympathetic response
Vasodilation/reflex adrenergic activation
(Above also in K+ channel openers, nitrates)
Describe rhythm disturbances and classification.
Rhythm disturbances
• Abnormalities of cardiac rhythm (arrhythmias/dysrhythmias)
affect around 700,000 people in UK.
- Aims of treatment are
- Reduce sudden death - cardiac arrest
- Prevent stroke - heart bot beating rhythmically so increased likelihood of blood clotting - to Brian = stroke
- Alleviate symptoms
• Management is complex; usually undertaken by specialists ; and
may involve cardioversion, pacemakers, catheter ablation therapy and implantable defibrillators as well as drug therapy
• May be associated with decreased heart rate (bradyarrhythmias) or increased heart rate (tachyarrhythmias).
• A simple classification of arrhythmias is based on site of origin:
• Supraventricular arrhythmias (e.g. amiodarone, verapamil)
• Ventricular arrhythmias (e.g. flecainide, lidocaine).
• Complex (supraventricular + ventricular arrhythmias) (e.g.
disopyramide).
Use Vaughan-Williams classification of anti-arrhythmic drugs
Class; mechanism of action
I; sodium channel blockers (prevented/ reduced depolarisation)
II, Beta adrenergic blockade (blocked B-receptors, generalised inhibitory affect on muscular contraction)
III, prolongation of repolarisation (‘membrane stabilisation’, mainly due to potassium channel blockade)
IV, calcium channel blockade
Limited classification due to many drugs having different effects
Describe anti-arrhythmic drugs.
Supraventricular arrhythmias
Adenosine usually treatment of choice for terminating paroxysmal supraventricular tachycardia because a very short duration of action (half life 20-30 secs but prolonged in those taking dipyridamole), side effects short lived. Unlike verapamil hydrochloride, adenosine can be used after a beta-blocker. VH may be preferable in asthmatics. (III, IV)
Used intravenously. Safer than verapamil
Binds on adenosine receptor (A1) in SAN/AVN —> inhibitory effect on adenyl cyclase —> decrease cAMP —> decrease If —> decrease depolarisation —> decrease chronotropy. Less powerful in vascular smooth muscle - A2 receptor —> increase cAMP —> relaxation
Verapamil
Reduction of ventricular responsiveness to atrial arrhythmias
Depresses SA automaticity and subsequent AV node conduction, block Ca2+ ion channels —> decrease ability to depolarise (increase time)
Amiodarone (hydrochloride)
Supraventricular and ventricular arrhythmias - often due to reentry (prevent reentry)
Used when other drugs are ineffective or contraindicated. Used for paroxysmal supraventricular, nodal and ventricular tachycardias, atrial fibrillation and flutter.
Intravenous or by mouth, advantage is cause little or no myocardial depression.
Amiodarone accumulates in the body (t1/2 10-100 days)
Has a number Of important adverse effects:
-photosensitive skin rashes
-hypo- or hyperthyroidism
-pulmonary fibrosis
MoA
In normal cardiac tissue, a.p. Has 2 pathways which are equal and cancel out therefore propagation of signal across cardiac tissue
When tissue is dead, there’s no cancelling out because 1 can travel, 2 can’t so uni-directional (depends on state of cardiac tissue e.g. hyperpolarised - not all cause contractility) , the pathway that can’t travel down, goes back up and reactivate tissue - jerky contractions- because tissue may have already gone into refractory period???, amiodarone prevents this by K+ channel blocker - prolongs repolarisation phase
Digoxin (cardiac glycoside) e.g. prevent stroke risk
Oral administration slows the ventricular response in cases of atrial fibrillation and atrial flutter but rarely effective for rapid control of ventricular rate.
Inhibition of Na+-K+-ATPase. Results in increased intracellular Ca2+ via effects on Na+/Ca2+ exchange —> positive inotropic effect (prevent Na+ leaving cell so less involved in Na+/Ca2+ exchange, Ca2+ remains in cell, more powerful contraction)
Central fatal stimulation causes increased refractory period and reduced rate of conduction through the AV node (slows heart down, so more rhythmical)
• Atrial fibrillation and flutter lead to a rapid ventricular rate that can impair ventricular filling (due to decreased filling time) and reduce cardiac output.
• Digoxin via vagal stimulation reduces the conduction of electrical impulses within the AV node. Fewer impulses reach the ventricles and ventricular rate falls.
Hypokalaemia (usually a consequence of diuretic use) lowers the threshold for digoxin toxicity - digoxin binding site is K+ ion binding site, if K+ decreases, digoxin has more easier target access so greater effect
• Adverse Effects
• dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity
)
Describe vascular tone/ peripheral vascular resistance.
Increase in sympathetic discharge to arteriolar (excluding brain and heart) —> increase in arteriolar constriction —> increase in peripheral resistance —> increase in arterial pressure
Contraction: radius decreases, resistance increases, blood flow decreases - vasoconstriction (less space for blood to flow to arteriolar so remain in arteries —> b.p. Increase)
Relaxation: increase in radius, decrease in resistance, increase in blood flow - vasodialtion
Arteriolar smooth muscle normally displays a state of partial constriction - vascular tone
Describe hypertension.
Physiology
• Blood pressure (BP) = cardiac output (CO) x total peripheral resistance (TPR)
Pathophysiology
• Hypertension is defined as being consistently above 140/90 mmHg (for everyone) ; normal is 120/80 (average male)
• Single most important risk factor for stroke,
causing about 50% of ischaemic strokes
• Accounts for ~25% of heart failure (HF) cases - work against hypertension, this increases to ~70% in the elderly
• Major risk factor for myocardial infarction (MI) & chronic kidney disease (KD)
• Ultimate goal of hypertension therapy —> reduce mortality from cardiovascular or renal events
May be symptomless
Describe the general treatment pathway of hypertension.
STEP 1 • Angiotensin converting enzyme (ACE) inhibitor OR angiotensin receptor blocker (ACEi or ARB CCB or Thiazide- ARB) for under 55s type diuretic • Calcium channel blocker (CCB) or thiazide-like diuretic for over 55s or afro-Caribbean's STEP 3 • Combination of ACEi/ ARB with CCB and thiazide-like diuretic is recommended STEP 4: Resistant Hypertension • Consider low-dose spironolactone • Consider beta-blocker or alpha blocker
Explain ACE inhibitors.
RAS = SNS activation/thirst, vasoconstriction, salt and water retention on kidneys, aldosterone secretion
Decrease renal Na+ reabsorption, decreased renal perfusion pressure and increase in sympathetic NS activate RAS
Angiotensin I to angiotensin II is inhibited along with breakdown of bradykinin to inactive metabolites being blocked, inhibit somatic form of angiotensin converting enzyme
Uses:
Hypertension - decrease TPR so decrease BP
Herat failure - decrease vasoconstriction, decrease afterload, heart doesn’t have to work as hard. Also less fluid retained by kidneys, less volume return to heart, decreased preload, decreased cardiac work
Post-myocardial infarction
Diabetic nephropathy
Progressive renal insufficiency
Patients at high risk of cardiovascular disease
Example: enalapril (end in pril = ACE inhibitor)
Explain angiotensin receptor blockers.
Example: Losartan
Antagonists of type (AT1) receptors for Ang II, preventing the renal and vascular actions of Ang II
Uses: hypertension, heart failure
Decrease vasoconstriction, salt and water retention, heart failure
Generally well tolerated
Cough (ACEI) - bradykinin - stop break down bradykinin, exacerbate cough
Hyperkalaemia (care with K supplements or K
sparing diuretics) - interfere with Na+ uptake, less water followed by osmosis, blood volume decreases. In kidneys its a problem because decreased K+ exchange so not excreted in urine.
Renal failure in patients with renal artery stenosis ( both) - if pressure falls in glomerulus - not efficient filtration, release Ang II, constrict efferent artery, blood cannot leaver glomerulus effectively, pressure in glomerulus increases and GFR restored. In renal failure, struggle to regulate glomerular filtration pressure
Hypotension (both)
Explain calcium channel blockers.
Smooth muscle contraction
1. Membrane depolarisation opens
voltage-gated calcium (Ca2+) channels
(VGCCs)
2. Ca2+ enters & binds to calmodulin (CaM) 3. Ca2+-CaM complex binds to & activates
myosin light chain kinase (MLCK)
4. MLCK mediated phosphorylation —>smooth muscle contraction
Calcium Channel Blockers (CCBs) Dihydropyridines (DHPs)
• More selective for blood vessels
• Amlodipine -does not cause any negative inotropy
• Also licensed for prophylaxis of angina
Non-DHPs (aka rate-limiting)
• Verapamil - large negative inotropic effect
For hypertension:
Dihydropyridines inhibit Ca2+ entry into vascular smooth muscle cells
↓ T.P.R. = ↓ B.P. N.B.
Powerful vasodilation can lead to reflex tachycardia and increased inotropy thus increased myocardial oxygen demand
Explain comparisons of hypertensive drugs.
ACEi or ARB given to younger than 55 as first line because more adherence
55 years older or Afro Caribbean given CCB or thiazide-type diuretic given. Afro - genetically have low plasma renin
The older you get, the more hypertension comes down to atherosclerosis therefore some things that normally control vascular tone desensitises a bit e.g. RAS doesn’t work against atherosclerosis
RAS vs CCBs • CCBs decrease SBP more than RAS inhibitors • RAS inhibitors decrease heart failure • RAS inhibitors increase stroke • No difference for all-cause death RAS vs thiazides • Thiazides decrease SBP more than RAS inhibitors • RAS inhibitors increase heart failure • RAS inhibitors increase stroke • No difference for all-cause death RAS vs beta-blockers • No difference in SBP reduction • RAS inhibitors decrease CV events • RAS inhibitors decrease stroke • No difference for all-cause death
Explain alpha adrenoceptor antagonists.
Alpha blockers - a1 adrenoceptor antagonists
E.g. prazosin, phentolamine
Used as antihypertensive because blocks vasoconstriction so TPR decreases, decreasing BP.
Why are cannabis, nicotine and cocaine misused?
ventral tegmental area —> Nucleus accumbens (ventral striatum)
part of central reward system - Mesolithic dopamine system
Dopamine release in reward system, feeling of reward, induce euphoria
Describe the routes of administration of drugs.
Give the classification of drugs of abuse.
Snort - intranasal, mucous membranes of nasal sinuses - slow absorption
Eat - oral, gastrointestinal tract, very slow absorption
Smoke - inhalation, small airways and alveoli, already in pulmonary circulation so only needs to enter left side of heart - most rapid route
Inject - intravenous - rapid absorption
Oral < intranasal < intravenous < inhalation
Classification
Narcotics/ painfullers - opiate like drugs e.g. heroin, morphine
Depressants - downers (slow things down), e.g. alcohol, benzodizepines (Valium), barbiturates
Stimulates - uppers (speed things up), e.g. cocaine, amphetamine (speed), caffeine, nicotine metamphetamine (Crystal meth)
Miscellaneous e.g. cannabis (depressant but also other properties), ecstasy (MDMA) “
Describe the pharmacokinetics of cannabis.
Cannabis/marijuana
Dose specific responses - as dose goes up, increase risk of negative vs positive
THC and cannabidiol administered, now more THC so effects decrease
Absorption
Oral - 5-15% (bioavailability) - delayed onset/slow absorption, first pass metabolism -liver metabolises some before entering systemic circulation
Inhalation (25-39%) - most exhaled out again, deeper you inhale, more likely to get into lungs to alveoli
Bioavailability doesn’t really matter because drug titrated
Distribution
Really lipid soluble, can cross plasma membrane to tissues - slowly accumulate in poorly perfumed fatty tissues (chronic use)
Fatty acid conjugated build up in fatty tissue, can slowly leak back into blood
Metabolism
Liver - 11-hydroxy-THC (phase 1 metabolite)
More potent than THC only so much can be conjugated per unit time
Excretion/ removal
GIT - 65%, bile - enterohepatic recycling to faeces, problem if non polar - reabsorbs into gut
Urine - 25%
Poor correlation between plasma cannabinol concentration and degree of intoxication
Effects of cannabis cigarette smoking can persist in body for 30 days - can sample hair
Describe the pharmacodynamics of cannabis.
In brain:
CB1 receptors, hippocampus/cerebellum/ cerebral cortex/ basal ganglia
In periphery:
CB2 receptors, immune cells
Depressive drug because binds to CBR which is negatively coupled to adenyl cyclase. Inhibitory G protein suppresses adenyl cyclase - cellular activity decreases
Same effect from endogenous anandamide (from cholesterol)
Euphoria
Cannabis bind to CB1 receptor on GABA interneurone - switch off so that reward system firing at a higher rate (GABA is natural suppressant on system). Therefore dopiminergic neurones from VTA to NAcc —> release dopamine
Psychosis, schizophrenia
The anterior cingulate cortex (ACC)
Error detection e.g. word green in red - brain senses something wrong
Involved with performance monitoring with behavioural adjustment in order to avoid losses
E.g. driving car on wide road, then saddening dark, rainy, narrow road so have to redirect cognitive resource so more focussed
Hypoactivity in cannabis users
Food intake -hypothalamus
Positive effect on orexigenic neurones in lateral hypothalamus (stimulates food intake)
1) presynaptic inhibition of GABA increases MCH neuronal activity
2) increased orexin production
Immunosuppressant
CB receptor expression, cannabinoid agonists
B cells, T cells, NK, mast cells .etc.
Memory loss - lambic regions (amnestied effects/ decrease BDNF - brain derived neurotrophic factor)
Psychomotor performance - cerebral cortex
Peripheral effects:
Immunosuppressant
Tachycardia/ vasodilation (conjunctivae - blood shot in eyes, TRPVI, Ca2+ entry)
Medulla - low CB1 receptor expression, important because cardiorespiratory control will decrease (sometimes seen as more safer than alcohol)
What is the medical application of cannabis?
High regulation of CB receptors:
Multiple sclerosis/ pain/ stroke - regulatory (protective effect in these diseases)
Fertility (decrease testosterone, inhibit PG gonadotrophins)/ obesity (CB1 in liver and adipose)- (pathological - high CB can cause these)
Agonists:
Dronabinol, nabilone
Sativex - analgesia, MS
Antagonist:
Rimonabant - anti-obesity but no longer a viable because decrease reward so increase suicide rates
Describe the pharmacokinetics of cocaine.
I.v., oral, intranasal, following can’t heat because will break down
Paste -80% cocaine (organic solvent)
Cocaine HCl - dissolve in acidic solution
Inhalation
Crack (crackles with heat) - precipitate with alkaline solution (e.g. baking soda)
Freebase - dissolve in non-polar solvent (e.g. ammonia and ether)
Smoking is low bioavailability because of pKa, smoke is acidic and drug has a high pKa
Oral cocaine ionised in GIT - pKa is 8.7 so in alkaline more unionised, ionised in stomach, mouth, oesophagus .etc. (Poor absorbed)
Slower absorbed, prolonged action
Metabolism
75-90% - inactive
T1/2 - 20-90 min (inactivated quickly)
Plasma/liver cholinesterases - liver and blood quickly metabolised
Pharmokinetics contribute to the addictive potential of the drug because:
1) speed on onset - quick onset
2) quick clearance
Describe the pharmacodynamics of cocaine.
