probably by an action on M3‐receptors.
9
Drugs acting on the sympathetic system
The sympathetic nervous system is important in regulating organs such as the heart and peripheral vasculature (Chapters 15 and 18). The transmitter released from sympathetic nerve endings is norepinephrine (NE) (noradrenaline,
Sympathomimetics (left) are drugs that partially or completely mimic the actions of norepinephrine and epinephrine. They act either directly on α‐ and/or β‐adrenoceptors (left, open column) or indirectly on the presynaptic terminals (top left, shaded), usually by causing the release of norepinephrine (
β2‐adrenoceptor agonists cause bronchial dilatation and are used in the treatment of asthma (Chapter 11). They are also used to relax uterine muscle in an attempt to prevent preterm labour. β1‐adrenoceptor agonists (dobutamine) are sometimes used to stimulate the force of heart contraction in severe low‐output heart failure (Chapter 18). α1‐agonists (e.g. phenylephrine) are used as mydriatics (Chapter 10) and in many popular decongestant preparations. α2‐agonists, notably clonidine and methyldopa (which acts after its conversion to α‐methylnorepinephrine, a false transmitter), are centrally acting hypotensive drugs (Chapter 15).
Sympathomimetic amines that act mainly by causing norepinephrine release (e.g. amfetamine) have the α1/α2 selectivity of norepinephrine. Ephedrine, in addition to causing norepinephrine release, also has a direct action. Its effects resemble those of epinephrine, but last much longer. Ephedrine is a mild central stimulant, but amfetamine, which enters the brain more readily, has a much greater stimulant effect on mood and alertness and a depressant effect on appetite. Amfetamine and similar drugs have a high abuse potential and are rarely used (Chapter 31).
β‐adrenoceptor antagonists (β‐blockers) (bottom right) are important drugs in the treatment of angina (Chapter 16), cardiac arrhythmias (Chapter 17), heart failure (Chapter 18) and glaucoma (Chapter 10). α‐adrenoceptor antagonists (α‐blockers) (middle right) have limited clinical applications. They are used in the treatment of benign prostatic hyperplasia (BPH), phaeochromocytoma and as a third‐line drug in hypertension (Chapter 15).
Reuptake of norepinephrine by a high‐affinity transport system (Uptake 1) in the nerve terminals ‘recaptures’ most of the transmitter and is the main method of terminating its effects. A similar (extraneuronal) transport system (Uptake 2) exists in the tissues but is less selective and less easily saturated.
Monoamine oxidase (MAO) and catechol‐O‐methyltransferase (COMT) are widely distributed enzymes that catabolize catecholamines. Inhibition of MAO and COMT has little potentiating effect on responses to sympathetic nerve stimulation or injected catecholamines (norepinephrine, epinephrine) because they are largely inactivated by reuptake.
α1‐adrenoceptors are postsynaptic. Their activation in several tissues (e.g. smooth muscle, salivary glands) causes an increase in inositol‐1,4,5‐trisphosphate and subsequently cytosolic calcium (Chapter 1), which triggers vasoconstriction or glandular secretion.
α2‐adrenoceptors occur on noradrenergic nerve terminals. Their activation by norepinephrine inhibits adenylyl cyclase. The consequent fall in cyclic adenosine monophosphate (cAMP) closes Ca2+ channels and diminishes further transmitter release.
β‐adrenoceptor activation results in stimulation of adenylyl cyclase, increasing the conversion of adenosine triphosphate (ATP) to cAMP. The cAMP acts as a ‘second messenger’, coupling receptor activation to response.
Sympathomimetics
Indirectly acting sympathomimetics
Indirectly acting sympathomimetics resemble the structure of norepinephrine closely enough to be transported by Uptake 1 into nerve terminals where they displace vesicular norepinephrine into the cytoplasm. The norepinephrine is then transported out of the nerve terminal by the reverse action of uptake 1 and activates adrenoceptors.
Amfetamines are resistant to MAO. Their peripheral actions (e.g. tachycardia, hypertension) and central stimulant actions are mainly caused by catecholamine release. Dexamfetamine and methylphenidate are sometimes used in hyperkinetic children. Dexamfetamine and modafinil may be beneficial in narcolepsy. Dependence on amfetamine‐like drugs is common (Chapter 31).
Cocaine, in addition to being a local anaesthetic (Chapter 5), is a sympathomimetic because it inhibits the reuptake of norepinephrine by nerve terminals. It has an intense central stimulant effect that has made it a popular drug of abuse (Chapter 31).
Directly acting sympathomimetics
The effect of sympathomimetic drugs in humans depends on their receptor specificity (α and/or β) and on the compensatory reflexes they evoke.
Epinephrine and norepinephrine are destroyed in the gut and are short lasting when injected because of uptake and metabolism. Epinephrine increases the blood pressure by stimulating the rate and force of the heartbeat (β1‐effects). Stimulation of vascular α‐receptors causes vasoconstriction (viscera, skin), but β2‐stimulation causes vasodilatation (skeletal muscle) and the total peripheral resistance may actually decrease.
Norepinephrine has little or no effect on the vascular β2‐receptors, and so the α‐mediated