9. SNS antagonists Flashcards
list the sympathetic effects on the body
- dilates pupil
- inhibits salivation
- relaxes bronchi
- accelerates heart
- inhibits digestive activity
- stimulates glucose release by liver
- secretion of epinephrine and norepinephrine from kidney
- relaxes bladder
- contracts rectum
what is the πΌ1 SNS receptor involved in?
vasoconstriction, relaxation of GIT
what is the πΌ2 SNS receptor involved in?
inhibition of transmitter release, contraction of vascular smooth muscle, CNS actions
what is the π½1 SNS receptor involved in?
increased cardiac rate and force of contraction, relaxation of GIT, renin release from kidney
what is the π½2 SNS receptor involved in?
bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis
what is the π½3 SNS receptor involved in?
lipolysis
where are autoreceptors and what do they do? Give an example of an autoreceptor
autoreceptors are found in the presynaptic membrane
they monitor the NT environment within the synapse and influence the synthesis and release of NT from the presynaptic knob
E.g. presynaptic πΌ2 adrenoreceptors have a negative effect on the synthesis and release of NA from the nerve terminal
describe the selectivity of common adrenoreceptor antagonists
carvedilol: non-selective (πΌ1+ Ξ²1 + Ξ²2) - alpha-1 blockade gives additional vasodilator properties
phentolamine: πΌ1 + πΌ2 (equal affinity)
propranolol: π½1 + π½2 (equal affinity)
prazosin: πΌ1
atenolol: π½1 selective
nebivolol: π½1 selective but also potentiates NO
sotalol: π½1 + π½2 but also inhibits K+ channels
what are the main clinical uses of SNS antagonists and false transmitters?
- hypertension
- cardiac arrhythmias
- angina
- glaucoma
what is hypertension defined as?
being consistently over 140/90mmHg
what is hypertension a major risk factor for?
- stroke (causes around 50% of ischaemic strokes)
- heart failure
- MI
- chronic kidney disease
what are the main tissue targets for anti-hypertensives?
- heart: sympathetic nerves innervate the heart and increase HR and CO
- kidneys: sympathetic nerves innervate the kidneys and increase renin production which increases blood volume
- arterioles: sympathetic nerves cause venoconstriction
where do beta-blockers work?
ANTIHYPERTENSIVE
- heart (π½1) to reduce HR and CO (but this effect disappears in chronic treatment)
- kidney (π½1) to reduce renin production, reduce angiotensin II release (which is a potent vasoconstrictor and causes aldosterone release)
common long-term feature is a reduction in peripheral resistance.
how do beta-blockers antagonise beta receptors?
presynaptic π½1 receptors increase NA release so blockade causes loss of NA promoting factors
what are the unwanted effects of beta antagonists?
- BRONCHOCONSTRICTION: in patients with asthma/COPD and patients with obstructive lung disease (e.g. bronchitis)
- CARDIAC FAILURE: in patients with heart disease who rely on a level of sympathetic drive to maintain an adequate CO
- FATIGUE: due to reduced CO and reduced skeletal muscle perfusion (due to π½2 blockade on vasculature)
- HYPOGLYCAEMIA: π½-blockers mask the symptoms of hypoglycaemia (sweating, palpitations, tremor) and inhibit glycogen breakdown (block π½2)
- COLD EXTREMITIES: loss of π½-receptor mediation vasodilation
what is the advantage of atenolol over propranolol?
propranolol is a non-selective beta blocker (for π½1 + π½2) whereas atenolol is π½1 selective (cardio-selective) so it antagonises the effects of NA on the heart but has less of an effect on airways so is safe with asthmatic patients
what is the advantage of carvedilol over atenolol and propranolol as an anti-hypertensive?
carvedilol antagonises both π½1 + πΌ1 receptors so can impact vasculature and TPR. it works more on π½1 receptors and causes a decrease in HR or CO
compare how πΌ1 and πΌ2 receptors work
both G-protein linked receptors
πΌ1-receptors: Gq- linked (PLC -> increased intracellular calcium), postsynaptic on vascular smooth muscle
πΌ2-receptors: Gi-linked (decreased cAMP -> decreased NA release), presynaptic autoreceptors inhibiting NA release
describe the actions of the alpha -blockers prazosin and phentolamine
prazosin: πΌ1 selective blocker which inhibits vasoconstrictor activity of NA
phentolamine: non-selective, used to treat pheochromocytoma-induced hypertension (has GI side effects)
what is the general effect of alpha adrenoreceptor blockers?