Local anaesthetic
8.7 pKa, 7.4 pH - pH closer therefore more unionised, outside cell so can enter cell more effectively
7 pH - more ionised and better at interacting with target (inside cell) and can’t leave cell
Blocks sodium channel, sodium influx so disrupts a.p.
Reuptake inhibition
Cocaine blocks noradrenaline reuptake transporter so more NA in synapse, enhances NA
Blocks dopamine transporter, dopamine builds up in synapse and can have an affect on D1R
Other effects:
Mild - sleep disturbance, anger, euphoria
Severe - anxiety, incoherent speech, anorexia
Cardiovascular: MI
Increase catecholamines ….
CNS: hyperthermia
Cocaine inhibits cutaneous vasodilation and enhances sweat production
Cocaine elevates threshold for sweating and cutaneous vasodilation
Describe the pharmacokinetics of nicotine.
Administration
Nicotine spray
Nicotine gum - across mucous membranes in mouth
Cigarettes - cigarette smoke is acidic, pKa 7.9 so no buccal absorption, breath out 50%
Nicotine patch - diffuse across skin
Absorption in alveoli independent of pH
Bioavailability: nicotine patch > nicotine gum > nicotine spray > cigarettes (addictive)
Metabolism
Hepatic CYP2A6 to cotinine (t 1/2 1-4 hrs)
Metabolised to inactive metabolite quickly, difference to cocaine (not metabolised in blood)
Describe the pharmacodynamics of nicotine.
Nicotine acts on nicotinic receptor in ventral tegmental area to cause dopamine release from nucleus accumbens.
Cardiovascular
Free fatty acids - increase in VLDL, LDL —> atherosclerosis
Metabolic
Increase metabolic rate
Neurodegenerative disorders - positive effect
Parkinson’s disease: increase cytochrome proteins —> neurotoxins (increased metabolism of toxins)
Alzheimer’s disease: decrease amyloid toxicity, decrease amyloid precursor protein (APP)
Describe the effect of caffeine.
Causes euphoria
Adenosine acts in A1 receptor and suppresses reward pathway
Caffeine blocks adenosine (adenosine receptor antagonist)
Describe the pharmacokinetics of alcohol.
Explain Disulfiram Genetic polymorphism.
Dosing
Units: 1 unit = 10 ml/ 8g of absolute alcohol
Administration
Alcohol leaves stomach into small intestine
Drinking on an empty stomach has a greater effect on you
When drinking on a full stomach, alcohol remains in the stomach and stomach is busy churning up the contents
Speed of onset is dependent on gastric emptying
20% in stomach, 80% in small intestines
Metabolism (90%), 85% in liver
Alcohol —> acetaldehyde
Via alcohol dehydrogenase (75%)
Mixed function oxidase (25%) - liver upregulates this enzyme —> tolerance to alcohol, better at metabolising and break down faster
First pass hepatic metabolism
Enzymes are saturable if not enough enzyme, alcohol leaks out to system
Therefore, the faster you drink, the higher the blood alcohol levels
15% - GIT (stomach)
Alcohol —> acetaldehyde (alcohol dehydrogenase)
Females have 50% less AD
Acetaldehyde —> acetic acid (aldehyde dehydrogenase)
Distribution
Alcohol is water soluble so distributes in water very effectively
Blood levels are higher in a woman than a ,am because
- more leaks out (enzyme)
-more concentrated (less body water)
Disulfiram Gentic polymorphism - Asian flush - don’t break down aldehyde dehydrogenase as well so acetaldehyde builds up = flush
Disulfiram can be effective as alcohol aversion therapy because it blocks the enzyme so acetaldehyde builds up
Describe the pharmacodynamics of alcohol.
Low pharmacological potency - small molecule so can bind to a lot of targets ‘lock and key’ but not so well so needs a lot more of it - high dose needed
Acute effects
CNS
Has positive effect on GABA, promote Cl- influx (direct) - high pre vs post-synaptic allopregnenolone (binds to GABA receptor) (increased inhibition )
NMDA receptors - low allosteric modulation (reduced excitation)
Ca2+ channels - low neurotransmitters (reduced excitation)
Overall
1) CNS is functionally complex
2) ethanol has low potency therefore low selectivity
Euphoria
Opiates/ alcohol act as GABA receptor agonist on u-receptor so reduced GABA inhibition and more dopamine release.
Also impair:
- corpus callosum - passes info from left (logic) to right (feelings)
- hypothalamus - controls appetite, emotions, temperature and pain sensation
- reticular activating system - consciousness
- hippocampus - memory
- cerebellum - movement and coordination
- basal ganglia - perception of time
CVS
Cutaneous vasodilation: flushing
Decrease Ca2+ entry: precapillary can’t contract so increase blood flow
Increase prostaglandins (vasodilation)
Heart rate increases, tachycardia
Alcohol depresses arterial baroreceptor so baroreceptor firing decreases so inhibition of sympathetic less
Endocrine system
Diuretics (polyuria) - AD suppresses vasopressin release
Chronic effects
CNS
Thiamine —> enzymes in metabolism —> cerebral energy utilisation
There are brain regions with high metabolic demand
Thiamine not enough in alcoholics therefore impaired metabolism, NMDA excitotoxicity, ROS
Dementia - cortical atrophy/ decreased volume of cerebral white matter - confusion (encephalopathy), oculomotor symptoms
Ataxia - cerebellar cortex degeneration - gait
Wernicke-Korsakoff syndrome (due to thiamine deficiency)
Wernicke’s encephalopathy (hypothalamus/ thalamus)
Korsakoff’s psychosis (deep brain e.g. hippocampus)
Liver
Use up NAD+
Decrease lipid metabolism
Decrease oyruvate into citric acid cycle
Decrease electron transport system therefore lipid increases, pyruvate —> lactic acid —> acidosis/ ketosis
Healthy liver —> fatty liver (reversible)
Glycerol and fatty acids deposited into hepatocytes as triacylglycerol (TAG) because of not enough NAD+
In hepatitis - mixed function oxidases are upregulated, generating free radicals so an inflammatory response, cytokine changes e.g. IL-6
Cirrhosis Fibroblasts (connective tissue cells) - increased fibrin depositions Hepatocytes regeneration decrease Fibroblasts increase Active liver tissue decrease
CVS
Beneficial effects
Decrease in mortality from coronary artery disease
Increase in HDLs
Increase in tPA levels, decrease platelet aggregation
Polyphenols in urine
GIT
Damage to gastric mucosa
Carcinogenic due to acetaldehyde
Endocrinology
Increase in ACTH secretion
Decrease in testosterone secretion
Hangover
Symptoms when blood alcohol concentration is 0, symptoms are worst
Nausea - acetaldehyde is irritant —> vagus —> vomiting centre
Headache - vasodilation
Fatigue - 1) sleep deprivation 2) rebound
Restlessness and muscle tremors - rebound
Polyuria and polydipsia - decrease in ADH secretion
Cure: sleep, drink water (clear our toxins - acetaldehyde?
Define haemostasis and thrombosis.
Haemostasis: physiological formation of a blood clot
Thrombosis: pathological formation of a blood clot
Describe the presentation of DVT and pulmonary embolism.
Describe the investigations of DVT and pulmonary embolism.
Describe the diagnosis and treatment of DVT and pulmonary embolism.
Describe the follow up of DVT and pulmonary embolism.
(In all investigation, check normal e.g. blood pressure, o2 etc.)
Immobility after surgery - susceptible to thrombosis
Right calf swollen and collateral superficial veins present
Palpation - localised tenderness and pitting oedema
Investigation
2 level Well’s score - around 5 (high - higher the score the more likely)
Blood taken for D-dimer testing (test for fibrin)
Proximal leg vein scan
Diagnosis and treatment
Positive D-dimer test - diagnosis of deep-vein thrombosis
Parenteral anticoagulant - Dalteparin (active antithrombin)
Ultrasound scan confirms DVT
Maintenance treatment with oral anticoagulant - rivaroxaban (FXa inhibitor)/ warfarin (VKA - vitamin K antagonist)
Follow up
Subsequent presentation:
-chest pain
-dyspnoea and tachypnoea
Investigations
Two level Wells score
CTPA
Diagnosis and treatment
CTPA confirms pulmonary embolism —> dalteparin/ heparin (more effective than dalteparin)
Ultrasound scan confirms DVT —> maintenance treatment - oral anticoagulant —> rivaroxaban/ warfarin
Describe the risk factors for DVT and pulmonary embolism.
Virchow’s triad
1) rate of blood flow
Blood flow slow/ stagnating —> no replenishment of anticoagulant factors and balance adjusted in favour of coagulation
(When immobile - slow rate to leg)
2) consistency of blood
Imbalance between pro-coagulation and anticoagulation factors (genetic)
3) blood vessel wall integrity
Damaged endothelia —> blood exposed to pro-coagulation factors (surgery, hypertension)
Describe acute coronary syndromes.
Background - NSTEMI
Non-ST elevated myocardial infarction (MI)
White thrombin —> partially occluded coronary artery
Treatment: antiplatelets
Background - STEMI
ST elevated myocardial infarction
White thrombus —> fully occluded coronary artery
Treatment: antiplatelets and thrombolytics
Caused by:
Damage to endothelium
Atheroma formation
Platelet aggregation
Describe the process of thrombosis.
Describe the anticoagulants in initiation and amplification.
Initial stages
Molecular level
Small-scale thrombin production
1) Tissue factor (TF)
TF bearing cells activate factors X and V forming prothrombinase complex
2) Prothrombinase complex
This activates factor II (prothrombin) creating factor IIA (thrombin)
3) Antithrombin (AT-III)
AT-III inactivated fIIa and fXa
Amplification
Cellular level
Platelet activation and aggregation
1) thrombin
Factor IIa —> activates platelets, high level of thrombin in artery —> activation of platelets
2) activated platelet
Changes shape
Becomes sticky and attaches to other platelets - aggregate, discoid —> skillet shape
Molecular level
Thrombin - binds to [rotease-activated receptor (PAR) on platelet surface
PAR activation —> rise in intracellular Ca2+ (changes shape of platelet)
Ca2+ rise —> exocytosis of adenosine diphosphate (ADP) from dense granules
1) ADP receptors
ADP activates P2Y12 receptors —> platelet activation/ aggregation (autocfrine effect, paracrine effect - from other platelets)
2) Cyclo-oxygenate
PAR activation —> liberates arachidonic acid (AA)
Cyclo-oxygenase (COX) generates thromboxane A2 (TXA2) from AA
3) glycoprotein IIb/IIIa receptor (GPIIb/ IIIa)
TXA2 activation —> expression of GPIIb/IIIa integrity receptor on platelet surface
GPIIb/IIIA - involved in platelet aggregation
Initiation: anticoagulants
1) Inhibit factor IIa
Dabiagatran (oral) - factor IIa inhibitor
2) Rivaroxaban (oral) - factor Xa inhibitor
3) increase activity of AT-III
Heparin (IV, SC) - activates AT-III (decrease fIIa and fXa)
Low-molecular weight heparina (LMWHs e.g. Dalteparin) - activate AT-III (decrease fXa)
4) Reduce levels of other factors
Warfarin (oral) - vitamin K antagonist
Vitamin K - required for generation of factors II, VII, IX and X
Activation
1) prevent platelet activation/ aggregation
Clopidogrel (oral) -ADP (P2Y12) receptor antagonist
2) inhibit production of TXA2 - low dose
Aspirin (oral) - irreversible COX-1 inhibitor
High doses no more effective but more side effects
3) Abciximab (IV, SC) - GpIIb/ IIIa targeted
Limited use and only by specialists
N.B. PAR receptor antagonists not used as much anymore
Propagation: thrombolytics Cellular level Generation of fibrin strands 1) activated platelets Large-scale thrombin production 2)thrombin Factor IIa —> binds to fibrinogen and converts to fibrin strands
Anticoagulants and Anti-platelets - do not remove pre-formed clots
Thrombolytics:
Convert plasminogen —> plasmin
Plasmin - protease degrades fibrin
Alteplase (IV) - recombinant tissue type plasminogen activator (rt-PA) - clotbluster
Only in emergency because high risk of excess bleeding
NB Antiplatelets used for prophylaxis, not specifically treatment of atherosclerosis Thrombolytics can be used to treat ruptured plaques but mainly indicated for ischaemic stroke
Describe the exogenous pathway and endogenous pathway of lipid metabolism.
Define remnant lipoproteins.
Exogenous
Dietary triglycerides and cholesterol —> intestine —> chylomicron —> LP lipase —> free fatty acids and chylomicron remnants (remain after partial breakdown of chylomicrons) —> chylomicron remnants deposited into vessels - atheroma/ liver - remnant receptor
FFA into skeletal muscle/ adipose tissue
Endogenous
Most LDL and HDL comes from this pathway.
LPL (lipoprotein lipase) and HL (hepatic lipase) metabolise most
IDL and LDL deposited into vessels - atheroma
HDL - reverse transport of cholesterol from vessels to liver
Remnant lipoproteins remain agter parietal breakdown of e.g. chylomicrons and high levels = prone to atherosclerosis. They can infiltrate through endothelium.
Include VLDL, chylomicron remnant, IDL
What are the lipoproteins?
Describe LDL and HDL.
Apoprotein A-1 - HDL
Apoprotein B - LDL
Can measure to see which one is higher - risk of heart disease.
LDL cholesterol Strongly associated with atherosclerosis and CHD events Modified by other risk factors: -low HDL cholesterol -smoking -hypertension -diabetes
HDL cholesterol Protective effect for risk of atherosclerosis and CHD 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
Describe the process of atherosclerosis.
Atherosclerosis - an inflammatory fibroproliferative disorder
1) LDL moves into subendothelium
2) LDL oxidised by macrophages and smooth muscle cells
3) release of growth factors and cytokines attracts additional monocytes
4) foam cell accumulation and SMC proliferation result in growth of the plaque
Endothelial dysfunction:
1) defective endothelium = leaky, increased endothelial permeability
2) upregulation of endothelial adhesion molecules
3) leukocyte adhesion
4) migration of leukocytes into the artery wall
Fatty streak formation:
1) adherence and entry of leukocytes
2) migration of smooth muscle cells
3) activation of T cells
4) adherence and aggregation of platelets
5) formation of foam cells
Complicated atherosclerotic plaque:
1) formation of fibrous cap
2) accumulation of macrophages
3) formation of necrotic core (macrophages and SMC’s die)
What are the types of atherosclerotic lesions.
