Autonomic Pharmacology Flashcards
List 4 effects of sympathetic stimulation of the cardiovascular system.
Give the receptor that is responsible for each effect.
1 - Increased heart rate (beta 1 receptors).
2 - Increased heart contractility (beta 1 receptors).
3 - Vasoconstriction (alpha 1 and 2 receptors).
4 - Vasodilation (beta 2 receptors).
In which layer of a vessel is the innervation found?
The tunica adventitia.
Describe the organisation of adrenoceptor subtypes.
- All adrenoreceptors are alpha or beta.
- There are 2 subtypes of alpha receptors (1 and 2).
- There are 3 subtypes of beta receptors (1, 2 and 3).
- There are 3 subtypes of alpha 1 receptors (alpha 1 a, b and d).
- There are 2 subtypes of alpha 2 receptors (alpha 2 a and b).
Which alpha receptors are found in cardiac tissue?
Which are found in vascular tissue?
All alpha receptors are found in vascular tissue only.
Which beta receptors are found in cardiac tissue?
Which are found in vascular tissue?
- Beta 1 receptors are found in cardiac tissue.
- Beta 2 receptors are found in vascular tissue.
List 2 alpha 1 agonists.
1 - Phenylephrine.
2 - Midodrine (actually a prodrug).
Give an example of an alpha 1 antagonist.
Doxazosin.
List 2 alpha 2 agonists.
1 - Clonidine.
2 - Brimonidine.
Give an example of a beta 1 agonist.
Dobutamine.
Give an example of a beta 1 antagonist.
Metoprolol.
Give an example of a beta 2 agonist.
Salbutamol.
List 4 effects of beta adrenoceptor stimulation in the heart.
1 - Increased heart rate.
2 - Increased contractility.
3 - Increased automaticity.
4 - Fast relaxation and recovery.
What type of receptors are adrenoceptors?
G protein coupled receptors.
Give an example of a non-selective beta agonist.
Isoprenaline.
Describe the intracellular pathway that beta receptors use to bring about their effects in the heart.
1 - Binding of a beta agonist to a beta receptor triggers the Gs pathway.
2 - PKA opens Ca2+ channels, allowing for faster depolarisation.
3 - PKA opens K+ channels, allowing for faster repolarisation.
4 - cAMP increases Na+/K+ ATPase activity, causing positive chronotropy by increasing the slope of the pacemaker potential.
5 - The Gs pathway also increases sarcoplasmic reticulum Ca2+ uptake by increasing SERCA activity via inhibition of phospholamban.
6 - The Gs pathway also increases Ca2+ sensitivity.
What type of drug is adrenaline?
Both a beta and alpha adrenoceptor agonist.
List 4 clinical uses of adrenaline.
1 - Used to treat asystole.
2 - Used to treat ventricular fibrillation.
3 - Used to treat anaphylaxis.
4 - When injected locally, causes vasoconstriction, so is commonly used in a mixture with local anaesthetics.
What is dobutamine used to treat?
It is used to treat cardiogenic shock by providing inotropic support.
Describe the intracellular pathway that alpha receptors use to bring about their effects in smooth muscle.
Classical pathway:
1 - Binding of an alpha agonist to an alpha receptor triggers the Gq pathway.
2 - IP3 acts on the sarcoplasmic reticulum to stimulate Ca2+ release.
Alternative pathway:
3 - PKC phosphorylates CPI-17, which activates myosin light chain kinase.
4 - Myosin light chain kinase phosphorylates the myosin, which facilitates myosin binding to actin and therefore increases contractility.
What is phenylephrine used to treat?
Nasal congestion.
What is midodrine used to treat?
How does it work?
- Postural hypotension.
- By causing venoconstriction (it is a prodrug for an alpha 1 agonist).
With which drug might you administer with midodrine to treat postural hypotension?
Why would this work?
- Fludrocortisone.
- Fludrocortisone is a mineralocorticoid that increases circulating volume, which will help treat the hypotension.
What is droxidopa?
A prodrug for noradrenaline.
What is droxidopa used to treat?
Postural hypotension in autonomic failure.
What is clonidine used to treat?
How do drugs of its class work?
- Hypertension.
- Alpha 2 agonists work by decreasing sympathetic drive in the CNS.
What is brimonidine used to treat?
Rosacea.
What type of drug is doxazosin?
An alpha 1 antagonist.
What is doxazosin used to treat?
How do drugs of its class work?
- Hypertension.
- Alpha 1 antagonists cause vasodilation because alpha 1 stimulation causes vasoconstriction.