- fall in TPR
- fall in BP
- postural hypotension
- CO/HR increases (reflex response to fall in arterial pressure) leading to baroreceptor mediated tachycardia
- blood flow through cutaneous and splanchnic vascular beds increases
why is phentolamine no longer in clinical use?
phentolamine causes vasodilation and a fall in BP due to blockade of πΌ1 adrenoceptors however blockade of presynaptic πΌ2 adrenoceptors removes the inhibitory effect on NA release so there is an increase in NA release. this enhances the reflex tachycardia, increases GIT motility and leads to diarrhoea
why do πΌ2 receptors and baroreceptors reduce the effectiveness of phentolamine?
blockade of πΌ2 receptors -> less negative feedback -> increased NA release -> NA competes with phentolamine for πΌ1 receptor -> reduced effectiveness
reduced arterial pressure -> reduced baroreceptor firing rate -> increased sympathetic and decreased parasympathetic activity from medulla -> if the overall effect is sympathetic this increases HR and CO
why is prazosin a better alpha blocker than phentolamine?
prazosin causes vasodilation and a fall in BP but because it is selective for πΌ1 the πΌ2 feedback remains intact
it decreases LDLs (decreases bad cholesterol) and increases HDLs (increases good cholesterol)
describe the actions of methyldopa
methydopa is an anti-hypertensive drug that is a βfalse transmitterβ
it is taken up by noradrenergic neurones and enters the NA synthesis pathway where it is decarboxylated and hydroxylated to form the false transmitter πΌ-methyl-NA. πΌ-methyl-NA enters the synapse, has much less of an effect on adrenoceptors and is not deaminated within the neurone by MAO so can accumulate in larger quantities than NA and displace it
what effect does πΌ-methyl-NA have on πΌ2 receptors?
πΌ-methyl-NA is a good πΌ2 receptor agonist so increases the negative feedback of NA via πΌ2 and therefore promotes sympathetic inhibition in 2 ways
this results in improved blood flow (less vasoconstriction)
what is the effect of πΌ-methyl-NA on pregnant women?
no adverse effects on the foetus despite cross the blood-placenta barrier
what are the side effects of methyldopa?
dry mouth, sedation, orthostatic hypotension, male sexual dysfunction
how may beta-blockers be used to treat arrhythmias?
π½-adrenoceptor antagonists act on π½1 receptors on the heart to increase the refractory period of the AV node which interferes with AV conduction on atrial tachycardias to slow ventricular rate. this means the arrhythmia is not aggravated from increased sympathetic drive to the heart
what is angina?
pain caused by poor blood flow through coronary vessels - strongly linked to atherosclerosis
what are the different types of angina?
STABLE - pain on exertion. increased demand on the heart due to fixed narrowing of the coronary vessels (e.g. atheroma)
UNSTABLE - pain with less and less exertion. 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
how may beta-blockers be used to treat angina?
at low doses, π½1-selective agents (metoprolol) reduce HR and contractile activity without affecting bronchial smooth muscle. myocardial work would be decreased which decreases oxygen demand while maintaining the same degree of effort (does cause some degree of exercise intolerance)
what is glaucoma characterised by and caused by?
characterised by an increase in intraocular pressure
caused by poor drainage of the aq. humour
describe how poor drainage of aq humour occurs in glaucoma
NA acts on π½1-receptors on the ciliary body which are linked to carbonic anhydrase. aq humour is produced by blood vessels in the ciliary body via the action of carbonic anyhdrase and the aq humour flows into the posterior chamber, through the pupil to the anterior chamber and then drains into the trabecular network and into the veins and canal of Schlemm. production and poor drainage causes glaucoma
how may beta-blockers be used to treat glaucoma?
beta-blockers reduce the effectiveness of carbonic anhydrase therefore less aq humour is produced
