SNS antagonists Flashcards
How does methyldopa work?
- Methyldopa takes place of DOPA in NA synthesis
- Converted to alpha-methyl NA (false transmitter)
- Less active at a1/b R - less effective at vasoconstriction
- More active on a2 Rs - autoinhibitory fb mech –> reduces NA release below normal levels
- Some CNS effects - stimulates vasopressor centre in BS to inhibit symp outflow –> improved blood flow
- Not metabolised by MAO
- More likely to accumulate and displace NA in vesicle
What are the clinical uses of methyldopa?
- Anti-hypertensive in pregnant women (no adverse effects on foetus despite crossing blood-placenta barrier)
- Also in kidney disease and cerebrovascular disease
What are the side effects of methyldopa?
- Dry mouth
- Sedation
- Orthostatic hypotension
- Male sexual dysfunction
What are the main clinical uses of adrenoceptor antagonists and false transmitters?
- Hypertension
- Cardiac arrhythmias
- Angina
- Glaucoma
What are the unwanted effects of alpha adrenoceptor antagonists?
Postural hypotension
What are the unwanted effects of beta antagonists?
Negative effects from b2 blockade:
- Bronchoconstriction - bad for asthma/COPD
- Cardiac failure - need some symp drive to heart to maintain adequate CO
- Hypoglycaemia - masks symptoms (sweating, palpitations, tremor)
- Block b2-mediated glycogenolysis - bad for diabetics
- Fatigue - reduced CO and muscle perfusion; impairs exercise
- Cold extremities - loss of bR-mediated vasodilation in cutaneous vessels
- Bad dreams
What is the mechanism of action of propranolol (non-selective beta antagonist)?
Positive effects from b1 blockade:
- Decrease HR, FoC, CO
- Heart doesn’t have to work as hard
- Reduced BP
- Decrease renin
- Decrease AngII
- Less vasoconstriction, less aldosterone
- Decreased TPR
- Block positive facilitatory effects of presynaptic b1Rs on NA release
What is the main clinical use of propranolol (non-selective beta antagonist)?
Anti-hypertensive (during exercise)
What are the main clinical uses of atenolol (cardioselective b1 antagonist)?
Beta blocker for CV diseases: hypertension, angina, acute MI, long QT syndrome, tachycardia
What are main clinical uses of carvediol (mixed B and a antagonist)?
- Mild to severe congestive HF
- Left ventricular dysfunction following heart attack in otherwise stable patients
- Anti-hypertensive
What are the 4 different types of SNS antagonists?
- Non-selective - propranolol
- b1-selective - atenolol
- Mixed a-b blockers - carvedilol
- Other - nebivolol - B1, also potentiates NO, sotalol - B, also inhibits K channels
What is the clinical use of phentolamine (non-selective alpha antagonist)?
Phaechromocytoma-induced hypertension
What is the clinical use of prazosin (selective a1 antagonist)?
Anti-hypertensive
What are the effects of a1 stimulation?
Vasoconstriction
GIT relaxation
What are the effects of a2 stimulation?
Inhibition of transmitter release (presynaptic - NA)
Contraction of VSM
CNS actions
What are the effects of b1 stimulation?
Inotropic effect
Chronotropic effect
GIT relaxation
Renin release
What are the effects of b2 stimulation?
Bronchodilation
Vasodilation
relaxation of visceral SM
Hepatic glycogenolysis
What are the effects of b3 stimulation?
Lipolysis
How does the sympathetic NS control BP?
SNS controls heart via b1Rs Major controller = symp drive to kidneys controlling rening release (b1) Renin release ATII production Powerful vasoconstrictor Aldosterone production Increases BP
What tissues do anti-hypertensives target?
Kidneys - regulate blood volume and vasoconstriction (renin)
Heart
Arterioles - determine TPR (a1-mediated vasoconstriction)
Symp nerves that release NA (vasoconstrictor)
CNS - determines BP set point
Do beta-blockers affect arterioles?
No
Do not antagonise a1 receptors
What are the side effects of propranolol (non-selective beta antagonist)?
All typical adverse effects due to b2 antagonism
What is the mechanism of action of atenolol (cardioselective b1 antagonist)?