Type I - lesion-prone location - adaptive thickening
Type II - macrophage foam cells
Type III - preatheroma - small pools of extracellular lipid
Type IV - atheroma - core of extracellular lipid
Type V - fibroatheroma - fibrous thickening
Type VI - complicated lesion - thrombus and fissure and haematoma
Describe differences between vulnerable plaque and stale plaque.
Vulnerable - thin fibrous cap, rich with lipids and macrophages
Division between lipid core and lumen can break down
Stable - thick fibrous cap - less likely to rupture even if thinner lumen
Describe the different drug therapies
Statins
HMG-CoA reductase inhibitors
o This halts the cholesterol synthesis pathway.
o Halts specifically the rate-limiting step.
o Reduces the modification of proteins involved in modifying gene translation to create LDL.
This has the effect of UP-REGULATING the LDL receptors expressed on hepatocytes in the liver which results in more LDL being removed from the blood.
This also results in more HDL levels in the blood.
Statin Properties
Selectivity ratio – the higher the selectivity ratio, the greater the chance of it being concentrated in the hepatocyte.
o I.E. Simvastatin gets into many cells as it’s very lipid soluble. Pravastatin is mainly hepatocytes.
Potency – the lower the number, the more powerful the drug is as an inhibitor of the enzyme.
Rule of 6: double the dose but only 6% reduction in LDL
Statins can be described to have a pleiotropic effect – both good and bad effects.
Statins have multiple effects not directly related to lowering cholesterol (e.g. anti-inflammatory action).
Fibrates
Main MoA is activation of PPAR alpha receptors (present in nucleus)
o PPAR – Peroxisome Proliferator Activated Receptors.
o Act on the liver.
Decrease FFAs and TGs.
Increases HDL very effectively but LDL doesn’t change a lot.
NOTE: Thiazolidinediones – PPAR-gamma receptor agonists.
o They are different!
o Act on adipose tissue.
Nicotinic acid
Should be very good but turns out in clinical practice it isn’t so not used very much.
Increase side effects and toxicity
Ezetimibe
Inhibits cholesterol absorption
Absorbed into intestines then activated as glucoronide
Can be co-administered with statins to avoid the “rule of 6” with statins to have a more dramatic effect at lowering LDL.
CETP inhibitors E.g. torcetrapib
CETP converts HDL into LDL and so inhibiting it increases HDL levels.
Can lead to raised BP due to activation of aldosterone synthesis?
PCSK9 inhibitors
PCSK9 is an inhibitor of the LDL receptor.
Monoclonal anti-PCSK9 antibodies have been made to inactivate PCSK9 and so more LDL can be absorbed by the liver.
One such group of patients that benefits from PCSK9 inhibition greatly are the people with Familial Hypercholesterolemia.
Vaccine?
Why are NSAIDs used?
Non-steroidal anti inflammatory drug
• Relief of mild-to-moderate pain (analgesic)
»Toothache, headache, backache »Postoperative pain (opiate sparing) »Dysmenorrhea (menstrual pain)
• Reduction of fever (antipyretic)
»Influenza
• Reduction of inflammation (anti-inflammatory)
»Rheumatoid arthritis
»Osteoarthritis
»Other forms of musculo-skeletal inflammation
»Soft tissue injuries (strains and sprains)
»Gout
How do NSAIDs work?
• Inhibition of prostaglandin and thromboxane
synthesis. These are:
• Lipid mediators derived from arachidonic acid
• Widely distributed
• Not stored pre-formed
• Receptor-mediated
NSAIDs inhibit cyclo-oxygenases (COXs 1 and 2) - rate limiting step, preventing formation of prostanoids e.g. prostaglandin, prostacyclin and thromboxane formation
COX-1 and COX-2 with different (but
overlapping) cellular distributions, very similar structures
Prostanoid receptors
10 known receptors e.g. DP1 and 2, EP 1,2,3,4 IP 1 and 2, TP
Named based on agonist potency
Prostanoids have both G protein-dependent and -independent effects
Physiological (desirable) and pro-inflammatory (undesirable)
State the way PGE2 (prostaglandin 2) activates receptor.
State the unwanted actions of PGE2.
Can activate 4 receptors, cAMP-dependent and independent downstream mechanisms
Unwanted actions: • Increased pain perception - lower threshold for • Increased body temperature • Acute inflammatory response • Immune responses • Tumorigenesis • Inhibition of apoptosis
Describe PGE2’s affect on pain perception.
Describe PGE2’s role in temperature increase.
Increases
Stimulation of PG receptors in the periphery sensitises the nociceptors which cause pain both acutely and chronically
EP4 receptor antagonist blocks the effect of the PGE2 analogue.
1 possible mechanism:
-cAMP mediated
-activates P2X3 nociceptors
-PGE2 only - PKA only
-PGE2 + inflammation Epac pathway activated and additional more PGE2 produced
Greater activation of P2X3 receptors = greater pain perception
2 possible mechanism:
EP1 receptors and/ or EP4 receptors (in periphery and spine)
Endocannabinoids (neuromodulators in thalamus, spine and periphery)
NSAIDs increase beta-endorphin in spine
Temperature
PGE2 is pyrogenic - inducing fever
Stimulates hypothalamic neurones initiating a rise in body temperature so NSAIDs reduce temperature.
State the desirable egg eyes of PGE2 (and other prostanoids).
• Bronchodilation (although there is evidence that
PGE2 can desensitise β2adrenoceptors)
• Gastroprotection
• Renal salt and water homeostasis
• Vasoregulation (dilation and constriction
depending on receptor activated)
Why shouldn’t NSAIDs be taken by asthmatics?
Describe the role of PGE2 in gastric cytoprotection.
Inhibit cyclo-oxygenase so block formation of products
Cyclooxygenase inhibition favours production of leukotrienes - bronchoconstrictors
Gastric cytoprotection
COX-1
PGE2 downrequlates HCl secretion
PGE2 stimulates mucus and bicarbonate secretion so gastric pH increases
NSAIDs can increase the risk of ulceration. Aspirin inhibits COX-1 so maybe inhibiting COX-2 can reduce these effects .e.g Coxib family - selectively reversible inhibit COX-2 (celecoxib)
Describe the effect of PGE2 in nephron.
Describe the effect of NSAIDs on CVS.
Both COX-1 and COX-2 in glomerulus • PGE2 increases renal blood flow • NSAIDs can cause renal toxicity -Constriction of afferent renal arteriole -Reduction in renal artery flow -Reduced glomerular filtration rate
COX-1 and COX-2 in glomerulus
COX-1 in collecting duct
COX-2 in ascending limb
So not like one enzyme is good and one is bad
CVS NSAIDS can have serious unwanted cardiovascular effects • Vasoconstriction • Salt and water retention • Reduced effect of antihypertensives 50% deaths from NSAIDs are cardiovascular • Hypertension • Myocardial infarction • Stroke
Evidence that selective COX-2 inhibitors
pose higher risk of cardiovascular disease
than conventional NSAIDS even though
mechanism is unclear
Coxibs MoA
Suppression of prostaglandins, causes loss of control on mediators which act physiologically to instigate thrombosis, increased platelet aggregation, BP and atherogenesis
Summarise the safety of NSAIDs.
Analgesic use
• Usually occasional
• Relatively low risk of side effects Anti-inflammatory use
• Often sustained
• Higher doses
• Relatively high risk of side effects (more likely in chronic conditions - usually elderly)
Strategies other than COX-2 selective NSAIDs for limiting GI side effects
• Topical application
• Minimise NSAID use in patients with history of GI
ulceration
• Treat H pylori if present - predisposes to ulcers
• If NSAID essential, 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
Development of newer NSAIDs which may be safer
• Dual COX and LOX inhibitors
For asthmatic patients
No safe option on the market (liver injury)
• Nitric oxide or Hydrogen sulphide releasing
NSAIDS (protective in GI)
NO and H2S protective to GI and CVS
A number of options undergoing testing
Late stage clinical trials
Inhibit both prostaglandins and leukotrienes so May decrease risk in asthmatics
Describe aspirin and its effects on platelet aggregation.
• Unique among the NSAIDS • Selective for COX-1 • Binds IRREVERSIBLY to COX enzymes • Has anti-inflammatory, analgesic and anti- pyretic actions • Reduces platelet aggregation
Effects of prostanoids on platelet aggregation
Thromboxane A2 from platelets causes platelet aggregation
Prostacyclin from endothelial cells inhibits platelet aggregation (PGI2).
Effects of aspirin on platelet aggregation
Irreversible blockage on thromboxane A2 made by COX-1, platelets - no nucleus so can’t make more platelets
Some downregulation, not complete blockade on PGI2 synthesis by COX-2 and COX-2, endothelial cells have nucleus so can replenish stores of COX-1 and COX-2 therefore decrease in platelet aggregation
Anti-platelet actions of aspirin 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
• Use low dose to allow endothelial resynthesis of COX-2
State the major side effects of aspirin seen at therapeutic doses.
• Gastric irritation and ulceration
• Bronchospasm in sensitive asthmatics
• Prolonged bleeding times
• Nephrotoxicity
• Side effects likely with aspirin because it
inhibits COX covalently, not because it is
selective for COX-1
Describe the link between aspirin and Reye’s syndrome.
Patients under 20 Viral infection and aspirin Damage to mitochondria leading to
ammonia production resulting in
damage to astrocytes – oedema in
brain
Describe paracetamol, its MoA and overdose.
• Is a widely used effective analgesic for mild-to-moderate pain which is available over the counter • Has anti-pyretic action • Has minimal anti-inflammatory effect • Therefore it is not a NSAID
MoA
• Not understood, probably central and peripheral
• ? COX- 3
• ? Via Cannabinoid receptors
• ? Interaction with endogenous opioids
• ?interaction with 5HT and adenosine receptors
Overdose
May cause irreversible liver failure
If glutathione is depleted the metabolite oxidises thiol groups of key hepatic enzymes and causes cell death
(Not enough glutathione to remove NAPQI)
Antidote for paracetamol • Add compound with –SH groups • Usually intravenous Acetylcysteine • Occasionally oral methionine • Could be added to the formulation but increased cost • Acetyl cysteine used in cases of attempted suicide and accidental poisoning • If not administered early enough, liver failure may be unpreventable – transplant only option
Now restriction how much you can buy
No more than 2 packs per transaction
What is an opiate? Describe the structure-activity.
Derived from the poppy
Morphine - natural Codeine - natural (Methylmorphine) Thebaine Papaverine (Opioid - anything that has opiate like activity)
Structure-activity
E.g. morphine
2 hydroxyl groups - position 3 and position 6, hydroxyl group at position 3 required for binding - codeine and heroin (diacetylmorphine) are pro drugs which need to be activated to reveal hydroxyl group so not as effective binding, hydroxyl at position 6 when oxidised increases lipophilicity of drug by 10 fold I.e. remove group (side note: heroin most lipid soluble because of acetyl groups)
Receptor interactions:
- hydrogen bonds
- van Dee Wallace forces
Tertiary nitrogen = analgesia and permits receptor anchoring, if quaternary decreases analgesia because can’t access brain as effectively
Extend side chain to 3+ carbons and you generate antagonist
‘Morphine rule’ Used to believe these were needed for activity -aromatic ring -spacer -quaternary carbon centre -basic nitrogen
Fentanyl most potent because it doesn’t have quaternary carbon
Describe the pharmacokinetics of opioids.
Route of administration/ bioavailability
Oral vs intravenous
Opioids are weak bases, pKa > 8
In blood and lymph least ionised so less access to tissues (pH low)
Lipid solubility: methadone/fentanyl»_space; heroin > morphine
More lipid soluble, more potent
Methadone has slow metabolism so can accumulate in adipose tissue and is slowly released back into bloodstream (used for heroin treatment not anymore)
The active metabolites of morphine, heroin and codeine are activity in the ability to cause euphoria but not restorative depression therefore positive
Morphine - morphine 3-G glucuronide, morphine 6-G glucuronide
Heroin - morphine
Codeine - morphine
Morphine has greater affinity to mu-receptors than M6G
Metabolism 1: morphine - morphine-6-glucuronide (10% active metabolite), fentanyl (fast metabolism) vs methaodne (slow metabolism)
Metabolism 2: 5-10% codeine —> morphine, CYP2D6 O-dealkylation - activates (slow); CYP3A4 - deactivates (fast)
Describe the pharmacodynamics of opioids.
Opioids act via specific opioid receptors
Endogenous opioid peptides include:
Endorphins (euphoria, analgesic)
Enkephalins
Dynorphins/ neoendorphins
Endorphins bind to mu or delta receptors in cerebellum, caudate nucleus, nucleus accumbens, PAG
It has a pain/sensorimotor function
Enkephalins bind to delta receptors in nucleus accumbens, cerebral cortex, hippocampus, putamen
Motor/cognitive function
Dynorphins bind to Kappa receptors in hypothalamus, putamen and caudate
Neuroendocrine function
Cellular MoA at opiate receptors:
Depressant - hyperpolarisation (increase potassium efflux), decrease Ca2+ inward current, decrease adenylate cyclase activity, decrease neurotransmitter release
-analgesia
-euphoria
-depression of cough centre (anti-tussive)
Other effects:
-depression of respiration (medulla)
-stimulation of chemoreceptors trigger zone (nausea/ vomiting)
-pupillary constriction
-GI effects
Describe the opioid effect on analgesia.
Decrease pain perception
Increase pain tolerance
Modulation of pain transmission
Periacqueductal gray region receives stimuli from different parts of the brain and determines level of response, cortex can modify e.g. allergy to wasps - previous experience reminded so increase pain, decrease pain tolerance, think it’s more painful OR twist ankle in sports, previous experience not bad so increase pain tolerance
Pathway:
Information from thalamus (mu) + —> cortex (mu, delta) +/- —> PAG (mu, kappa)—> + NRM (delta) - —> dorsal horn (mu, kappa)—> periphery (or thalamus directly acts on PAG)
Cortex, thalamus, dorsal horn and periphery, hypothalamus involved in pain perception
PAG, NRM, NRPG involved in pain tolerance
On top of the above, hypothalamus (kappa) can also modulate response to PAG e.g. state of health - if poor health - exacerbate pain; good health - reduce pain
LC (sympathetic) suppresses painful stimulito dorsal horn e.g. for fight or flight
Substantia gelatinosa within spinal cord in dorsal horn modifies signal from NRM to determine how much inhibition is needed on the sensory neurones
Opioids act on dorsal horn and periphery to depress pain perception
On PAG To enhance firing by surpressing GABA which has an inhibitory effect on pain tolerance centres
On NRPG to enhance firing “
Describe the opioids’ effect on euphoria.
Opiates act on mu-receptor and decrease GABA exocytosis, reducing the inhibition on VTA so more dopamine is released from nucleus accumbens
Describe opioids’ action as an anti-tussive.
