– or -receptor affinity) or mode of action (direct or indirect).

High-Yield Terms to Learn

Anorexiant A drug that decreases appetite (causes anorexia) Catecholamine A dihydroxyphenylethylamine derivative (eg, norepinephrine, epinephrine), a relatively polar molecule that is readily metabolized by catechol-O-methyltransferase Decongestant An -agonist drug that reduces conjunctival, nasal, or oropharyngeal mucosal vasodilation by constricting blood vessels in the submucosal tissue Mydriatic A drug that causes dilation of the pupil; opposite of miotic Phenylisopropylamine A derivative of phenylisopropylamine (eg, amphetamine, ephedrine). Unlike catecholamines, phenylisopropylamines usually have oral activity, a long half-life, some CNS activity, and an indirect mode of action Selective agonist, agonist Drugs that have relatively greater effects on or adrenoceptors; none are absolutely selective or specific Sympathomimetic A drug that mimics stimulation of the sympathetic autonomic nervous system Reuptake inhibitor An indirect-acting drug that increases the activity of transmitters in the synapse by inhibiting their reuptake into the presynaptic nerve ending. May act selectively on noradrenergic, serotonergic, or both types of nerve endings

Classification

Mode of Action

Sympathomimetic agonists may directly activate their adrenoceptors, or they may act indirectly to increase the concentration of catecholamine transmitter in the synapse. Amphetamine derivatives and tyramine cause the release of stored catecholamines; these sympathomimetics are therefore mainly indirect in their mode of action. Another form of indirect action is seen with cocaine and the tricyclic antidepressants; these drugs inhibit reuptake of catecholamines by the norepinephrine transporter (NET) and the dopamine transporter (DAT) in nerve terminals (see Figure 6-2) and thus increase the synaptic activity of released transmitter.

Blockade of metabolism (ie, block of catechol-O-methyltransferase [COMT] and monoamine oxidase [MAO]) has little direct effect on autonomic activity, but MAO inhibition increases the stores of catecholamines and related molecules in adrenergic synaptic vesicles and thus may potentiate the action of indirect-acting sympathomimetics that cause the release of stored transmitter.

Spectrum of Action

Adrenoceptors are classified as or receptors; both groups are further subdivided into subgroups. The distribution of these receptors is set forth in Table 9-1. Epinephrine may be considered a single prototype agonist with effects at all receptor types (1, 2, 1, 2, and 3). Alternatively, separate prototypes, phenylephrine (an agonist) and isoproterenol () may be defined. Dopamine receptors constitute a third class of adrenoceptors. The just-mentioned drugs have relatively little effect on dopamine receptors, but dopamine itself is a potent dopamine receptor agonist, and when given as a drug, can also activate receptors (intermediate doses) and receptors (larger doses).

TABLE 9-1 Types of adrenoceptors, some of the peripheral tissues in which they are found, and their major effects.

Type Tissue Actions 1

Most vascular smooth muscle Contracts ( vascular resistance) Pupillary dilator muscle Contracts (mydriasis) Pilomotor smooth muscle Contracts (erects hair) Liver (in some species, eg, rat) Stimulates glycogenolysis 2

Adrenergic and cholinergic nerve terminals Inhibits transmitter release Platelets Stimulates aggregation Some vascular smooth muscle Contracts Fat cells Inhibits lipolysis Pancreatic (B) cells Inhibits insulin release 1

Heart Stimulates rate and force Juxtaglomerular cells of kidney Stimulates renin release 2

Airways, uterine, and vascular smooth muscle Relaxes Liver (human) Stimulates glycogenolysis Pancreatic (B) cells Stimulates insulin release Somatic motor neuron terminals (voluntary muscle) Causes tremor Heart Stimulates rate and force 3

Fat cells Stimulates lipolysis Dopamine 1 (D1)

Renal and other splanchnic blood vessels Dilates ( resistance) Dopamine 2 (D2)

Nerve terminals Inhibits adenylyl cyclase

Chemistry & Pharmacokinetics

The endogenous adrenoceptor agonists ( epinephrine, norepinephrine , and dopamine ) are catecholamines and are rapidly metabolized by COMT and MAO. If used as drugs, these adrenoceptor agonists are inactive by the oral route and must be given parenterally. When released from nerve endings, they are subsequently taken up (by NET or DAT) into nerve endings and into perisynaptic cells; this uptake may also occur with norepinephrine, epinephrine, and dopamine given as drugs. These agonists have a short duration of action. When given parenterally, they do not enter the central nervous system (CNS) in significant amounts. Isoproterenol, a synthetic catecholamine, is similar to the endogenous transmitters but is not readily taken up into nerve endings. Phenylisopropylamines, for example, amphetamines, are resistant to MAO; most of them are not catecholamines and are therefore also resistant to COMT. Phenylisopropylamines are orally active; they enter the CNS, and their effects last much longer than do those of catecholamines. Tyramine, which is not a phenylisopropylamine, is rapidly metabolized by MAO except in patients who are taking an MAO inhibitor drug. MAO inhibitors are sometimes used in the treatment of depression (see Chapter 30).

Mechanisms of Action

Alpha1 Receptor Effects

Alpha1 receptor effects are mediated primarily by the trimeric coupling protein Gq. When Gq is activated, the alpha moiety of this protein activates the enzyme phospholipase C, resulting in the release of inositol-1,4,5-trisphosphate (IP 3) and diacylglycerol (DAG) from membrane lipids. Calcium is subsequently released from stores in smooth muscle cells by IP3, and enzymes are activated by DAG. Direct gating of calcium channels may also play a role in increasing intracellular calcium concentration.

Alpha2 Receptor Effects

Alpha2 receptor activation results in inhibition of adenylyl cyclase via the coupling protein Gi.

Beta Receptor Effects

Beta receptors (1, 2, and 3) stimulate adenylyl cyclase via the coupling protein Gs, which leads to an increase in cyclic adenosine monophosphate (cAMP) concentration in the cell.

Dopamine Receptor Effects

Dopamine D1 receptors activate adenylyl cyclase via Gs in neurons and vascular smooth muscle. Dopamine D2 receptors are more important in the brain but probably also play a significant role as presynaptic receptors on peripheral nerves. These receptors act via Gi and reduce the synthesis of cAMP.

Organ System Effects

Central Nervous System

Catecholamines do not enter the CNS effectively. Sympathomimetics that do enter the CNS (eg, amphetamines) have a spectrum of stimulant effects, beginning with mild alerting or reduction of fatigue and progressing to anorexia, euphoria, and insomnia. Some of these central effects probably reflect the release of dopamine in certain dopaminergic tracts. Repeated dosing of amphetamines results in the rapid development of tolerance and dependence. These CNS effects reflect the amplification of dopamine’s action in the ventral tegmental area and other CNS nuclei (see Chapter 32). Very high doses of amphetamines lead to marked anxiety or aggressiveness, paranoia, and, less commonly, seizures. Overdoses of cocaine very commonly result in seizures.

Eye

The smooth muscle of the pupillary dilator responds to topical phenylephrine and similar agonists with contraction and mydriasis. Accommodation is not significantly affected. Outflow of aqueous humor may be facilitated by nonselective agonists, with a subsequent reduction of intraocular pressure. This probably occurs via the uveoscleral drainage system. Alpha2-selective agonists also reduce intraocular pressure, apparently by reducing synthesis of aqueous humor.

Bronchi

The smooth muscle of the bronchi relaxes markedly in response to 2 agonists. These agents are the most efficacious and reliable drugs for reversing bronchospasm.

Gastrointestinal Tract

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