ANS Pharmacology Flashcards
What is the structure of ach
Quaternary amine in the choline moiety
Ester with a negative charge
What type of muscurinic receptors are antagonised by atropine
Where are they found
M1-3
M1 CNS, autonomic ganglia and gastric parietal cells
M2 heart and presynaptic sites
M3 smooth muscle, vascular endothelium, exocrine glands
Examples of muscarinic agonists
Carbachol, pilocarpine
Structure of pilocarpine and consequences of this
Like ach except
Quaternary amine to a tertiary amine
Removed the ester
Increased length of the aliphatic component
Effects are decreased potency but also decreased hydrolysis so increased half life.
Uses of muscarinic agonist
Pupillary constriction to reduce IOP in glaucoma
Improve micturation by increasing detrusor muscle contraction
Systemic effects of muscarinic agonists
Bradycardia
Hypotension
Low SVR
Increased rs mucus production
Bronchoconstriction
Increased gi propulsion
Increased gi secretions
Urinary sphincter tone decreased
detrusor tone increased
Miosis
Lacrimation increased muscle
Examples of mucarinic antagonists
Which are naturally occurring
Structure and consequence
Atropine, glycopyrrolate, hyoscine
Nat occurring are atrop and hyoscine - these are tertiary amines and can cross the bbb
Glycopyrrolate is synthetic quaternary amine and can’t cross bbb
Effects of muscarinic antagonists
Increase Herat rate
Increase Bp
Inhibit secretions and sweating
Decreased ruination
Dilated pupils, blocked accommodation and blurred vision
Bronchodilation
What is atropines structure
Similar to ach but with an aromatic group instead of the acetyl group and a tertiary amino group in place of the quaternary one
Synthesised from plants as S but spontaneously becomes racemic
What local anaesthetic is atropine related to
Consequence
Cocaine!
Weak local anaesthetic effect
Effect of atropine on CNS
Crosses bbb
Causes initial excitement then depression
What drug dose glycopyrronium have a similar duration of action too?
Neostigmine
Which form of atropine and hyoscine have most clinical effect
L form
What are the different preparations of hyoscine and what is it used for
What is the iV dose difference
Hydrobromide (scopolamine) - CNS depression (sedative and antiemetic)
Butylbromide - smooth muscle relaxant (GI and GU spasm reduction
100fold dose difference! Hydrobromide approx 400mcg sc, butylbromide 20mgSC
Example of nicotinic ACh agonist
Effect?
Nicotine!
Mainly autonomic ganglia - vasoconstriction, hypertension, sweating, salivation
Examples of nicotinic ACh antagonists
Muscle relaxants
D-turobocurane blocks ganglia - drops Bp, causes postural hypotension
What substances prevent neurotransmitter release
How
Magnesium and Aminoglycosides - inhibit presynaptic calcium entry into cells
Botulinum and beta bungarotoxin - bind to nicotinic nerve terminals preventing neurotransmitter release
Effect of anticholinesterases and organophosphates
Clincial effects
Block acetylcholinesterase
Initially cause parasympathetic response, in high enough dose cause a depolarising neuromuscular block
Order of effect of adrenaline, noradrenaline and isoprenaline on alpha adrenoreceptors
Noradrenaline > adrenaline > isoprenaline
Order of effect of adrenaline, noradrenaline and isoprenaline on beta adrenoreceptors
Isoprenaline > adrenaline > noradrenaline
Effects of alpha 1 stimulation and mechanism
Postsynaptic excitatory GPCR Gq
Vasoconstriction, gut smooth muscle relaxation, salivation, hepatic glycogenolysis
Effects of alpha 2 stimulation and mechanism
Inhibitory GPCRs on presynaptic membrane Gi
Inhibit of autonomic (NA and ACh) neurotransmitter releases, stimulation of platelet aggregation
Effects of beta 1 stimulation and mechanism
Postsynaptic excitatory gpcr Gs
Increases heart rate, contractility. Causes gut smooth muscle relaxation and lipolysis
Effects of beta 2 stimulation and mechanism
Postsynaptic inhibitory GPCRs
Vasodilation, bronchodilation, viceral smooth muscle relaxation, glycogenolysis, muscle tremor
Effects of beta 3 stimulation and mechanism
Postsynaptic GPCR
Lipolysis, thermogenesis
Effects of adrenaline (receptors and clinical)
Issues
Mainly beta with moderate alpha
Both inotropy and chronotropy