Stimulation of mechano or chemo receptors (throat, respiratory passages or stretch receptors in lungs) —> afferent impulses to cough center (medulla) —> efferent impulses via parasympathetic and motor nerves to diaphragm, intercostal muscles and lung —> increased contraction of diaphragmatic, abdominal and intercostal (ribs) muscles = noisy expiration (cough)
Peripherally: opioids act on Ach-NK-C fibres relaying to vagus (inhibit) (between stimulation of mechano… and afferent impulses)
Centrally: act on 5HT1A receptors (between afferent and efferent impulses…) (inhibit)
Centrally: act on
Describe opioids’ role in respiratory depression.
Opioids act on mu2 receptors. There central chemoreceptors which detect PaCO2. They depress receptors detecting PaCO2 therefore urge to breath also depressed because reduced firing of chemoreceptors to the medullary control centre (inspiratory and expiratory actions)
Occurs at high dose
Describe opioids’ role in nausea and vomiting.
Opioids act on mu receptors which switches of GABA disinhibiting the chemoreceptor trigger zone
This causes vomiting reflex from medullary vomiting centre
Describe opioids’ role in miosis.
Opioids act on mu receptors within the Edinger-Westphalia nucleus which switches of GABA increasing parasympathetic nerve firing rate
Unconsciousness and tightly constricted pupils = opioid/ heroin overdose ‘pin-prick eyes’
Normally when unconscious, pupils are dilated
Describe opioids’ role in gastro-intestinal disturbance.
Role in urticaria?
There are lots of opioid receptors in the myenteric plexus (mu and kappa)
Opioids cause decreased gastric motility, increase in water reabsorption, decrease in gastric emptying
Urticaria
Looks like allergic response but isn’t - non-IgE mediated
Some opioids’ OH groups cause mast cell degranulation
Massive histamine release from mast cells under the skin
PKA mediated, not receptor mediated (mu receptor)
Can switch opioids given
Describe tolerance, dependence and overdose in opioid use.
Tolerance
Increased opioid use = high arresting which mediates receptor internalisation
Therefore tissue less receptive to opioids
Dependence
Withdrawal associated with:
-psychological craving
-physical withdrawal - cells compensate, opioids cAMP decreases so cells upregulated cell activity increasing adenyl cyclase so muscular contractions and cramps
Overdose
- coma
- respiratory depression
- pin-point pupils
- hypotension
- treatment: naloxone (opioid antagonist) I.v.
- resembling flu
Describe inflammatory bowel disease and its risk factors.
There are two major forms: ulcerative colitis and Crohn’s disease
Can’t distinguish in 10% of patients
Affects children, adolescents and adults
Genetic risk factors
Genetic predisposition
201 loci identified
People of White European origin most susceptible
Environmental
- diet
- medication -antibiotics can upset the stomach and cause diarrhoea
- smoking
- microbiome - chicken and egg situation, change in microbiome caused by disease or caused the disease
Autoimmune disease
Defective interaction between mucosal immune system and gut flora - infection
Complex interplay between host and microbes —> disrupted innate immunity and impaired clearance —> pro-inflammatory compensatory responses —> physical damage and chronic inflammation
Describe the differences between CD and UC.
Table
Describe the clinical features of IBD.
Can be systemic as well as local • Abdominal pain and cramping • Diarrhoea, bloody faeces • Mouth ulcers • Anaemia • Fever • Arthritic pain • Skin rashes • Uveitis • Weight loss
Give a summary of the therapies used for IBD.
Table
What are the supportive therapies given for IBD (acutely sick patients)?
What are the classic symptomatic treatments?
Fluid/ electrolyte replacement (diarrhoea)
Blood transfusion/ oral iron (anaemia)
Nutritional support (malnutrition common when you can’t eat)
Classic symptomatic treatments For active disease and prevention of relapse -aminosalicylates e.g. mesalazine -glucocorticoids e.g. prednisolone -immunosuppressive e.g. Azathioprine
Describe aminosalicylates.
Mesalazine to 5-aminosalycylic acid (5-ASA)
Olsalazine (2 linked 5-ASA molecules)
Anti-inflammatory
Pharmacokinetics:
Mesalazine - no need to be metabolised, site of absorption is in small bowel and colon (absorbed throughout)
Olsalazine - metabolised by colonic flora, absorbed in colon (active in colon where split)
Aminosalicylates have anti-inflammatory actions by modulating transcription.
Down regulate pro-inflammatory molecules such as TNF-alpha, IL-1beta, IL-6
Considered to be a safe drug
Effective at induction and maintenance of remission
Combined oral and rectal administration probably more effective than either alone for generalised disease
Rectal delivery better for localised disease (proctitis)
Probably better than glucocorticoids
Usually first line treatment in UC
CD
Ineffective in inducing remission of CD
Other therapies preferable
Describe glucocorticoids in IBD.
E.g. prednisolone, fluticasone, budesonide (not absorbed so fewer side effects for budesonide)
- Powerful anti-inflammatory and immunosuppressive drugs.
- Derived from the hormone cortisol
- Activate intracellular glucocorticoid receptors which can then act as positive or negative transcription factors
Potent anti-inflammatory and immunosuppressive actions of GCs due to downregulation of inflammation cascade caused by macrophages and T cells (works in CU
When given systemically, chronic glucocorticoid administration causes many unwanted effects
Budesonide is safe but standard oral glucocorticoids better at inducing remission in active CD
UC:
Strong evidence that aminosalicylates are superior and glucocorticoids are not recommended
CD:
GCs drugs of choice for inducing remission, budesonide preferred if mild, avoid as maintenance therapy due to side effects
Describe the use of azathioprine.
A pro-drug activated by gut flora to 6-mercaptopurine.
Now also give 6-mercaptoturine directly
Purine antagonist
Immunosuppressive
Interferes with DNA synthesis and cell replication
Effects on immune responses It impairs: -cell and antibody-mediated immune responses -lymphocyte proliferation -mononuclear cell infiltration -synthesis of antibodies It enahnces: -T cell apoptosis
CD:
Not recommended for active disease
Azathioprine or other immunosuppressants recommended for maintaining remission - need to be given for few months before you see an effect
Glucocorticoid sparing
Slow onset - 3 to 4 months treatment for clinical benefit
If ineffective move to biological therapies (antibodies) but more potent
Unwanted side effects: Pancreatitis Bone marrow suppression Hepatotoxicity Increased risk (around 4 fold) of lymphoma and skin cancer
Interferes with DNA synthesis and cell replication; metabolites cause side effects:
6-MeMP is hepatotoxic
Allopurinol inhibits Xanthine oxidase - given for gout, wont form 6-TU so other pathways increased, increasing side effects
6-TGN (incorporation into DNA) - beneficial but also causes myelosuppression
What are some strategies for minimising unwanted effects of drugs?
Administer topically - fluid or foam enemas or suppositories - at site of action - not too much systemic
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 systematic circulation.
What are some strategies for targeted drug delivery?
PH dependent polymer coating system - e.g. can’t degrade in stomach but can in gut
Pressure/ osmotic controlled coating system - semi-permeable membrane; push layer pushing drug out
Time-dependent polymer coating-system - gradual swelling of coating leading to drug release
Prodrug based conjugates - enzymes in specific organs can degrade
Now can combine time and pH - potential to give better targeting of frugs to areas of inflammation (higher conc. to site of damage and reduce side effects because reduce overall dose)
What are potential curative therapies for IBD?
Describe one of them.
1) manipulation of the microbiome
2) biological therapies
Manipulation of the microbiome:
Exclusive enteral nutrition (EEN)
-liquid diet
-allows ‘resting’ of the mucosa and recovery of the gut flora because not a lot of work needed to be done
-unpalatable and hard to maintain
-only recommended for induction of remission if patient cannot take steroids
Probiotic therapies
- different organisms have different effects so difficult to generalise
- no evidence for probiotics in CD
- weak evidence for maintenance of remission in UC
Faecal macrobiota replacement (FMT) therapies
- faeces from healthy patient put into unhealthy patient, unhealthy bacteria outnumbered by healthy bacteria
- unclear if help because cause or effect of microbiome
Antibiotic treatment - rifaximin
- interferes with bacterial transcription by binding to RNA polymerase
- reduces inflammatory mediator mRNA
- may be microbiome modulator
- not absorbed from gut
- some evidence for sustained remission in moderate CD
- only recommended if complications relating to infection
Describe biological therapies in IBD.
-Anti-TNFalpha antibodies (anti-tumour necrosis factor alpha)
E.g. infliximab (iv)
-Other antibodies effective but some have more side-effects
-New humanised antibodies coming on stream e.g. entanacept
MoA
Works on both TNF-alpha on cell membranes and and solubilised form
Stops binding to receptors
-Anti-TNFalpha reduces activation of TNF-alpha receptors in the gut
-reduces downstream inflammatory events
-binds to membrane associated TNF-alpha
-induces cytolysis of cells expressing TNF-alpha
-promotes apoptosis of activated T cells
Pharmacokinetics
- infliximab given intravenously
- very long half-life (9.5 days)
- most patients relapse after 8-12 weeks
- therefore repeat infusion every 8 weeks
Used successfully in treatment of CD
Potentially curative, but many patients relapse
Successful in some patients with refractory disease and fistulae (leakage can spread infection)
Very good for maintaining fistula closure
Problems and adverse effects:
- responders lose response due to production of anti-drug antibodies and increased drug clearance
- 4x-5x increase in incidence of tuberculosis
- risk of reactivation dormant TB
- increased risk of septicaemia
- worsening of heart failure
- increased risk of demyelinating disease
- increased risk of malignancy
- can be immunogenic - azathioprine reduces risk but raises TB/ malignancy risk
Early use better than last resort
Combined infliximab and azathioprine therapy recommended rather than monotherapy
New targets:
- integrins (needed for cells to migrate)
- interleukins (IL12; IL17; IL23)
- interleukin receptors
- Janus kinase (JAK) cytoplasmic cell signalling
Describe the proximal convoluted tubule.
From inside to outside:
Lumen, microvilli (maximise absorption), tubule cell, basal interdigitation, interstitium
Capillaries surround
There are aquaporins on apical side of proximal tubule cell. H2O flows through this, Na+ can enter the cell freely (transceullular)
Glucose and amino acids can be reabsorbed into cell by being coupled with Na+ (cotransporter)
There is also a Na+/H+ transporter
CO2 and H2O enter freely and are converted to H+ and HCO3- by carbonic anhydrase within the cell
On the basal side there is a Na+/K+ ATPase to maintain the concentration gradient; Na+ leaves the cell and K+ enters the cell
There is also a Na+/HCO3- cotransporter which leave the cell to allow water absorption
Within the tubule lumen (on apical side) there are no proteins, within the interstitium (basal side) there is oncotic pressure due to lots of protein drawing in water
Paracellular pathway includes H2O, Na+, Cl-, HCO3-
Exogenous agents -drugs e.g. glucoronide is excreted
Describe the Loop of Henle.
Descending limb
H2O enters transcellularly and paracellularly leading to a isotonic tubule lumen and hypertonic interstitium ; NO ions
Ascending limb
Impermeable to H2O
Na+/Cl-/K+ cotransporter on apical side
Na+/K+ ATPase and K+/Cl- cotransporter on basal side
Countercurrent effect
- Na+ leaves the ascending limb and enters medullary interstitium - concentrating it
- Fluid in ascending limb decreases in osmolarity (H2O from ascending into descending within tubule -equilibrate)
- More concentrated medullary interstitium draws water from the permeable descending limb
- Fluid in descending limb increases in osmolarity (Na+ from descending into ascending to equilibrate)
- More fluid enters and forces fluid from descending to ascending limb - this fluid has increased in osmolarity due to increased Na+ concentration in the medulla
- Na+ leaves the ascending limb and enters medullary interstitium
- Fluid in ascending limb decreases in osmolarity
- Na+ leaves ascending limb again entering medullary interstitium and fluid in ascending limb decreases further in osmolarity
Describe the distal tubule.
Early distal tubule
On apical membrane there is a Na+/Cl- cotransporter
On basal membrane there is a Na+/K+ ATPase and K+/Cl- cotransporter
Impermeable to free water reabsorption
Aldosterone acts on MR and increases Na+ channel and Na+/K+ ATPase
Late distal tubule/ collecting duct
On apical there is a Na+ transporter for free movement of Na+
Impermeable to free water reabsorption but there are aquaporins (AQP2)on apical membrane which can allow water to enter (mediated by vasopressin acting on V2 on basal membrane), H2O leaves through AQp 3/4 on basal membrane
No free water movement because it would disturb the concentration gradient. Osmolarity increases down the medulla so water would just flow into the tubule.
How do diuretics work?
What are the 5 main classes of diuretics? And where they act on.
1) inhibit the reabsorption of Na+ and Cl-; increase excretion
2) increase the osmolarity of tubular fluid I.e. decrease the osmotic gradient across the epithelia
Classes
1) osmotic diuretics e.g. mannitol; proximal tubule, descending limb, collecting duct
2) carbonic anhydrase inhibitors e.g. acetazolamide; proximal tubule
3) loop diuretics e.g. frusemide (furosemide); ascending limb
4) thiazides e.g. bendrofluazide (bendroflumethiazide); distal tubule
5) potassium sparing diuretics e.g. a milo ride, spironolactone; late distal tubule
First 2 not really used as diuretics
Explain loop diuretics.
Block Na+/Cl- cotransporter on apical membrane, usually K+ enters lumen but LD reduces this
Therefore ability to concentrate interstitium decreases, can’t absorb as much from CD, interferes with counter current mechanism
Potassium recycling drives the positive lumen potential, a lack of this leads to a loss of Ca2+ and Mg2+
Action on Na+ reabsorption: inhibit Na+ and Cl- reabsorption in ascending limb - 30%
Action on H2O reabsorption: increase tubular fluid osmolarity/ decrease osmolarity of medullary interstitium = decraesed H2O reabsorption in the collecting duct
Other effects: increased delivery of Na+ to distal tubule because can’t reabsorb in ascending limb which increases K+ loss
Ca2+ and Mg2+ - loss of K+ recycling
Explain thiazides.
Block Na+/Cl- cotransporter on apical membrane. Lose NaCl because prevent reuptake
Not affecting Loop of Henle so not affecting counter current so not too powerful
Action on Na+ reabsorption: inhibit Na+ and Cl- reabsorption in early distal tubule
Action on H20 reabsorption: increased tubular fluid osmolarity = decreased H20 reabsorption in the collecting duct
Other effects:
Increased delivery of Na+ to distal tubule, in tased K+ loss (increased Na+/K+ exchange) -in common with thiazides
Increased Mg2+ loss and increased Ca2+ reabsorption (unknown)
Describe the problem of thiazides and loop diuretics.
One stimuli fro renin is low tubular Na+; diuretics cause more Na+ to distal tubule so sending more Na+ to macula dense. This inhibits renin but this is only short term (1-2 days)
In the long term, it promotes Na+ and water loss; stimuli for renin secretion is reduced renal perfusion pressure and Na+ loss. Macula densa recognises this and causes renin production.
