W3 - 11 Autonomic Pharmacology II Flashcards
How is sympathetic function mediated?
Effects mediated via noradrenaline from postganglionic fibres, or adrenaline from the adrenal medulla
What is the exception to sympathetic effects mediated by NAd or Ad?
Sweat glands are cholinergic
What are sympathetic effects?
Increase in heart rate and contractility
Vasoconstriction (a) and vasodilation (b)
Bronchodilation
Decreased gut motility
Piloerection
Glycogenolysis and gluconeogenesis
Renin secretion
What action do sympathetic nerves have on blood vessels?
Nerves run in the outside of the blood vessel, regulating smooth muscle tone. Almost all autonomic control of blood vessels is by sympathetic nerves,
What adrenoceptors are there?
alpha adrenoceptors - a1 and a2 - vascular
beta adrenoceptors - b1 (cardiac), b2 (vascular) b3
Give agonists for each adrenoceptor
Phenylephrine and midodrine- a1 agonist
Clonidine - a2 agonist
Dobutamine - b1 agonist
Salbutamol - b2 agonist
Mirabegron - b3 agonist
Give example antagonists for a1 and b1 adrenoceptors
Doxazosin - a1
Metoprolol - b1
What effects on the heart do b-adrenoceptor activation have?
Increased heart rate
Increase contractility rate
Increased automaticity
Fast relaxation and recovery
What effects on intracellular pathways do b-adrenoceptor activation have?
More Ca2+ entry and increase Ca2+ sensitivity
Faster repolarisation
Increase sodium potassium ATPase activity
What are the clinical uses of adrenaline (b/a agonist) in the CVS?
Used to treat asystole, ventricular fibrillation and other severe arrhythmias
Anaphylaxis
Locally causes vasoconstriction (a1), commonly used in LA
How does adrenaline affect arrhythmias?
b/a agonist
Increases ability of the heart to generate spontaneous rhythm
How does adrenaline help anaphylaxis?
b/a agonist
During anaphylaxis, blood pressure falls and airways constrict. Adrenaline effects on the heart will increase HR and contractility, and bronchodilate the lungs.
Fast acting - helpful in emergency. In epi-pens.
What is the clinical use of dobutamine?
B1 agonist
Used to treat cardiogenic shock
What is salbutamol used for?
Asthma (bronchodilation of the airways) or delay of premature labour (relaxes smooth muscle)
What is salbutamol?
Selective B2 receptor agonist
What are side effects of salbutamol?
Tachycardia, arrhythmia, tremor
How can salbutamol be taken?
Usually given as inhaled aerosol or powder. Oral or intravenous.
What is terbutaline salmererol?
Selective b2 receptor agonist, same as salbutamol but for more severe asthma.
Given by aerosol. Longer acting. Same side effects
What is phenylephrine?
a1 agonist
What is phenylephrine used to treat and how?
Treats nasal congestion.
Upper respiratory tract infection causes blood vessels to dilate here, leading to increase in mucous production and tissue fluid, giving a sense of congestion. This vasoconstriction it and decreases symptoms.
What is doxazosin?
a1 antagonist
What does doxazosin cause?
a1 antagonist causes vasodilation (by blocking sympathetic vasoconstriction), drops TPR by opposing resting tone, lowering blood pressure
What is doxazosin used to treat?
Hypertension (severe after ACE inhibitors or b-adrenoceptor antagonists)
Raynaud’s syndrome (inappropriate or excessive cutaneous vasoconstriction)
Give examples of beta blockers
b-adrenoceptor antagonists
Propranolol - b1/b2
Metoprolol, atenolol - b1
What effect do beta blockers have (b adrenoceptor antagonists)?
Decrease work done by the heart by slowing heart, decreasing contractility and decreasing ability to be spontaneously active
Anti-platelet aggregation
What are beta blockers used to treat?
Angina, heart failure, cardiac arrhythmias, hypertension
What is carvedilol and what is it used for?
Mixed b and a adrenoceptor antagonist
Used to treat heart failurw
What terminates the action of noradrenaline once it is released from a sympathetic nerve terminal?
Action is terminated by recycling or update through the noradrenaline transporter (NAT) and back into nerve terminals
What packages NA into vesicles?
VMAT - vesicular monoamine transporter
What breaks down NA?
Monoamine oxidase (MA) and catechomethyl transferase (COMT)
Neuronal uptake of NAd mediated by NAT is a secondary active transporter (requiring sodium and chloride ions). What drugs can block these effects? (Drugs affecting reuptake)
Blocked by cocaine and tricyclic antidepressants eg imipramine
What peripheral side effects come from inhibiting NAT?
Won’t reuptake NAd, so it stays in the junctional cleft for longer and can activate its receptors, amplifying sympathetic transmission: increase HR, cause increased risk of cardiac arrhythmias thus increased risk of cardiac death and amplifies sympathetic vasoconstriction (excessive) of the upper airways, which can cause ischaemia. Snorting cocaine can cause nasal septal defect.
What drugs affect the release of NA?
Indirectly acting sympathomimetic amines - eg tyramine, ephedrine, amphetamine (speed)
What is the action of drugs affecting release of NA (sympathomimetic amines)?
They cause reversal of NA transport through NAT, causing release of NA.
They displace NA from sympathetic terminals. These drugs are also substrates for NAT, and will switch the configuration of NAR so that it is more likely to transport NA out of the cell, so it no longer takes it up but releases NA.
Why are they indirectly acting sympathomimetic amines?
Acts in the nerve terminals to cause the release of NA, which will cause action on the adrenoceptors. So systemic action will then amplify sympathetic transmission.
What drugs might affect synthesis of NA?
Carbidopa - used in treatment of Parkinson’s disease
What drug is used for hypertension in pregnancy?
Methyldopa
Drops central sympathetic drive and thus decreases BP, safe for baby.
Which drugs affect metabolism?
Blockers of monoamine oxidase (MAO) - MAOIs
COMT - blocked by entacapone
What are the cardiovascular effects of catecholamines?
NA should activate beta receptors in the heart, but when injected, it drops heart rate. This is because the increase in peripheral resistance causes an increase in BP, causing a baroreceptor mediated fall in sympathetic tone, causing a net fall in heart rate.
