sympathetic nervous system Flashcards
adrenoceptor antagonists 1: list the clinical uses, principal pharmacological features, mechanism of action and unwanted effects of selective and non-selective α and β adrenoceptor antagonists, and compare the pharmacology of selective and non-selective adrenoceptor antagonists
what sections of spinal cord have sympathetic innervation
thoracic and lumbar
what sections of spinal cord have parasympathetic innervation
cervical and sacral
sympathetic innervation from thoracic section: effects
dilate pupil, inhibit salivation, relax bronchi, accelerate heart, inhibit digestive activity
sympathetic innervation from lumbar section: effects
stimulate glucose release by liver, secretion of adrenaline and noradrenaline from kidney, relaxes bladder, contracts rectum
effects of a1 adrenoceptor stimulation
vasoconstriction, relaxation of GIT
effects of a2 adrenoceptor stimulation
inhibition of transmitter release and contraction of vascular smooth muscle, CNS actions
effects of B1 adrenoceptor stimulation
increased cardiac rate and force, relaxation of GIT, renin release from kidney
effects of B2 adrenoceptor stimulation
bronchodilation, vasodilation (no PSNS innervation), relaxation of visceral smooth muscle, hepatic glycogenolysis
effect of B3 adrenoceptor stimulation
lipolysis
SNS synapse pathway (a1, B1, B2 and a2) in VSMCs
tyrosine to noradrenaline -> packaged in vesicles -> action potential down presynaptic sympathetic neurone -> release of noradrenaline by exocytosis and Ca2+ influx into synaptic cleft -> bind to and stimulation of a1, B1 or B2 receptor on postsynaptic VSMC -> effect e.g. vasoconstriction -> a2 receptor-mediated negative feedback by preventing further noradrenaline release from presynaptic neurone
non-selective (a1, B1 and B2) and selective a1 and a2 adrenoceptor antagonists
non-selective: carvedilol (B-blocker with a1 blockade, giving additional vasodilator properties), selective: phentolamine
selective a1 adrenoceptor antagonist
prazosin
selective B1 and B2 adrenoceptor antagonist
propranolol
selective B1 adrenoceptor antagonist (cardioblockers)
atenolol
4 clinical uses of adrenoceptor antagonist
treatment of: hypertension, arrhythmias, angina, glaucoma
what adrenoceptor antagonist can be used to treat hypertension
B-blockers and a-blockers, false transmitters
what adrenoceptor antagonist can be used to treat arrhythmias, angina and glaucoma
B-blockers
physiology: calculation of blood pressure
cardiac output x total peripheral resistance
pathophysiology of hypertension
consistently above 140/90 mmHg when sitting/lying for average male; risk factor for stroke, heart failure, myocardial infarction, chronic kidney disease
3 main contributers of blood pressure and targets for B-blockers
blood volume, cardiac output, vascular tone
tissue targets for anti-hypertensives and how they contribute to blood pressure
heart (cardiac output), sympathetic nerves that release noradrenaline (vasoconstrictor), kidney (blood volume and vasoconstriction), arterioles (determine peripheral resistance), CNS (determines blood pressure set point and regulation)
tissue targets for anti-hypertensives and relevant B adrenoceptors
heart (B1), sympathetic nerves that release noradrenaline (B1/B2), kidney (B1), CNS (B1/B2); arterioles have a adrenoceptors
effect of B-blockers when treating hypertension: heart
B-adrenoceptor coupled with adenyl cyclase so causes production of cAMP and drives cell activity, so antagonist will decrease heart rate and force of contraction, decreasing cardiac output
effect of B-blockers when treating hypertension: kidney
decrease sympathetic ability to produce renin, decreasing angiotenin II release, preventing vasoconstriction and aldosterone production (ultimately blood volume)
effect of B-blockers when treating hypertension: presynaptic B-adrenoceptors
block facilitatory effects of noradrenaline release, which may contribute to antihypertensive effect
2 other B-blockers which have other targets
nebivolol, sotalol
nebivolol therapeutic effect
B1 and potentiates NO (vasodilator)
solatol therapeutic effect
B1, B2 and inhibits K+ channels (interferes cell hyperpolarisation)
6 unwanted effects of selective and non-selective a and B adrenoceptor antagonists
bronchoconstriction, cardiac failure, hypoglycaemia, fatigue, cold extremities, bad dreams
how might bronchoconstiction be a worse unwanted effect of selective and non-selective a and B adrenoceptor antagonists
wouldn’t give to patients with asthma/COPD
why could selective and non-selective a and B adrenoceptor antagonists be problematic in patients with cardiac failure
need some sympathetic drive to heart
why could selective and non-selective a and B adrenoceptor antagonists cause hypoglycaemia
mask symptom of hypoglycaemia/inhibit glycogen breakdown; wouldn’t give to diabetics
why could selective and non-selective a and B adrenoceptor antagonists cause fatigue
decrease cardiac output and muscle perfusion (B2 adrenoceptors cause dilation of skeletal muscle)