Particular problem with loop diuretics because inhibits protein which puts Na+ in macula densa (triple transporter)
Loop diuretics are most powerful because they cause most sodium retention in tubule
Loop diuretic battling with RAAS to do opposite effect so give ACEi along with diuretics
Explain potassium sparing diuretics.
Weakest diuretic because acts at end of kidney
Spironolactone is a mineralocorticoid receptor antagonist and reduces effects of aldosterone on Na+ transporters, reduced Na+/K+ exchange so reduced K+ loss
Action on Na+ reabsorption: inhibit Na+ reabsorption (and concomitant K+ secretion) in early distal tubule - 5%
Action on H20 absorption: increased tubular fluid osmolarity = decreased H20 reabsorption in the collecting duct
Other effects: decreased reabsorption of Na+ to distal tubule, increased H+ retention (decreased Na+/ H+ exchange)
What are some common side effects of diuretics.
Loop diuretics: hypovolaemia, metabolic alkalosis (Cl- loss), hyperuricemia, hypokalaemia, hyponatraemia
Thiazides: metabolic alkalosis, hyperuricemia, hyponatraemia, hypokalaemia
Potassium sparing diuretics: hyperkalaemia
Hyperuricemia
Uric acid uses same transporter as diuretic (organic anion transporter), excretes uric acid into lumen (too big through glomerulus), both uric acid and diuretic compete so reduced excretion of uric acid
What are the clinical uses of diuretics?
Thiazides - 1st line treatment in most countries for hypertension
Salt sensitive
55 or older of Afro Caribbean
Second line in combination with ACEi in those younger than 55.
Thiazides slightly more effective but people pee all the time
More effective because:
Initial response (4-6 weeks) - due to decreased plasma volume
After 4-6 weeks: plasma volume restored because of RAS
Chronic thiazides: decrease in TPR because activation of eNOS (endothelium)/ Ca2+ channel antagonism - prevent contraction of vascular smooth muscle / opening of KCa channel (smooth muscle)
Short term - diuretic effect
Long term: vasodilator effect
Explain the use of diuretics in the treatment of heart failure.
Loop diuretics can cause acute reduction in congestion - blood builds up in venous system because heart not effective —> exertion of pressure —> oedema (reduced)
But can activate RAS increasing renin secretion
Additional use of potassium sparing diuretics can be used to combat this
Decreased Na+/K+ exchange later therefore greater effect of water and Na+ retention
Define psychoses and its symptoms.
Psychoses can be split into schizophrenia (disorder of thought process) or affective disorders (disorder of mood).
Affective disorders can be further be split into mania and depression
Symptoms Emotional (psycho-logical): -misery, apathy, pessimism -low self-esteem -loss of motivation -anhedonia - loss of ability to enjoy activities
Biological (somatic)
- slowing of thought and action (psychomotor retardation)
- loss of libido
- loss of appetite, sleep disturbance
Describe the two types of depression.
1) Unipolar depression/ depressive disorder
-mood swings in same direction
-relatively late onset
-reactive depression (response from external events) - stressful life events .e.g. death
(Non-familial, not hereditary)
-endogenous depression (response from inside body) - unrelated to external stresses - familial pattern (hereditary)
-drug treatment similar for endogenous and reactive
2) Bipolar depression/ maniac depression
- oscillating depression/ mania - opposite to depression e.g. aggression and increased activity
- less common
- early adult onset
- strong hereditary tendency
- drug treatment (lithium - mood stabiliser, affects intracellular secondary messenger systems e.g. decrease cAMP, narrow therapeutic window - dosage needs to be controlled)
Explain the monoamine theory of depression.
Changes in transmission of NA and 5-HT:
Depression = functional deficit of central MA transmission
Mania = functional excess
Based on pharmacological evidence
Biochemical evidence inconsistent - chemicals depressed = decrease in monoamine metabolites in urine = reduction in turnover of monoamine in brain so supports but no pattern seen when seeing from mild to severe - we don’t see further decrease, no correlation
Delayed onset of clinical effect of drugs - may be due to adaptive changes instead of MA theory:
-down-regulation: a2, beta, 5HT receptors (may be what’s causing the anti-depressive activity)
Other reasons:
HPA axis (hypothalamic pituitary adrenal axis (increase in CRH (cortiocotrophin releasing hormone levels) - high in clinical depression
Hippocampus neurodegeneration
Pharmacological evidence supporting MA
E.g. TCA’s, block NA and 5-HT reuptake, mood increases
MAO inhibitors, increase stores of NA and 5-HTR, mood incraeses
Reserpine, inhibits NA and 5-HT storage (inhibits loading of vesicles in pre-synaptic terminal), mood decreases
State the types of antidepressants drugs.
1) TCAs
2) MAOIs
3) SSRIs
Explain TCAs.
Example: amitriptyline
MOA:
-3 ring structure
-neuronal monoamine re-uptake inhibitors
NA=5-HT
Other receptor actions:
- a2 - a2 antagonist = enhanced release
- mAChRs
- histamine
- 5-HT
Delayed down-regulation of B-adrenoceptors and 5-HT2 receptors - delayed action of anti-depressants
Pharmacokinetics:
- rapid oral absorption
- highly PPB (90-5%) - plasma protein bound
Unwanted effects:
At therapeutic dosage
-atropine-like effects (amitriptyline) - inhibits muscarinic receptors - dry mouth, dry skin, constipation, blurred vision
-postural hypotension (vasomotor centre) -a2 receptors in vasomotor
-sedation (H1 antagonism) - may be used for sleep disturbance
Acute toxicity (overdose)
- CNS: excitement, delirium, seizures (lowers seizure threshold) —> coma, respiratory depression
- CVS: cardiac dysrhythmias —> ventricular fibrillation/ sudden death
- care - attempted suicide
Drug interactions:
- PPB: highly plasma protein bound so other drugs can interact and displace from binding site so more circulation, TCA effects increased by aspirin, phenytoin, warfarin
- hepatic microsomes enzymes: increase TCA effects - drugs that use same enzymes will compete therefore metabolised more slowly
- potentiation of CNS depressants (alcohol)
- antihypertensive drugs (monitor closely)
Describe MAOIs.
Example: Phenelzine
MOA:
MAO-A: NA and 5-HT
MAO-B: DA
-most are non-selective MAOIs - A and B
-irreversible inhibition —> long d.o.a
-structure consists of a highly reactive hydrazine
-rapid effects: increase cytoplasmic NA and 5-HT (lipid soluble into brain and inhibits MAO in NA terminals, increase cytoplasmic NA, enhanced release of NA, increase synaptic, increase neuronal action
-delayed effects: clinical response: down-regulation of B-adrenoceptors (B1 and B2)
and 5-HT2 receptors
-inhibition of other enzymes - not entirely specific
Pharmacokinetics:
- rapid oral absorption
- short plasma t1/2 (few hours) but longer d.o.a. (Irreversible inhibition, hydrazine tightly covalently binds)
- metabolised in liver, excreted in urine
Unwanted effects:
-atropine-like effects ( hypertensive crisis (throbbing headache, increase b.p., intracranial haemorrhage)
Tyramine-containing foods can act on NA terminals and push NA out of vesicles; indirectly acting symptomimetic drug like amphetamine - tyrosine
Tyramine broken down by MAO; dietery restriction: decrease marmite, mature cheese, red wine
-MAOIs and TCAs —> hypertensive episodes (avoid)
-MAOIs and pethidine (opioid analgesic, interact with MAOI) —> hyperpyrexia (increase body temperature), restlessness, coma and hypotension
New: moclobemide: reversible MAO-A inhibitor (RIMA), decrease drug interactions, decrease doa
Describe SSRIs.
Example: fluoxetine
MOA:
- selective 5-HT re-uptake inhibition
- less troublesome side-effects; safer in overdose (not prone to cheese reaction)
- but less effective vs severe depression
Pharmacokinetics:
- p.o. Administration
- plasma t1/2 (18-24 hours)
- delayed onset of action (2-4 weeks)
- fluoxetine competes with TCAs for hepatic enzymes (avoid co-administration) enhance each other;s effect = toxic
Unwanted effects:
-fewer than TCAs/MAOIs
-nausea, diarrhoea, insomnia and loss of libido
-interact with MAOIs (avoid co-administration)
Fluoxetine (Prozac): currently most prescribed antidepressant drug
Describe other antidepressant drugs.
Venlafaxine: dose-dependent reuptake inhibitor
5HT > NA»_space; DA (SNRI)
2nd line treatment for severe depression
Mirtazapine: a2 receptor antagonists
Increased NA and 5-HT release
Other R interactions (sedative)
Useful in SSRI-intolerant patients
Describe how adverse drug events can be classified.
Onset
Severity
Type
Onset of event:
- acute: within 1 hour e.g. anaphylaxis
- sub-acute: 1 to 24 hours
- latent: > 2 days
Severity of reaction: -mild: requires no change in therapy -moderate: requires change in therapy, additional treatment hospitalisation -severe: disabling or life-threatening Results in death Life-threatening Requires or prolongs hospitalisation Causes disability Causes congenital anomalies Requires intervention to prevent permanent injury
Type A
-extension of pharmacological effect
-usually predictable and dose dependent
-responsible for at least two-thirds of ADRs
E.g. atenolol and heart block, anticholinergics and dry mouth, NSAIDs and peptic ulcer
(Expect from the pharmacology of the drug:predictable)
Side note: digoxin constant increase in ADR with dose, paracetamol rapid increase at high dose (diagram)
Type B
-idiosyncratic (in some people, not others) or immunologic reactions
-includes allergy and “pseudoallergy”
-rare (even very rare) and unpredictable
-e.g. chloramphenicol and aplastic anaemia (total bone marrow failure)
ACE inhibitors and angioedema
Many serious ADRs are totally unexpected e.g. Herceptin and cardiac toxicity
Type C
- associated with long-term use
- involves dose accumulation
- e.g. methotrexate (immunosuppressant, cancer) and liver fibrosis, antimalarials and ocular toxicity
Type D
- delayed effects (sometimes dose independent)
- carcinogenicity (e.g. immunosuppressants)
- teratogenicity (e.g. thalidomide)
Type E
-withdrawal reactions: opiates, benzodiazepines, corticosteroids (lost ability to make steroids by themselves)
-rebound reactions - when stop the drug; situation is worse than before giving frug
Clonidine, beta-bookers, corticosteroids
-adaptive reactions - anti-psychotics
Neuroleptic (major tranquillisers)
Augmented pharmacological effect
Bizarre
Chronic
Delayed
End-of-treatment
Describe the classification of allergies.
Describe pseudoallergies.
Type I - immediate, anaphylactic (IgE)
E.g. anaphylaxis with penicillins
Type II - cytotoxic antibody (IgG, IgM)
E.g. methyldopa and haemolytic anaemia
Type III - serum sickness (IgG, IgM)
Antigen-antibody complex
E.g. procainamide-induced lupus
Type IV - delayed hypersensitivity (T cell)
E.g. contact dermatitis
Pseudoallergies: not associated with any immune response; just a pharmacological reaction
Aspirin/ NSAIDs - bronchospasm (drugs stopping prostaglandins being made in lungs but still making leukotrienes - pro-inflammatory and bronchoconstrictors
ACE inhibitors - cough/ angioedema (Afro-Carribean)
What are the common causes of ADRS?
Describe ADR detection
- antibiotics
- antineoplastics
- anticoagulants
- cardiovascular drugs
- hypoglycemics
- antihypertensives
- NSAID/ Analgesics
- CNS drugs
The more medications, the more adverse reactions.
ADR Detection: Subjective report -patient complaint Objective report -direct observation of event -abnormal findings: physical examination, laboratory test, diagnostic procedure
Yellow card scheme: introduced after thalidomide
- for established drugs only report serious adverse reactions
- for black triangle drugs (newly licensed, usually <2 years) - report any suspected adverse reaction
Explain drug-drug interactions.
Explain the first one.
Pharmacodynamic: related to the drug’s effects in the body
-receptor site occupancy
Pharmacokinetic: related to the body’s effects on the drug
-absorption, distribution, metabolism, elimination
Pharmaceutical: drugs interacting outside the body (mostly IV infusions)
Pharmacodynamic drug interactions:
Additive, synergistic (one drug potentials another drug - more effective/ toxic) or antagonistic effects from co-administration of two or more drugs
-synergistic actions of antibiotics
-overlapping toxicities - ethanol and benzodiazepines
-antagonistic effects - anticholinergic mediations (amitriptyline and acetylcholinesterase inhibitors)
Asthma: anticholinergic and B-agonists both bronchodilator but different mechanisms
Explain pharmacokinetic drug interactions.
Pharmacokinetic drug interactions:
- alteration in absorption
- protein binding effects - albumin binding effects
- changes in drug metabolism
- alteration in elimination
Alterations in absorption:
Chelation
-irreversible binding of drugs in the GI tract
-tetracyclines, quinolone antibiotics - ferrous surface (Fe2+), antacids (Al3+, Ca2+, Mg2+), dairy products (Ca2+) - insoluble compound formed
Protein binding interactions:
-competition between drugs for protein or tissue binding sites - increase in free (unbound) concentration may lead to enhanced pharmacological effect
-many interactions previously thought to be protein binding interactions were found to be primarily metabolism interactions
-protein bound interactions are not usually clinically significant but a few are (mostly with warfarin)
Displace —> free drug, short time as free drug can be metabolised and excreted
Drug metabolism and elimination 3 different pathways drug can take: 1) excreted, unchanged by kidney .e.g. diuretic 2) phase 1 —> liver/kidney 3) phase 1 —> phase 2 —> kidney
Phase 1 metabolism
- oxidation (key pathway)
- reduction
- hydrolysis
Phase II metabolism
- conjugation
- glucuronidation
- sulphation
- acetylation
Drug metabolism interactions
-drug metabolism inhibited or enhanced by coadministration of other drugs
CYP450 substrates:
- Metabolism by a single isozyme (predominantly)
- Metabolism by multiple isozymes: most drugs metabolised by more than one isozyme; if co-administered with CYP450 inhibitor, some isozymes may “pick up slack” for inhibited isozyme
CYP450 inhibitors
- climetidine - H2 antagonist in peptic ulcers
- erythromycin and related antibiotics
- ketoconazole
- ciprofloxacin and related antibiotics
- ritonavir and other HIV drugs
- fluoxetine and other SSRIs
- grapefruit juice
CYP450 inducers
- rifampicin
- carbamazepine
- (phenobarbitone)
- (phenytoin)
- St John’s wort (hypericin) - similar to SSRIs
Inhibition is very rapid
Induction takes hours/ days
Drug elimination interactions:
Almost always in renal tubule
-probenecid and penicillin (good) - stop elimination of penicillin
-lithium and thiazides (bad) - increased excretion of sodium in the expense of lithium; retain lithium
Deliberate interactions
- levodopa and carbidopa (infrareds efficacy of levodopa in CNS)
- ACE inhibitors and thiazides (anti-hypertensive)
- penicillins and gentamicin (staphylococcal infections)
- salbutamol and ipratropium
Describe the presentation, diagnosis, pathophysiology and of a H-pylori positive uncomplicated peptic ulcer.
