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Autonomic pharmacology 2

Dr Keith Brain Institute of Clinical Sciences

•  Most effects are mediated via noradrenaline, from post-ganglionic fibres, or adrenaline, from the adrenal medulla.

•  Sympathetic effects –  increase in heart rate and contractility –  Vasoconstriction (α) and vasodilation (β) –  bronchodilation –  decreased gut motility –  piloerection –  glycogenolysis and gluconeogenesis –  renin secretion

Targeting Sympathetic function through noradrenergic

transmission

Norepinephrine Transporter (NET)=Uptake 1

Drugs affecting synthesis tyrosine

DOPA tyrosine hydroxylase

dopamine dopa decarboxylase

noradrenaline

dopamine β-hydroxylase

adrenaline PNMT

α-methyl tyrosine

Carbidopa*

disulfiram

Enzyme Inhibitor

Drugs affecting storage

•  Reserpine: •  inhibits transport into vesicles by inhibiting vesicular monoamine transporter-2 (VMAT-2)

•  depletes terminals of NA

•  used as an antihypertensive in some countries

NET

reserpine

VMAT-2

NAd -

Drugs affecting exocytosis

•  Bretylium & Guanethidine: Enter sympathetic terminals through NET, and inhibit exocyctosis. Very rarely used clinically (anti-dysrhythmic drug), but useful experimental tools.

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Drugs affecting reuptake •  Two methods of clearing noradrenaline:

– Norepinephrine transporter (Uptake 1): •  Neuronal •  Cotransports Na+ with noradrenaline •  Can transports many other molecules •  blocked by cocaine and tricyclic antidepressants

eg imipramine – Uptake 2:

•  non-neuronal •  Mediated by several different transport proteins

Drugs affecting metabolism

•  Two main metabolising enzymes: – Monoamine oxidase (MAO):

•  MAOA and MAOB

•  Blockers are called by MAOIs eg phenelzine, iproniazid

•  selegiline is a selective MAOB inhibitor

– Catechol O-methyltransferase (COMT): •  blocked by entacapone

Drugs affecting release (cont) •  Indirectly acting sympathomimetic

amines –  tyramine, ephedrine, amphetamine – Reverse NET-mediated transport of NAd

and so cause release

NET

NAd Na+

NET

amphet. Na+

NAd

NET

Indirectly acting sympathomimetic amines

•  Mimic the effects of sympathetic stimulation: – Effects greatly enhanced by monoamine

oxidase inhibitors (eg. phenelzine) – “the cheese reaction”

– Effects blocked by cocaine

Drugs that act at receptors

•  The availability of sub-type selective drugs means that many drugs that act at adrenoreceptors are clinically useful. – cf muscarinic receptors and drugs

influencing the parasympathetic system.

Adrenoreceptor sub-types

NA>adr>isoprenaline phentolamine

isoprenaline>adr>NA propranolol

α β

α1A α1B α1C

α2A α2B

α1 α2 β1 β2 β3

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Selective agonists and antagonists

agonist antagonist α1 midodrine* doxazosin α2 clonidine yohimbine β1 dobutamine metoprolol β2 salbutamol β3 mirabegron

* Actually a prodrug for the active desglymidodrine

Main uses of α-adrenoreceptor agonists

•  vasoconstrictors with local anaesthetics (α) – adrenaline, noradrenaline

•  nasal decongestants (α) – Phenylephrine, pseudoephedrine

•  hypertension (α2) – Centrally acting (eg. clonidine)

α2-receptors

•  α2-adrenoceptors on some blood vessels: –  lead to vasoconstriction

•  BUT α2-receptors in CNS –  lead to decreased BP

•  Presynaptic α2-receptors on sympathetic nerves –  lead to decrease NA release

Main uses of adrenoreceptor agonists

•  cardiac failure (β1) – adrenaline, dobutamine

•  asthma (β2) – salbutamol, terbutaline

•  anaphylactic shock (α/β) – adrenaline

Main uses of α antagonists

•  Hypertension (doxazosin) •  Benign Prostatic Hyperplasia

–  tamsolusin (α1) •  Phaeochromocytoma (v. rare), a

catecholamine-secreting tumor – phenoxybenzamine (irreversible α-

antagonist)

Main uses of β antagonists

eg propranolol (β1/2), metoprolol (β1) •  angina, cardiac arrythmias •  hypertension •  anxiety states •  locally for glaucoma (timolol)

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Uses of adrenoceptor agonists

Salbutamol - selective β2 receptor agonist - asthma, delay of premature labour - usually given as inhaled aerosol or powder - can be given orally or intravenously - mainly excreted unchanged - plasma half-life of ~ 4 hours - s/e: tachycardia, arrhythmia, tremor

Terbutaline - as for salbutamol (but not given orally) Salmeterol - selective β2 receptor agonist

- asthma - given by aerosol - long acting: plasma half-life of ~ 8 hours - s/e: as for salbutamol

An example of the cardiovascular effects of catecholamines

Further Reading •  Rang et al., Pharmacology, 7th Ed., chapters (9-11)

on “Chemical mediators and the autonomic nervous system”, “Cholinergic Transmission”, and “Noradrenergic Transmission”, or

•  Yagiela et al. (2005), “Pharmacology and Therapeutics for Dentistry” 5th Ed., chapters 5-10 - “Introduction to Autonomic Nervous System Drugs”, “Adrenergic Drugs”, “Adrenergic Blocking Drugs”, “Cholinergic Drugs”, “Antimuscarinic drugs”, “Drugs affecting nicotinic receptors”, or,

•  Seymour, Meechan and Yates. “Pharmacology and Dental Therapeutics”, 1999 Oxford UP, Chapt 14.