Vasoconstriction generally but dilation of skeletal muscle arterioles
Sensitises myocardium to arrhythmia and makes it hyper excitable
Actions of dobutamine (receptor and clinical)
Issues
Non selective beta agonist (no alpha)
Chronotropy, ionotrophy
Some vasodilation so may require concurrent alpha agonist
Actions of dopamine (receptor and clinical)
Specific use
Dopamine receptors, Non selective beta but also mild alpha 1 agonist
Dose dependent - just dopamine receptors at lower doses then starts effecting beta then alpha with increasing dose
Dopamine receptors peripherally are located renally and cause vasodilation thus maintains renal perfusion
Actions of dopexamine (receptor and clinical)
Issues
Beta 2 and peripheral D1 and 2
Inhibits NA reuptake
Positive inotrope with peripheral vasodilation (splanchnic and renal) improving cardiac output
Actions of isoprenaline receptor and clinical)
Use
Beta 1 and 2 agonist
Treats Bronchospasm, bradycardia and heart block
Actions of noradrenaline (receptor and clinical)
Issues
Primarily alpha agonist causing vasoconstriction
Has some beta effects
Can cause a reflex bradycardia if hypotension overcorrected
Actions of salbutamol (receptor and clinical)
Uses
Issues
Selective beta 2 agonist
Relieves bronchospasm, causes uterine relaxation
Some beta 1 effects including tachycardia at higher doses
Actions of clonidine ( preceptor and clinical)
Uses
Alpha 2 agonist
Inhibits neurotransmitter (NA) release causing decreased blood pressure
Analgesia, sedative, prolongs epidurally administered local anaesthetics
Actions of metaraminol (receptor and clinical)
Issues
Mixed alpha and beta agonism (mainly alpha)
Increases SVR and PVR
Bradycardia, reduces cerebral and renal blood flow, increases uterine tone, increases BM in diabetics
Main uses of alpha 1 antagonists
Antihypertensives
BPH
Cardiovascular effect effect of alpha blockade
Vasodilation with reflex increase in heart rate and cardiac output
Examples of alpha antagonists
Alfuzosin, doxazocin, tamsulosin, phenoxybenzamine
What receptors does phenoxybenzamine antagonise
How does it bond and behave
Alpha
5HT
Histamine
Covalently bonds so detaches very slowly acting as competitive irreversible antagonist
Which beta blocker also blocks alpha receptors
Clinical effect when given iV and oral
When IV predominant alpha blockade but reflex tachycardia reduced by the beta blockade function
When given orally beta blockade predominates
What receptors do tamsulosin and alfuzosin effect
Alpha 1A receptors targeting prostate smooth muscle
Difference between selective and non selective beta blockers
Selective only target beta 1
Non selective target both
What is the effect of a beta receptor partial agonist
Stimulation at low levels then blockade at higher levels - may mitigate bradycardia effect and maintaining perfusion
Examples of full antagonist selective beta blockers
Atenolol
Bisoprolol
Betaxolol
Exmolol
Metoprolol
Nadolol
Examples of non selective beta blockers full antagonists
Propranolol
Sotalol
Timolol
Examples of beta receptor partial agonists
Acebutalol
Alprenolol
Celiprolol
Oxprenolol
Pindolol
Uses of beta blockers
Htn
Heart failure
Angina
Glaucoma
Migraine
Anxiety
Thyrotoxicosis
Phaeochormocytoma
Clinical effects of beta blockade
CVS - negative chronotrophy and inotropy, decreased BP and myocardial work, decreased coronary blood flow
RS - bronchoconstriction
Renal - decreseased renin secretion
Metabolic - less free fatty acid realises, reduced glycogenolysis, and insulin release, lipolysis, thermogenesis
Eye - reduced production of aqueous humour
Central - reduced sympathetic tone, reduced anxiety, tiredness, nightmares, sleep disturbance
Which beta blockers are water soluble,
Clinical effect
Atenolol, celiprolol, nadolol Sotolol
Don’t penetrate bbb well
Excreted in urine
Which beta blockers have minimal first pass metabolism
Bisoprolol
Sotolol
Effect of beta blockers on myocardial demands
Reduces coronary blood flow but proportionally less than the reduction in myocardial oxygen demand
Side effects of beta blockers
Bradycardia
Bronchoconstriction
Hypoglycaemia esp on exercise
Sleep disturbance
Cold extremities
Bioavailability of atenolol
Excretion?