ACUTE
Presentation
-epigastric pain, burning sensation that occurs after meals
Investigations and diagnosis
- carbon-urea breath test - positive (detect urea in breath positive likely to have H pylori positive ulcer)
- stool antigen test - positive
- H-pylori positive peptic ulcer
Pathophysiology
Helicobacter pylori (H Pylori)
-dissolves mucus layer - protects epithelia from acidic environment
-causes epithelial cell death
-increased acidity —> peptic under; bleeding - blood loss in severe ulceration
Treatment
- amoxicillin and clarithromycin/metronidazole - antibiotics
- proton pump inhibitor (PPI) - reduces acid production
(Combination therapy used for peptic ulcers in general to eliminate bacterial infection and decrease H+ produced in stomach)
Describe H-pylori.
Helicobacter pylori
- gram negative, motile (can form ulcers in other parts of stomach), microaerophilic bacterium
- resides in human GI tract - exclusively colonising gastric-type epithelium (commensal)
Ulcer formation
- increased gastric acid formation - increase gastrin or decrease somatostatin
- gastric metaplasia - cell transformation due to excessive acid exposure
- downregualtion of defence factors - decrease epidermal factor and decrease bicarbonate production
Virulence
- urease - catalysed urea into ammonium chloride and monochloroamine —> damage epithelial cells
- urease - antigenic (can be detected in stool)—> evokes immune response (can further damage epithelia)
- certain virulent strains produce CagA (antigenic) - inflammatory response or VacA (cytotoxic - damages cells directly ) - more intense tissue inflammation
Describe the presentation, diagnosis, pathophysiology and treatment of a H pylori positive complicated peptic ulcer.
1st line not effective, CHRONIC - has had infection before and has been treated before
Presentation
-epigastric pain, burning sensation
Investigations and diagnosis
- carbon-urea breath test - positive
- stool antigen test - positive
- H pylori positive peptic ulcer
Pathophysiology Helicobacter pylori (H pylori) -dissolves mucus layer: urease enzyme -causes epithelial cell death: exotoxins and inflammation -increased acidity -> peptic ulcer
Treatment
- antibiotics for H pylori (amoxicillin and clarithromycin/ metronidazole)
- consider quinolone, tetracycline - bismuth, sucralfate (alkylating agents) - decreases acidity, harder for bacteria enter
- proton pump inhibitor (omeprazole) - 4-12 weeks
Describe proton pumps.
H+-K+-ATPase (proton pump)
- expressed ons excretory vesicles within parietal cells
- increase Ca2+ —> increase cAMP —> translocation of secretory vesicles to parties like cell apical surface —> H+ secretion
Ulcer formation
-increased activity of proton pump - increased H+ secretion and reduction gastric pH
1) increase Ca2+
2) increase cAMP cause incraese proton pumps, pump out H+ ions in exchange for K+ ions
Describe the presentation, diagnosis, pathophysiology and treatment of a H pylori negative peptic ulcer.
Presentation
-epigastric pain, burning sensation
Investigations and diagnosis -carbon-urea breath test - negative -stool antigen test - negative -NSAID use - positive (None of the above are not due to H-pylori)
Pathophysiology NSAID -directly cytotoxic -reduces mucus production -increases likelihood of bleeding -increased acidity —> peptic ulcer
Treatment
- removal of NSAID - if for heart, removing can cause heart problems
- proton pump inhibitor or histamine H2 receptor antagonist (Ranitidine) - 4-8 weeks (PPI more cheap and effective)
- H2 receptor increases acid secretion
Explain gastric acid regulation.
gastric acid regulation
1) acetylcholine (ACh) released from neruones (vagus/enteric) acts on muscarinic (M3) receptors - increase Ca2+
2) prostaglandins (PGs) released from local cells act on EP3 receptors - decrease cAMP (decrease expression, protective)
3) histamine released from enterochromaffin-like cells (ECL) act on H2 receptors - increase cAMP
4) gastrin released from G-cells, acts on cholecystokinin B receptors - increase Ca2+
Gastric acid secretion
- increase Ca2+ and cAMP —> translocation of secretory vesicles to parietal cell apical surface —> H+ secretion
- somatostain - peptide that inhibits G-cells, ECL cells and parietal cells
Describe the background of Alzheimer’s.
Epidemiology
-main risk factor = age
-huge economic cost but low research investment - lots of drug failures - low probability of success
-genetics - APP, PSEN, ApoE (hereditary - early onset of Alzheimer’s)
(2 types - age; genetics)
Clinical symptoms
- memory loss - especially recently acquired information
- disorientation/ 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
Explain the pathophysiology of Alzheimer’s.
Amyloid hypothesis - beta-amyloid plaques in brain
Physiological processing:
1) amyloid precursor protein (APP) cleaved by alpha-secretase
2) sAPPalpha released - C83 fragment remains
3) C83 digested by gamma secretase
4) products removed
Pathophysiological processing:
1) APP cleaved by beta-secretase - cleaves at different site, giving longer protein to be digested
2) sAPPbeta released - C99 fragment remains
3) C99 —> digested by gamma secretase released beta-amyloid (Abeta protein)
4) Abeta forms toxic aggregates - primarily form outside neurones but in Alzheimer’s primarily within
May cause immune reaction, destruction of neurones, produce toxins and destroy
Tau hypothesis
Physiology:
-soluble protein present in axons
-important for assembly and stability of microtubules
Pathophysiology:
-hyperphosphorylated tau insoluble —> self-aggregates to form neurofibrillary tangles
-these are neurotoxic
-this also results in microtubule instability
Primarily found intracellular you (in neurones)
Usually first Tau, second Abeta
Inflammation hypothesis
Physiology - microglia
-specialised CNS immune cells - similar to macrophages
Pathophysiology - Microglia
- increased release of inflammatory mediators and cytotoxic proteins
- in tased phagocytosis
- decreased levels of neuroprotective proteins
Tau/ Abeta can activated these
NSAIDs (ibuprofen) less likely getting Alzheimer’s
Explain the pharmacotherapy of Alzheimer’s disease.
Anticholinesterases:
1) donepezil (used for severe form; most effective; only need to be administered once)
- reversible acetyl cholinesterase inhibitor - (Bentyl-cholinesterase mostly in CNS, acetyl everywhere)
- long plasma half-life
2) rivastigmine
- pseudo-reversible AChE and BChE inhibitor
- 8 hour half-life (don’t want BChE inhibition = side effects but counteracted when given as a patch - more selective to AChE)
- reformulated as transdermal patch
3) Galantamine
- reversible cholinesterase inhibitor
- 7-8 hour half life
- alpha7 nAChR agonist
NMDA receptor blocker
4) Memantine
- use dependent* non-competitive (different site of binding) NMDA receptor blocker with low channel affinity
- only licensed for moderate-severe AD
- long plasma half life
- effective only if excessive NMDA activity, glutamate bind to NMDA (happens in severe neurodegeneration)
2 and 3 for mild - moderate disease
Drugs don’t relate to pathophysiology
(side note: 5 units in acetylcholine receptor arranged differently in NMJ and CNS)
Describe the treatment failures.
1) gamma-secretase inhibitors
Tarenflurbil (like Ibuprofen) and Semagacestat
-Tarenflurbil binds to amyloid precursor protein (APP) molecule
-Semagacestat is a small molecule gamma-secretase inhibitor, also inhibits enzyme notch - increase skin cancer
Also involved in physiological processes
2) B-amyloid
Bapineuzumab and Solanezumab
-humanised monoclonal antibodies
-developing Aducanumab - acts on aggregates and monomers different (vaccine in early stages of development)
3) Tau inhibitors
Methylene blue
-licensed for the treatment of methaemoglobinaemia - not much money to do clinical trials; make skin slightly blue
Describe dopamine synthesis and metabolism.
Describe the dopaminergic pathways.
Synthesis
-L-tyrosine —>(via tyrosine hydroxylase) L-DOPA —> (via DOPA decarboxylase) dopamine (DA)
Tyrosine hydroxylase is rate-;limiting step, lots of tyrosine can be flooded by tyrosine hydroxylase needed
Metabolism
- DA removed from synaptic cleft by dopamine transporter (DAT) and noradrenaline transporter (NET) - transport back into neurone
- Three enzymes metabolise DA:
1) monoamine oxidase A (MAO-A): metabolises DA, NE and 5-HT
2) MAO-B: metabolises DA (more selective)
3) Catecholamines-O-methyl transferase (COMT): wide distribution, metabolises all catecholamines
MAO A and B found in cell membranes of mitochondria
COMT in glial cell; post synaptic membrane
Major locations of dopaminergic pathways
1) Nigrostriatal pathway - substantia nigra pars compacta (SNc) to the striatum. Inhibition results in movement disorders
2) Mesolimbic pathway - ventral tegmental area (VTA) to the Nucleus Accumbens (NAcc). Brain reward pathway
3) Mesocortical pathway - VTA to the cerebrum. Important in executive functions and complex behavioural patterns
4) Tuberoinfundibular pathway - arcuate nucleus to the median eminence. Inhibition results in hyperprolactinaemia (endocrine pathways; side effects in drugs)
Describe the pathophysiology and clinical presentation of Parkinson’s disease.
Epidemiology
- 1-2% of individuals over 60 years old
- around 5% do cases are due to mutations in certain genes (e.g. SNCA, LRRK2) - early onset
Pathophysiology
- severe loss of dopaminergic projection cells in SNc
- Lewy bodies and Lewy neurites —> found respectively within neuronal cell bodies and axons
- consist of abnormally phosphorylated neurofilaments, ubiquitous and alpha-synuclein
Clinical presentation
- motor symptoms —> resting tremor (early onset), bradykinesia, rigidity (late onset), postural instability (cardinal symptoms)
- autonomic nervous sue stem effects —> olfactory deficits, orthostatic hypotension, constipation
- neuropsychiatric —> sleep disorders, memory deficits, depression, irritability
Lewy bodies start at frontal so first neuropsychiatric —> motor symptoms
Explain the treatment for Parkinson’s disease.
1) dopamine replacement
L-tyrosine (TYR) (not given because need enzyme) —> dopamine (DA)
Rate-limiting enzyme: tyrosine hydroxylase (TH)
Dopamine not given because has effects in periphery so not enough enters CNS
Levodopa (L-DOPA)
- rapidly converted to DA by DOPA decarboxylase (DOPA-D)
- can cross blood-brain barrier (BBB)
- peripheral breakdown by DOPA-D —> leads to nausea and vomiting (give protector transport molecules - refer to adjuvants
- long term side effects: dyskinesias and on-off effects*.NOT disease modifying; does not prolong life, just better QoL, target symptoms
*on = L-DOPA pill give large dose in one go, dopamine doesn’t last long - wear off = off
Counteracted by being given as intestinal gels -slow release
Adjuncts
DOPA decarboxylase inhibitors: Carbidopa and Benserazide
-do not cross BBB —> prevent peripheral breakdown of levodopa
-reduce required levodopa dosage because more goes to CNS
COMT inhibitors: Entacapone and Tolcapone
-increase amount of levodopa in brain; prevent breakdown of L-DOPA but not as effective as gels
Receptor activation
-dopamine (DA) can act on D1,5(Gs linked) or D2-4 9Gi linked) receptors
-DA is re-uptaken by the dopamine transporter (DAT) and metabolised by monoamine oxidase (MAO) enzymes
D2 receptors in post-synaptic do not disappear in neurodegeneration - don’t need intact presynaptic neurone
2) Dopamine receptor agonists
Ergot derivatives: Bromocriptine and Pergolide
-act as potent agonists of D2 receptors
-associated with cardiac fibrosis - valve problems
Non-ergot derivatives: Ropinirole and Rotigotine
-Ropinirole also available as extended-release formulation
-Rotigotine also available as a patch
Can get hallucinations as side effect
3) Monoamine oxidase B (MAOB) inhibitors
Selegiline (deprenyl) and Rasagiline
-reduce the dosage of L-DOPA required
-can increase the amount of time before levodopa treatment is required
Cheese reaction
Describe the background of schizophrenia.
Epidemiology
- affects 1% of population and has genetic influence
- onset of symptoms between 15-35 years
- higher incidence in ethnic minorities e.g, Afro-Caribbean immigrants - stick to their ethnicities
- Patients’ life expectancy 20-30 years lower than average because lifestyle choices they make e.g. drugs, alcohol, suicide (not because of neurodegenration)
Symptoms Positive symptoms: -increased mesolimbic dopaminergic activity -hallucinations: auditory and visual -delusions: paranoia -thought disorder: denial about oneself
Negative symptoms: -decreased mesocortical dopaminergic activity Affective flattening: lack of emotion -alogia: lack of speech -avolition/ apathy: loss of motivation
Explain the treatment for schizophrenia.
First generation antipsychotics
Chlorpromazine:
-discovered whist developing new antihistamines (histamine receptor antagonist)
-primary mechanism of action - possibly D2 receptor antagonism
Side effects
-high incidence - anti-cholinergic, especially sedation
-low incidence - extrapyramidal side effects (EPS) motor disorders like Parkinson’s
Haloperidol
-very potent D2 antagonist (around 50x more potent than chlorpromazine)
-therapeutic effects develop over 6-8 weeks
-little impact on negative symptoms
Side effects
-high incidence - EPS
Second generation antipsychotics
Clozapine
-most effective antipsychotic
-very potent antagonist of 5-HT2A receptors
-only drug to show efficacy in treatment resistant schizophrenia and negative symptoms
Side effects
-can cause potentially fatal neutropenia, agranulocytosis, myocarditis and weight gain
=metabolic side effects; black box warning
Risperidone
-very potent antagonist of 5-HT2A and D2 receptors
Side effects
-more EPS and hyperprolactinaemia than other atypical antipsychotics
Quetiapine
-very potent antagonist of H1 receptors
Side effects
-lower incidence of EPS than other antipsychotics
Aripiprazole (third generation??)
-partial agonist of D2 and 5-HT1A receptors (when too much activity , decrease DA, when to little increase DA)
-no more efficacious than typical antipsychotics
Side effects
-reduced incidences of hyperprolactinaemia and weight gain than other antipsychotics
Microchip can be inserted in drug to monitor compliance
Explain GABA neurotransmission, metabolism.
GABA neurotransmission
- GABA neurones in brain are short axon interneurones in specific areas in the brain, can easily inhibit, e.g. reduce hyperactivity in hippocampus.