why could selective and non-selective a and B adrenoceptor antagonists cause cold extremities
loss of B-receptor mediated vasodilation in cutaneous vessels
advantage of atenolol over propranolol
atenolol is more selective for B1 receptors, so doesn’t have disadvantages of bronchoconstriction and hypoglycaemia (can give to asthmatics and diabetics), as these have B2 adrenoceptors
advantage of carvedilol over atenolol
more powerful hypotensive effect: carvedilol is a dual acting B1 and a1 antagonist, with a1 blockade preventing arteriole vasoconstriction, thus reducing peripheral resistance; also induces decrease in heart rate, cardiac output and blood volume (B effect in heart and kidneys; wanes with chronic use)
features of a1 adrenoceptors
Gq-linked (stimulatory), with effect on postsynaptic VSMCs
featurs of a2 adrenoceptors
Gi-linked (inhibitory), with effect of presynaptic autoreceptors inhibiting noradrenaline release
example of a non-selective a-blocker
phentolamine
what was phentolamine used to treat
pheochromocytoma-induced hypertension (block a1 to dilate vasculature)
side effects of non-selective a-blocker e.g. phentolamine
fall in arterial pressure causing postural hypotension, causing reflex response of increasing cardiac output and heart rate (B receptors); also increased GIT motility, causing diarrhoea
example of an a1 specific blocker
prazosin
effect of prazosin and clinical use
inhibits noradrenaline vasoconstrictor activity, but only has modest blood pressure lowering effects so used as adjunctive treatment
why do a2 receptors and baroreceptors reduce phentolamine effectiveness
a2 is inhibitory, so phentolamine reduces inhibition of release of noradrenaline (prevents negative feedback), so competition between noradrenaline and phentolamine in synapse; baroreceptors detect drop in arterial pressure so decrease firing, increasing SNS activity further
phentolamine vs prazosin
both cause vasodilation and fall in arterial pressure; prazosin induces less reflex tachycardia as no a2 action so don’t increase noradrenaline release from nerve terminals, and fall in venous pressure due to dilation causes decreased cardiac output; doesn’t affect cardiac function much, but postural hypotension is troublesome; also causes increased HDL and lower LDL; both cause baroreceptor firing rate to drop and compensatory increase in SNS activity though
define arrhythmia
abnormal or irregular heart beats
main cause of death due to arrhythmias
myocardial infarction
what can precipitate or aggravate arrhythmias
increase in sympathetic drive to heart via B1
treatment of arrhythmias using B1 adrenoceptor antagonists: 2 features
decrease sympathetic drive to heart, and increased refractory period of AVN, interfering with AV conduction in atrial tachycardias and slowing ventricular rate (better blood flow from atria to ventricle)
drug used to treat arrhythmias
propranolol
features of propranolol which make it effective in treating arrhythmias
non-selective B-antagonist but mainly B1, reduces mortality of patients with myocardial infarction, with particular success in arrythmias occuring during exercise or mental stress
3 types of angina (in order of normal progression)
stable, unstable, variable
define angina
pain that occurs when O2 supply to myocardium is insufficient for its needs
pain distribution of angina
chest, arm, neck
when is angina typically brought on
exertion or excitement
features of stable angina
pain on exertion; increased demand on heart; due to fixed narrowing of coronary vessels e.g. atheroma
features of unstable angina
pain with less and less exertion, culminating with pain at rest; platelet-fibrin thrombus assoicated with ruptured atheromatous plaque, but without complete occlusion of vessel; risk of infarction
features of variable angina
occurs at rest; caused by coronary artery spasm; associated with atheromatous disease
drug used to treat angina
low dose metoprolol
how does metoprolol treat angina
B1-selective, so reduces heart rate and myocardial contractile activity, blood flow better matched to tissue demand; doesn’t affect bronchial smooth muscle, so reduces O2 demand whilst maintaning same degree of effort
negative effects of metoprolol and other B-blockers
impair ability to do exercise
what causes glaucomas, what are they characterised by and what is untreated outcome
caused by poor drainage (or excess production) of aqueous humour, with increase in intraocular pressure resulting; if untreated, permanant damage to optic nerve, causing blindness
route of aqueous humour in normal eye
produced by blood vessels in ciliary body (by carbonic anhydrase) -> flows into posterior chamber, through pupil, to anterior chamber -> drains into trabecular network and into veins and canal of Schlemm
what is aqueous humour production indirectly related to
blood pressure and blood flow in ciliary body
what is used to treat glaucoma, and how does it work
B1-selective adrenoceptor by decreasing aqueous humour production on ciliary body (B1 receptor on carbonic anhydrase, so no production of HCO3- for aqueous humour)
