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