1) action potential arrives at presynaptic nerve terminal and
2) causes the ecocytosis of vesicles containing GABA
3) acts on postsynaptic Cl- ionophore receptor (GABA A) - type 1 receptor
4) uptake into presynaptic or into glial cells to inactivate
5) converted into SSA (succinct semialdehyde by GABA-T transaminase) - GABA is synthesised from glutamate (precursor) by GAD (glutamate decarboxylase)
- autoreceptor in presynaptic membrane act like a2 receptors - regulate GABA release (GABA B)
GABA metabolism
GABA —>(via GABA-T) succinic semialdehyde —> (SSDH - succinic semialdehyde dehydrogenase) succinic acid
- GABA-T and SSDH are mitochondrial enzymes
- Succinic acid goes to TCA cycle (cycle because glutamate also from TCA “GABA shunt”)
- GAD is a cytoplasmic enzyme - cytoplasm of presynaptic membrane, specific to GABA so can map GABA neurones
-Inhibitors of GABA metabolism —> large increase in brain GABA
Examples:
-sodium valproate (epilim) - works by inhibiting voltage sensitive sodium channels; weak GABA-T inhibitor, inhibits SSDH as well
-vigabatrin (sabril) - GABA-T inhibitor - binds covalently to GABA-T “suicide inhibitor”
Above two can also be used as anti-convulsants in epilepsy
-Vigabatrin (Sabril)
Explain the GABA A receptor complex.
Differentiate between the actions.
Consists of 4 main proteins: GABA receptor protein, GABA modulin, BDZ receptor protein, Barbiturate receptor protein
GABA receptor protein:
- GABA binds, links with BDZ by GABA modulin
- this causes opening of chloride channel protein (transient)
- Cl- flows through GABA receptor into postsynaptic cell (influx)
- membrane potential drops, making it harder to excite the postsynaptic cell
BDZ receptor protein:
- Benzodiazepines binds to own receptor
- enhances Cl- influx into PSC because of GABA
- binding of GABA to GABA receptor increased because of better affinity
- enhanced BDZ binding because of GABA binding
Barbiturate receptor protein:
- barbiturates enhance normal action of GABA (Cl- influx)
- enhance binding of GABA
- barbiturates bind here but doesn’t enhance barbiturate binding
- also different to BDZ because higher conc. of barbiturates can directly act on Cl- channel
Bicuculline - competitive GABAA antagonist, competes with GABA for GABA binding site
-Flumazenil - benzodiazepine antagonist and competes with BDZ
BZs and BARBs have no activity alone (allosteric action - not agonists, different sites to GABA; PAMs - positive allosteric modulation)
They have different binding sites and different mechanisms:
- BZs increase frequency of openings
- BARBs increase duration of openings
BARBs are less selective than BZs
- decrease excitatory transmission: reduce glutamate mediated excitation
- other membrane effects: direct effect on Cl- channel
This may exploding its use in induction of surgical anaesthesia and its low margin of safety
State the clinical uses of BZs and BARBs.
Define the and the ideal criteria.
- anaesthetics (BARBs only: thiopentone - inducing general anaesthesia)
- anticonvulsants (diazepam; (BZ) clonazepam; (BZ) phenobarbital (BARB))
- anti-splastics (diazepam) - reduce muscle tone
- anxiolytics
- sedatives/ hypnotics
Definitions
- anxiolytics: remove anxiety without impairing mental or physical activity (used to be called minor tranquillisers)
- sedatives: reduce mental and physical activity without producing loss of consciousness
- hypnotics: induce sleep
When increase anxiolytic, increase hypnotic effect
When decrease hypnotic dose, increase anxiolytic effect
Ideally they should:
- hand wide margin of safety
- not depress respiration
- produce natural sleep (hypnotics)
- not interact with other drugs
- not produce ‘hangovers’
- not produce dependence
Describe barbiturates.
Ring structure, -tone, -tol, -tal Range of clinical uses (refer to previous flash card) including: - sedative/ hypnotic E.g. amobarbital Severe intractable insomnia T1/2 20-25 hrs
Unwanted effects (not drugs of 1st choice)
- low safety margins
- depress respiration
- overdosing lethal
After natural sleep (decrease REM —> hangovers/ irritability)
- enzyme inducers: if another drug administered that is metabolised by same set of drugs - less effective e.g. warfarin
- potentiate effect of other CNS depressants (e.g. alcohol) can increase risk of overdose
- tolerance
- dependence: withdrawal syndrome - insomnia, anxiety, tremor, convulsions, death
Describe benzodiazepines.
-Epam, -epate 3 ring structure -20 available, all act at GABA receptors -All similar potencies and profiles, MoA -Pharmacokinetics largely determine use
Pharmacokinetics
- administration - well absorbed P.O (mainly administered orally)
- peak plasma - 1hr
- IV vs status epilepticus (severe prolong seizure activity)
- distribution: bind plasma proteins strongly, highly lipid soluble, wide distribution
- metabolism - usually extensive (liber)
- excretion —> urine; glucuronide conjugates
Duration of action vary greatly:
1) short acting
2) long-acting - slow metabolism and/ or generate active metabolites (which have BZ like activity)
Metabolism Long acting: Diazepam —> temazepam —> oxazepam —> glucuronide Short acting: Temazepam —> oxazepam —> glucuronide
Uses: Anxiolytics: diazepam (valium) Chlordiazepoxide (Librium) Nitrazepam (Long acting)
Oxazepam - hepatic impairment (Shrina acting used in hepatic failure, longer because failure)
Sedative/hypnotics: temazepam
Oxazepam
(Short acting)
Nitrazepam - daytime anxiolytic effect (longer, early morning waking)
BZ advantages:
- wide margin of safety
- overdose —> prolonged sleep (rousable), flumazenil given to decrease BZ
- mild effect on REM sleep
- do not induce liver enzymes
Unwanted effects:
- sedation, confusion, amnesia, ataxia (impaired manual skills)
- potentiate other CNS depressants (alcohol, BARBs) - increase risk of overdose
- tolerance (less than BARBs; ‘tissue’ only)
- dependence —> withdrawal syndrome, similar to BARBs (less intense) - withdraw slowly
- free plasma by aspirin, heparin - displace BZ from binding site
Describe other sedatives/hypnotics and anxiolytics.
Other sedative hypnotics
Zopiclone:
-short acting (t1/2 5 hrs)
-acts at BZ receptors (cyclopyrrolone) increase GABA, not BZ
-similar efficacy to BZs
-minimal hangover effects but dependency still a problem (used side by side with BZ)
Other anxiolytics
Some antidepressant drugs
-SSRIs
-less sedation and dependence/ delayed response/ long-term treatment - generalised anxiety disorder (can co-treat depression and anxiety)
Some antiepileptic drugs
-Valproate, tiagabine (both increase GABA inhibition)
Some antipsychotic drugs
-olanzapine, quetiapine (atypical antipsychotics)
Propranolol
-improves physical symptoms: tachycardia (B1), tremor 9B2) - damps down fast heart beats and shakes off anxiety
Buspirone
-5HT1A agonist
-fewer side effects (< sedation)
-slow onset of action (days/ weeks)
What are the desirable characteristics of general anaesthesia?
- Loss of consciousness (all anaesthetics at low conc)
- Suppression of reflex responses (immobile) (all anaesthetics at high conc)
- relief of pain (analgesia)
- muscle relaxation
- amnesia (forgetting experience)
What are the molecular targets of general anaesthesia. (MoA)
Gaseous/ inhalation
- nitrous oxide
- diethyl ether
- halothane
- enflurane
Intravenous
- propofol (also has euphoric effects)
- etomidate
All anaesthetics structurally very different
Mechanism of action
-lipid theory: the more lipid soluble the anaesthetic, the more the potency
-anaesthetic potency increases in direct proportion with oil/ water partition coefficient
(Meyer/Overton correlation)
Problems:
1) at relevant anaesthetic conc. change in bilateral was minute
2) how would this change impact membrane proteins?
Mechanism of action cam either be due to reduced neuronal excitability or altered synaptic function
Altered synaptic function Intravenous agents: -increased activity of GABAA receptors -B3 subunit = suppression of reflex responses -A5 = amnesia
Inhalational agents: (halogenated agents)
- GABA A (brain; 50% less effective)/ glycine receptors (SC)
- a1 - suppression of reflex responses
-Less specific - more places they act
-Blocks NMDA-type glutamate receptors
Probably compete with co-agonist glycine
- Suppress receptor - neuronal nicotinic ACh receptors
- Analgesic
- as you increase conc. of anaesthetic, the activation of receptors decreases
Reduced neuronal excitability
Inhalational agents:
-TREK (background leak) K+ channels - mediated hyperpolarisation of neurones; slowly leak K+ out
-consciousness
Describe the neuroanatomy of general anaesthetics. (MoA)
Loss of consciousness
-depress excitability of thalamocortical neruones “time to sleep”
-influences reticular activating neurones (TREK switched on)
Cortical neruones and reticular activating neurones are GABA A receptor rich.
Suppression of reflex responses
-depression of reflex pathways in the spinal cord - disconnect brain from SC
GABA and glycine important in relaying painful stimuli from spinal cord to brain
Amnesia
-decrease synaptic transmission in hippocampus/ amygdala
Impair memory - a5 subunit in GABA receptor
Describe the use of general anaesthetics in clinical setting.
Inhalation vs intravenous anaesthetic
If Anaesthetic has a low blood: gas partition coefficient = doesn’t dissolve well in blood, remains in gaseous state - allows transfer into brain
When stop giving anaesthetic to remove it, low blood: gas partition coefficient means that anaesthetic can be quickly removed, diffuse into blood to lungs quickly
(Can diffuse across because lipid soluble)
If high blood:gas partition coefficient, not much transferred to brain, trapped in blood and slower removal
Inhalation anaesthetics -rapidly eliminated -rapid control of the depth of anaesthesia (Good control over excretion) Intravenous anaesthetics -fast induction (already in blood) -less coughing/ excitatory phenomena (Little control on removing it because rely on liver to metabolise)
Loss of consciousness and suppression of reflex responses
Induction: propofol (induce with intravenous agent —> fast onset of anaesthesia) then remove
Maintenance: enflurane (inhalational to maintain - control over anaesthesia)
Relief of pain (analgesia) - opioid (e.g. i.v. Fentanyl)
Muscle relaxation - neuromuscular blocking drugs (e.g. suxamethonium)
Amnesia - benzodiazepines (e.g. i.v. Midazolam)
Describe the generation of a neuronal action potential.
Describe the structures of local anaesthetics.
1) depolarisation - resting Na+ channels open (voltage sensitive), Na+ enters cells
2) repolarisation - Na+ channels close (inactivation) - flip, K+ channels open, K+ leaves cell
3) Na+ channels restored to resting state but K+ channels still open therefore cells refractory
4) Na+ and K+ channels restored to resting state therefore cell will respond normally to further depolarising stimulus
Structures
3 main areas: aromatic region, ester or amide bonds, basic amine side-chain
Cocaine is an ester, lidocaine is an amide
Benzocaine is an exception, it has no amine side chain, only alkyl group - weak LA but good solubility therefore used as a surface anaesthetic
Explain the interaction of local anaesthetics with sodium channels.
Most LA’s are basic
Unionised form of anaesthetic allows it to cross membranes (both outer membrane - connective tissue sheath and axon is membrane)
Ionised form binds inside of Na+ channels
Ion channels need to be open (use dependent pathway - hydrophilic) - the more rapidly neurones fire, the more LA can have an effect
In hydrophobic pathway, channels can be closed
LA more effective on open sensory neurones
Selectivity of pain - nociceptive neurones fire more rapidly than motor
Describe the effects of LAs.
1) percent generation and conduction of APs
2) do not influence resting membrane potential (unlike GABA)
3) may also influence channel gating - states of Na+ resting, inactivated and activated. LA may hold in inactivated state - refractory for longer
4) selectively block small diameter fibres and non-myelinated fibres (block more than myelinated as can enter more easily)
LAs are weak bases (pKa 8-9)
Infected tissue is acidic therefore higher proportion of LA imposed so not enough, need high concentration
Describe the routes/ methods of administration of LAs.
1) surface anaesthesia
- mucosal surface (mouth, bronchial tree)
- spray (or powder) or ointment
- high concentrations —> systemic toxicity
2) infiltration anaesthesia
- directly into tissues —> sensory nerve terminals
- minor surgery - can keep to minimal area - don’t want systemic toxicity - low in bloodstream
- adrenaline co-injection (NOT extremities) - vasoconstrictor therefore confines LA and minimises amount in bloodstream (systemic toxicity) and can also help stop bleeding; don’t use in extremities (fingers) - ischaemia, shut blood supply
3) Intravenous regional anaesthesia (directly into bloodstream)
- i.v. Distal to pressure cuff - restrict blood flow therefore regional
- limb surgery eg reset bone
- systemic toxicity of premature cuff release - when release early, can get bolts which can go straight to brain and heart (Atleast 20 mins)
4) Nerve block anaesthesia
- close to nerve trunks e.g. dental nerves
- widely used - low doses - slow onset
- vasoconstrictor co-injection (need accurate injection)
5) spinal anaesthesia (intrathecal)
- sub-arachnoid space (CSF found) - spinal roots
- abdominal, pelvic, lower limb surgery
- low does - limit systemic toxicity
- low bp.( preganglionic neruones, blocked too - small diameter and close) prolonged headache - pass to brain
- glucose (increase specific gravity) - restricting LA, bonus can move up or down, LA localise more L3/L4
6) Epidural anaesthesia
- fatty tissue of epidural space - spinal roots
- uses as for 5) and painless childbirth
- slower onset - higher doses (systemic toxicity)
- more restricted action - less effect on bp
Compare lidocaine and cocaine.
Absorption (mucous membranes)
Lidocaine (Amide) - good
Cocaine (ester) - good
Plasma protein binding
70%
90%
Metabolism:
Hepatic N-dealkylation
Liver and plasma non-specific esterases
Plasma t1/2
2hr (more stable)
1hr
(Bupivacaine (doa 6 hrs; epidural anaesthesia)
Unwanted effects Lidocaine: CNS -central stimulation -restlessness -confusion -tremor (Above are paradoxical - higher conc. dampen down) CVS -myocardial depression -vasodilation -low bp (Above due to Na+ channel blockade)
Cocaine: CNS -euphoria -excitation (dopamine re-uptake) CVS -high CO -vasoconstriction -high bp (Both CNS and CVS effects are sympathetic actions)
Summarise the physiological control of nausea/vomiting and identify the main mechanistic triggers.
Physiological control: Chemoreceptor trigger zone (CTZ) - receives multiple inputs from areas including stomach and vestibular nuclei
CTZ communicates with the vomiting centre —> nausea and vomiting
Mechanistic triggers: cytotoxic drugs, motion sickness, gastrointestinal problems, pregnancy, other higher functions
Describe anti-emetics in chemotherapy patients.