50%
Urinary excretion
Vaughn Williams classification
1 - Na blockade
1a - moderate reduction phase 0 slope, increases AP duration and refractory period
1b - mild reduction phase 0 slope, reduces AP duration and refractory period
1c - significant reduction phase 0 slope, no effect on AP duration and refractory period
2 beta blockers
3 k blockers
4 ca blockers
Half life of esmolol
How
9 minutes
Red cell esterases
Bioavailability of propranolol
Lipid solubility and proteins binding
10-30%:
Highly lipid soluble and protein bound
Action of carbidopa
Inhibits dopa decarboxilase preventing formation of dopamine
Doesn’t cross bbb thus formation still occurs in CNS
Actions of methyldopa
False substrate for dopa decarboxilase forming methylnoradrenaline which is inactive. Causes displacement of true neurotransmitter thus reduces blood pressure
Mechanism of reserpine
Blocks uptake and reuptake of na, dopamine and 5HT
Effect of guanethidine
Causes release of NA then inhibits release of diminishing levels of NA
Used in chronic pain medicine regionally (like a biers block) to stop reflex sympathetic dystrophy
Which calcium channel blocker is used to treat vascular spasm in SAH
Nimodipine
How does sodium nitroprusside work
Same as organic nitrates (NO3-)
Converted in vascular smooth muscle to nitrates NO2- then react with hydrogen ions to form nitric oxide NO
Stimulates guanylyl cyclase thus GTP to cGMP
cGMP relaxes smooth muscle
Effect of nitrates and sodium nitroprusside
Vasodilation (mainly venous)
Decreases preload thus lower myocardial work and oxygen demand
Higher doses dilate arterioles reducing afterload and dilating coronary arteries
Metabolism of GTN
Rapidly hydrolysed by liver
Small amounts of GDN which is mildly active with t1/2 w hrs
Pharmacokinetics of isosobide dinitrate
Slow release preparation gradually absorbed
Converted to IMN in liver
T1/2 4 hrs
Use of inhaled nitric oxide
Treats pulmonary hypertension
Why doesn’t inhaled nitric oxide have a systemic effect
Enters vascular system and combines with hb forming methaemoglobin
How is sodium nitroprusside administered
Side effects
Protected from light - brown syringe, yellow infusion lines
Metabolism produces cyanide ions which cause methaemoglobin
Also forms thiocyanate which combines with b12 forming cyanocobalamin
In high doses cyanide will interupt electron transfer chain
How is sodium nitroprusside monitored
Thiocyanate levels
Example of potassium: channel activator
Mechanism
Nicorandil
Opens k channels, hyperpolarisation so reduced electrical activity, relaxes smooth muscle reducing SVR
Also dilates coronary arterioles
Mechanism of ivabradine
If current inhibitor
Reduces slow depolarisation stage thus reducing heart rate
Examples of endothelin receptor antagonists
Mechanism
Uses
Bosentan, sitaxsentan
Endothelin causes increased free calcium thus vasoconstriction
Agonists thus cause vasodilatation and can be used in pulmonary hypertension
Examples of prostacyclins
Uses
Epoprostenol, iloprost
Vasodilation and inhibition of platelet aggregation
Pulmonary hypertension
Class and effect of sildenfil
Pde5 inhibitor
Inhibits nitric oxide stimulation of guanylyl cyclase thus causes smooth muscle relaxation and vasodilation
What is diazoxide
Mechanism
A thiazide that causes sodium and water retention!
What is hydralazine
Causes vascular smooth muscle relaxation and some alpha blocking actions
Mechanism of action of phenylephrine
Alpha 1 agonist
Effect of adrenaline in gi tone and splanchnic blood flow
Decreases
Effect of adrenaline on renal blood flow
Increases
Metabolim of adrenaline
Comt in liver
Mao in neurones
To inactive metabolites
General strength of atropine preparation
600mcg in 1ml
Oral bioavailability of atropine
10-25%
Intra operative dose of atropine
Organophosphate poisoning dose of atropine
300-600mcg
2mg
Contraindications to atropine
Glaucoma, hyperpyrexia
Non cardiovascular effects of atropine
Bronchodilator
Reduced rs secretions
Reduced gi motility
Antispasmodic
Pupillary dilatation and increased IOP
Metabolism of atropine
Hydrolysed to Tropine and tropic acid in liver
Excreted by urine
Structure of atropine
Tertiary amine
Onset, peak and Duration of action of clonidine
10mins, 30-60mins, 3-7hrs
Effects of clonidine
Transient increase in SVR and Bp from alpha 1
Then decreased SVR and Bp from alpha 2
Analgesia
Metabolism of clonidine
65% unchanged in urine , 20% in faeces, 15% inactivated in liver
Effects of increasing dopamine infusions
1-5mcg/min increases renal blood flow
5-15 inotropic
15-20 vasoconstrict
Side effects of dopamine
Nausea, tachycardia, arrhythmias, prolactin inhibition
Elimination of ephedrine
99% unchanged in urine
Bioavailability of gycopyrrolate
5%
Excretion of glycopyrrolate
85% unchanged in urine and 15% in faeces
Issue with glycopyrrolate
High doses can be nicotinic antagonist effecting myasthenia gravis patients
Metabolism of hyoscine dervivitives
Hepatic to scopine
Dosing of labetaolol
Slow bonuses of 50mg at 50 minute intervals
IV infusion at 15-160mg/hr
Half life of labetolol
Metabolism
60 mins
Hepatic
Effect of NA on gravis uterus
Reduces perfusion so can cause fetal hypoxia