What type of drug is propranolol?
A beta 1 and beta 2 antagonist.
What type of drug is atenolol?
A beta 1 antagonist.
List 4 effects of beta antagonists.
1 - Negative chronotropic actions.
2 - Negative inotropic actions.
3 - Inhibits automaticity.
4 - Inhibits platelet aggregation.
List 4 conditions that can be treated with beta blockers.
1 - Angina.
2 - Heart failure.
3 - Cardiac arrhythmias.
4 - Hypertension.
What type of drug is carvedilol?
- A mixed beta and alpha adrenoceptor antagonist.
- An inhibitor of a particular cardiac K+ channel.
What is carvedilol used to treat?
Heart failure.
If beta 2 receptors cause vasodilation, why do beta blockers decrease blood pressure? List 3 reasons.
1 - Antagonising beta 1 receptors reduces cardiac output, especially during exercise.
2 - Beta 1 receptors in the kidney lead to renin release, which leads to the production of angiotensins, which cause vasoconstriction and fluid retention.
3 - Beta antagonists inhibit the trophic effect of catecholamines in the heart, and hence inhibit cardiac hypertrophy associated with both hypertension and heart failure.
Other than antagonising the effects of beta 1 agonists, how might beta antagonists decrease blood pressure in the context of chronic hypertension?
By resetting baroreceptors.
List 2 effects of parasympathetic stimulation of the heart.
1 - Negative chronotropic effect through action at the sinoatrial node.
2 - Reduction of AV node conduction speed.
Give an example of an effect of parasympathetic stimulation of vascular tissue.
Vasodilation by stimulating nitric oxide release, however the effect is limited due to limited innervation, despite the ubiquity of endothelial mAChRs.
List 2 parasympathetic signalling pathways in the heart.
1 - Direct G-protein mediated activation of M2 muscarinic potassium channels.
2 - Inhibition of adenylyl cyclase, opposing PKA mediated actions.
What type of drug is atropine?
A muscarinic antagonist.
What type of drug is pilocarpine?
A muscarinic agonist.
List 6 non-cardiac effects of muscarinic antagonism.
1 - Decreased secretions in the mouth, airways and gut.
2 - Bronchodilation.
3 - Constipation.
4 - Urinary retention.
5 - Pupillary dilation.
6 - Confusion / hallucinations.
What is atropine used to treat?
Supraventricular bradycardia.
Describe the intracellular pathway that leads to the release of monoamines into muscles from vascular tissue.
1 - Tyrosine is converted into DOPA.
2 - DOPA is converted into dopamine by DOPA decarboxylase.
3 - Dopamine may be converted into noradrenaline or may remain as dopamine to be transported to the muscle.
4 - Some of the monoamine is broken down by monoamine oxidases.
5 - The rest is transported by vesicular monoamine transporter (VMAT) out of the endothelium.
6 - Some of the monoamine diffuses into myocytes.
7 - Some of the monoamine returns to the vasculature. Reuptake of noradrenaline is mediated by noradrenaline transporter (NAT) in a process called ‘uptake 1’.
What type of transporter is noradrenaline transporter (NAT)?
A secondary active transporter (requiring Na+ and Cl-).
List 2 drugs that block noradrenaline transporter (NAT).
1 - Cocaine.
2 - Tricyclic antidepressants such as imipramine.
Give an example of an effect of noradrenaline transporter (NAT) blockers.
Arrhythmias.
How do sympathomimetic amines cause positive inotropy?
By causing reversal of noradrenaline transport, resulting in release rather than uptake.
List 3 sympathomimetic amines.
1 - Tyramine.
2 - Ephedrine.
3 - Amphetamine.
Give an example of a source of tyramine.
Cheese.
Why might monoamine oxidase inhibitors result in positive inotropy?
Because less monoamine is broken down, so more is released into the circulation.
List the subtypes of monoamine oxidases.
1 - Monoamine oxidase A.
2 - Monoamine oxidase B.
List 3 monoamine oxidase inhibitors.
Which of these exhibits selectivity? For which subtype of monoamine oxidase is the drug selective?
1 - Phenelzine.
2 - Iproniazid.
3 - Selegiline - selective for monoamine oxidase B.
What is the first line treatment for hypertension in pregnancy?
Methyldopa.
How does methyldopa work?
Two mechanisms:
1 - By inhibiting DOPA decarboxylase, resulting in less peripheral NAd.
2 - Methyldopa is converted into methylnoradrenaline, an alpha 2 agonist.