Presentation
- chemotherapy (cisplatin) for lung cancer
- chemotherapy induced nausea and vomiting (CINV)
Pathophysiology
- cisplatin is toxic to enterochromaffin cells (ECs) - release of free radicals
- free radicals - excessive 5-HT release
- 5-HT activates 5-HT3A receptors on nerve fibres to chemoreceptor trigger zone (CTZ) - outside BB eventhough in midbrain, also called area postrema
- CTZ activates nerves fibres to vomiting centre (VC)
- VC —> nausea
Treatment
-Ondansetron - 5-HT3A receptor antagonist (early stage nausea)
-glucocorticoids - reduce free radical production (anti-inflammatory - reduce nausea)
-aprepitant - neurokinin-1 receptor antagonist (activate by substance P from higher centres) - later stage nausea
(Triple therapy)
Describe anti-emetics in motion sickness.
Presentation
-motion sickness
Pathophysiology
- labyrinth (inside ear canals) - neural mismatch (seeing and moving mismatch) —> activates histamine receptors on vestibular nuclei
- vestibular nuclei activate muscarinic receptors on CTZ
- CTZ activates VC, which causes nausea
Treatment
- Promethazine - H1 receptor antagonist
- Hyoscine (scopolomine) - non-selective muscarinic receptor antagonist (more serious)
Describe anti-emetics in gastroparesis.
Presentation
- vomiting due to unknowingly cause
- abdominal pain and bloating
Pathophysiology
-gastroparesis - delayed emptying of the stomach
-reduced stomach contraction
-5-HT activates 5-HT3A receptors on CTZ
-CTZ activates nerve fibres to vomiting centre (VC)
-VC —> nausea
(D2 receptor activation on CTZ can —> nausea)
Treatment Metoclopramide -dopamine D2 receptor antagonist Pro kinetic - stimulates gastric emptying Inhibits D2 receptors in CTZ -5-HT3A receptor antagonist Inhibits activation of CTZ
Summarise the principle side effect profile of each class of anti-emetic drug.
5-HT3A receptor antagonists: headaches and constipation (because affects GI tract)
Histamine H1 receptor antagonists: drowsiness (beneficial - long journey, want to be drowsy to go to sleep)
Muscarinic receptor antagonists: dry mouth and drowsiness
Dopamine D2 receptor antagonists: galactorrhoea and extrapyramidal side effects
Describe the background for bacteria.
- single-cell microorganisms - cell wall and cell membrane
- an entire phylogenetic domain
- around 1/3 are pathogenic
Membrane properties
Gram positive bacteria
-prominent peptidoglycan cell wall
E.g. Staphylococcus aureus
Gram negative bacteria
-outer membrane with lipopolysaccharide
E.g. Escherichia coli
Mycolic bacteria
-outer mycolic acid layer
-e.g. mycobacterium tuberculosis
(Not differentiated by gram stain)
Describe prokaryotic protein synthesis.
Describe protein synthesis inhibitors.
1) Nucleic acid synthesis Dihydropteroate (DHOp) -produced from paraaminobenzoate (PABA) -converted into dihydrofolate (DHF) Tetrahydrofolate (THF) -produced from DHF by DHF reductase -THF —> important in DNA synthesis
2) DNA replication
DNA gyrase
-topoisomerase —> releases tension (unplait hair)
3) RNA synthesis
RNA polymerase
-produces RNA from DNA template
-differ from eukaryotic RNA polymerase
4) protein synthesis
Ribosomes
-produce protein from RNA templates
-differ from eukaryotic ribosomes
Protein synthesis inhibitors
1) DHOp - sulphonamides inhibit DHOp synthase
THF - trimethoprim inhibits DHF reductase
2) DNA gyrase- fluoroquinolones e.g. Ciprofloxacin inhibit DNA gyrase and topoisomerase IV
3) RNA polymerase
Rifamycins e.g. Rifampicin inhibits bacterial RNA polymerase - tuberculosis
4) RIbsomes inhibited by:
- aminoglycosides e.g. Gentamicin
- chloramphenicol
- macrolides e.g. Erythromycin
- tetracyclines
Describe bacterial wall synthesis and bacterial wall inhibitors.
1) Peptidoglycan (PtG) synthesis (produced intracellularly to be incorporated into cell wall)
- a pentapeptide is created on N-acetyl muramic acid (NAM)
- N-acetyl glucosamine (NAG) associates with NAM forming PtG
2) PtG transportation
- PtG is transporters across the membrane by bactoprenol
3) PtG incorporation
- PtG is incorporated into the cell wall when trasnpeptidase enzyme cross-links PtG pentapeptides.
Inhibitors
1) Glycopeptides e.g. Vancomycin bind to the pentapeptide preventing PtG synthesis
2) Bacitracin inhibits bactoprenol regeneration preventing PtG transportation
3) B-lactams bind covalently to transpeptidase inhibiting PtG incorporation into cell wall. B-lactams include: -carbapenems -cephalosporins -penicillins (B-lactam ring in structures)
4) Lipopeptide e.g. daptomycin disrupt gram +ve cell walls
Polymyxins - bind to LPS and disrupts gram -ve cell membranes
State the causes of antibiotic resistance.
State the types of resistance.
Unnecessary prescription
Lifestock farming
Lack of regulation
Lack of development - very few antibiotics in recent years
Types of resistance
1) destruction enzymes
2) additional target
3) alteration of target
4) alteration in drug permeation
5) hyperproduction
Describe destruction enzymes.
B-lactamases hydrolyse C-N bond of the lactation ring.
Examples -Penicillins G and V —> gram +ve -flucloxacillin and temocillin —> B-lactamase resistant because steric hindrance -amoxicillin —> broad spectrum: Gram -ve activity Co-administered with Clavulanic acid
(Side note: gram -ve and +ve different antibiotics won’t work in each other)
Describe additional target.
Bacteria produce another target that is unaffected by the drug
Example: E.coli produce different DHF reductase enzyme making them resistant to trimethoprim.
Describe enzyme alteration.
Alteration to the enzyme targeted by the drug. Enzyme still effective but drug now ineffective
Example
S Aureus - mutations in the ParC region of topoisomerase IV confers resistance to quinolones
Describe alteration in drug permeation.
Reductions in aquaporins and increased efflux systems.
Examples
Primarily of importance in gram -ve bacteria
Describe hyperproduction.
Bacteria significantly increase levels of DHF reductase
Example:
E. coli produce additional DHF reductase enzymes making trimethoprim less effective
Not very effective compared to others because bacteria have to work hard.
Describe anti-fungals.
Fungal infections
Can be classified in terms of tissues/organs:
1) superficial - outermost layers of skin
2) dermatophyte - skin, hair or nails
3) subcutaneous - innermost skin layers
4) systemic - primarily respiratory tract
Drug details
- 15 anti-fungal drugs licensed in the UK
- two most common categories:
1) Azores: fluconazole
2) Polyenes: Amphotericin
Azores
- inhibit cytochrome p450 dependent enzymes involved in membrane sterol synthesis (sterol needed for cell membranes)
- Fluconazole (oral) —> candidiasis and systemic infections
Polyenes
-interact with cell membrane sterols forming membrane channels
-Amphotericin (I-V) —> systemic infections
(Puncture holes in fungal membranes)
Describe the structure of a virus.
genetic material (RNA and DNA) present in every virus
Capsid (protein shell surrounding the genetic material of the virus) in every virus
Envelope proteins in some
Lipid envelope in some
Describe viral hepatitis.
Tropism
-liver hepatocytes
Hepatitis (Hep) B and C
-only chronic infection requires treatment
Hep B treatment
-Tenofovir —> nucleotide analogue (block replication), given sometimes with Peginterferon Alfa
Contains disease, not cure, if stop drug, disease comes back
Hep C treatment -Ribavirin and Peginterferon Alfa Ribavirin —> nucleoside analogue prevents viral RNA synthesis -Boceprevir —> protease inhibitor Most effective against Hep C genotype 1
The goal of HCV treatment is to cure virus
The specific drugs and duration of treatment depend on:
-HCV genotype (genetic structure of virus)
-viral load
-past treatment experience
-degree of liver damage
-ability to tolerate prescribe treatment
-need for liver transplant
Describe the HIV life cycle and its treatment.
1) Attachment and entry
- viral membrane proteins interact with leukocyte membrane receptors
- Viral capsid endocytosis
2) replication and integration
- within cytoplasm - reverse transcriptase enzymes converts viral RNA —> DNA
- DNA transported into nucleus and integrated into host DNA
3) assembly and release
- host cell’s machinery utilised to produce viral RNA and essential proteins
- virus is assembled within cell —> mature virion is released
HIV entry inhibitors
1) Attachment and entry
- HIV glycoprotein (GP)120 attaches to CD4 receptor
- GP120 also binds to either CCR5 (needs this) or CXCR4
- GP41 penetrates host cell membrane and viral capsid enters
Enfuvirtide
-binds to HIV GP41 transmembrane glycoprotein
Maraviroc
-blocks CCR5 chemokine receptor
(Side note: bone marrow chemotherapy with delta 32 mutation, no CCR5)
HIV replication inhibitors 2) a) replication Reverse transcription • Viral single-stranded RNA —> double stranded DNA by reverse transcriptase 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
HIV integrase inhibitors 2) b) integration DNA integration • Viral integrase inserts viral DNA into host DNA Integrase inhibitors • Raltegravir - first of 3 licensed integrase inhibitors
HIV protease inhibitors
3) Assembly and release
• Gag precursor —> encodes all viral structural proteins
• HIV protease cleaves Gag precursor protein
Protease inhibitors (PI)
• Saquinavir - 1st generation PI
• Low dose Ritonavir reduces PI
metabolism —> co-administered as ‘booster’
Describe herpes simple virus.
Describe influenza.
Virology • Double-stranded DNA • Surrounded by tegument & enclosed in a lipid bilayer Tropism • Herpes Simplex Virus (HSV)-1 —> cold-sores • HSV-2 —> genital herpes Treatment • Nucleoside analogues —> Aciclovir
Influenza
Virology
• Multipartite single stranded RNA virus
• Envelope protein neuraminidase —>release Tropism
• Nose, throat & bronchi
Treatment
• Neuraminidase inhibitor —> Oseltamivir (Tamiflu); need to take within 48 hours of symptoms
Summarise the mechanisms of actions of antiretroviral drugs.
Describe the actions of other antiviral drugs.
® Entry inhibitors - Enfuvirtide & Maraviroc
® RT inhibitors - Nucleoside analogues (Zidovudine), Non-nucleoside analogues (
Efavirenz)
® Integrase inhibitors - Raltegravir
® Protease inhibitors - Saquinavir
Antiviral
® Nucleotide analogues - Ribavirin, Aciclovir
® Protease inhibitors - Boceprevir
® Neuraminidase inhibitors - Oseltamivir
Define epilepsy.
Describe its prevalence and diagnosis.
Definition
• A neurological condition causing
frequent seizures
• Seizures are “sudden changes in behaviour caused by electrical hypersynchronization of neuronal networks in the cerebral cortex” (overactivity of brain)
Prevalence & Incidence
• Prevalence between 2-7% of the population
• Incidence increased over the last 30-40 years
Diagnosis
• Brain activity can be measured using:
• Electroencephalography (EEG) - neurone activity
• Magnetic resonance imaging (MRI) - brain damage
Describe the different seizure types in epilepsy.
General Seizures
Begins simultaneously in both hemispheres of brain
Seizure types & Symptoms
1. Tonic-clonic seizures: loss of consciousness —>muscle stiffening—>jerking/twitching —>deep sleep —>wakes up
2. Absence seizures: brief staring episodes with behavioural arrest
3. Tonic/atonic seizures: sudden muscle
stiffening/sudden loss of muscle control
4. Myoclonic seizures: sudden, brief muscle
contractions
5. Status epilepticus: > 5 min of continuous seizure activity (any of above for >5 mins)
Partial/ focal Seizures
Begins within a particular area of brain and may spread out
Seizure types & Symptoms
6. Simple: retained awareness/consciousness
Complex: impaired awareness/consciousness
Describe the glutamatergic synapse.
Neurotransmission
1. Voltage-gated Na+ channel (VGSC) opens —> membrane depolarisation
2. Voltage-gated K+ channel (VGKC) opens —> membrane repolarisation
3. Ca2+ influx through voltage-gated calcium
channels (VGCCs) —> vesicle exocytosis
a) Synaptic vesicle associated (SV2A) protein
allows vesicle attachment to presynaptic
membrane
4. Glutamate activates excitatory post-synaptic receptors (e.g. NMDA, AMPA & kainate receptors)
Describe the drugs used at glutamatergic synapse for epilepsy.
Voltage gated Na+ channel blockers/antagonists
Carbamazepine
Pharmacodynamics
• Stabilises inactive state of Na+ channel —> reducing neuronal activity
Pharmacokinetics
• Enzyme inducer
• Onset of activity within 1 hour
• 16-30 hour half-life (long duration)
Indications
• Tonic-clonic seizures; partial seizures
NB: potential severe side-effects (SJS & TEN) in individuals with HLA-B*1502 allele (skin conditions SJS, TEN)
Lamotrigine
Pharmacodynamics
• Inactivates Na+ channels —> reducing glutamate neuronal activity
Pharmacokinetics
• Onset of activity within 1 hour
• 24-34 hour half-life
Indications
• Tonic-clonic seizures; absence seizures
(More safer in pregnancy than carbamazepine)
Voltage gated calcium channel blocker/antagonist
Ethosuximide
Pharmacodynamics
• T-type Ca2+ channel antagonist (CNS, cardiac pacemaker) —>reduces activity in relay thalamic neurones - prevent excitation Pharmacokinetics
• Long half-life (50 hours) also fats onset
Indications
• Absence seizures
Glutamate exocytosis and receptors
Levetiracetam (SV2A inhibitor)
Pharmacodynamics
• Binds to synaptic vesicle associated protein (SV2A) —>preventing glutamate release Pharmacokinetics
• Fast-onset (1 hour); half-life (10 hours) Indications
• Myoclonic seizures
Topiramate (glutamate receptor antagonist)
Pharmacodynamics
• Inhibits NMDA & kainate receptors
• Also affects VGSCs & GABA receptors Pharmacokinetics
• Fast-onset (1 hour); long half-life (20 hours)
Indications
• Myoclonic seizures
Describe the GABAergic synapse.
Describe the drugs used for epilepsy.
Neurotransmission
1. GABA can be released tonically & also following neuronal stimulation
2. GABA activates inhibitory post-synaptic
GABAA receptors
3. GABAA receptors are chloride (Cl-)
channels —> membrane hyperpolarisation
4. GABA is taken up by GAT & metabolised by
GABA transaminase (GABA-T) to glutamate
Diazepam Pharmacodynamics • GABA receptor, PAM —> increases GABA- mediated inhibition Pharmacokinetics • Rectal gel - Fast-onset (within 15 min); half- life (2 hours) Indications • Status epilepticus
Sodium Valproate Pharmacodynamics • Inhibits GABA transaminase —> increases GABA-mediated inhibition (also less glutamate) Pharmacokinetics • Fast onset (1h); half-life (12h) Indications • Indicated for ALL forms of epilepsy