- Mainly antagonises effect of NA in heart - reduces HR, BP, CO
- Also affects any tissue with b1R, e.g. kidneys
What are the side effects of atenolol (cardioselective b1 antagonist)?
- Typical adverse effects due to b2 antagonism
- Less effect on airways than non-selective drugs, but still not safe for asthmatics
- Higher T2DM risk
What is the mechanism of action of phentolamine (non-selective alpha antagonist)?
- Vasodilation and reduced BP due to a1 blockade
- a2 blockade removes inhibitory effect of a2Rs on NA release –> increased NA release –> more NA in synapse to compete with drug
What are the side effects of phentolamine (non-selective alpha antagonist)?
- Increased GIT motility - diarrhoea
- Reflex tachycardia
What is the mechanism of action of prazosin (selective a1 antagonist)?
- Inhibits vasoconstrictor activity of NA –> vasodilation and reduced BP
- Decreases LDL, increases HDL cholesterol
- Decreases CO due to fall in venous pressure as a result of dilation of capacitance vessels
What are the side effects of prazosin (selective a1 antagonist)?
- Reflex tachycardia
- Postural hypotension
What is an arrhythmia?
Irregular heart beat
What is the main cause of death from an arrhythmia?
Myocardial ischaemia
Why are beta blockers a good way of controlling arrhythmias?
- Beta blockers modulate sympathetic drive
- Sympathetic drive controls pacemaker current and atrioventricular conductance
- Increase in sympathetic drive to heart via B1 can precipitate or aggravate arrhythmias
- Beta blockers INCREASE AVN REFRACTORY PERIOD
- Interferes w/AV conduction in atrial tachycardias and slows down ventricular rate
- Re-entry type electrical activity won’t stimulate another heart beat bc still in refractory period
Which class of SNS antagonist may be used as an anti-arrhythmic?
- Propranolol - non-selective beta antagonist
- Positive effects mainly from B1 antagonism
- Reduces mortality of MI patients
- Particularly successful in arrhythmias that occur during exercise or mental stress
What is angina?
Pain that occurs when the oxygen supply to the myocardium is insufficient for its needs
- Pain in chest, arm, neck
- Tends to be brought on by exertion or excitement
What are the types of angina and what causes them?
- Stable - pain on exertion due to a fixed narrowing of the coronary vessels (e.g. atheroma) leading to an increased demand on the heart
- Unstable - pain w/less and less exertion; culminates w/pain at rest; atheromatous plaque starting to rupture; platelet-fibrin thrombus forms but w/o complete occlusion of vessel; high risk of infarction
- Variable - occurs at rest; caused by coronary artery spasm; associated w/atheromatous disease
What class of SNS antagonist may be used to treat angina?
Beta 1 antagonist
Why are b1 antagonists used to treat angina?
- At low doses, they reduce myocardial oxygen demand by decreasing HR, SBP and cardiac contractile activity without affecting bronchial smooth muscle
- Match oxygen demand to amount of work required
- Beta blocker + exercise –> can do same level of work at much lower HR –> heart has to work less hard –> decreased myocardial oxygen demand
What are the adverse effects of using a beta blocker in angina?
- Fatigue
- Insomnia
- Dizziness
- Sexual dysfunction
- Bronchospasm
- Bradycardia
- Heart block
- Hypotension
- Decreased myocardial contractility
When should beta blockers not be used in angina?
- Bradycardia (<55) bc you risk further compromising symp drive to heart
- Bronchospasm
- Hypotension (SBP<90)
- AV block or severe congestive HF - risk MI
How do selective and non-selective beta antagonists help treat glaucoma?
- Aqueous humour is produced by blood vessels in ciliary body via actions of carbonic anhydrase
- Reduce rate of AH formation by blocking B1 receptors on ciliary body –> reduced CA activity producing bicarbonate
Why do a1-selective antagonists cause less tachycardia than non-selective a antagonists?
- a1-selective have no a2 effect
- tf don’t remove inhibitory (-ve fb) effect of a2Rs on NA release on presynaptic membrane
- Decrease NA release
- Less tachycardia
