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Chapter 2 λ Cholinergic Pharmacology

Table II-2-7. Characteristics of Ganglion Blocking Agents

Ganglionic blocking

drugs do not prevent Vasoconstrictor Vasodilator

changes in HR elicited directly by the drug (β1 or M2 agonists).

Figure II-2-4. Algorithm: Reflex Control of Heart Rate

Neuromuscular Blocking Drugs

See CNS Pharmacology, chapter on Drugs Used in Anesthesia.

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Section II λ Autonomic Pharmacology

Chapter Summary

λAcetylcholine (ACh) is synthesized from acetate and choline in the synaptic nerve via choline acetyltransferase and is stored in the synaptic vesicles and released by Ca2+ influx upon depolarization. The ACh then binds to a receptor on the other side of the synaptic junction, thereby transmitting the signal. Acetylcholinesterase (AChE) hydrolyzes the ACh and ends the signal. Cholinergic drugs are those that affect this process either by influencing ACh levels or by acting directly on the nicotinic or muscarinic receptors.

λCholine uptake is inhibited by hemicholinium. Botulinum toxin binds to synaptobrevin and prevents ACh release, and AChE inhibitors slow its rate of breakdown. Several reversible AChE inhibitors are useful pharmacologic agents; the irreversible AChE inhibitors are generally poisons.

λA cholinomimetic is a drug that imitates ACh. Nicotine acts as a cholinomimetic on nicotinic receptors, whereas bethanechol and pilocarpine are cholinomimetics that act on muscarinic receptors.

λOther drugs are ACh receptor blockers. Specific blocking agents acting on

ganglionic nicotinic (NN) receptors are hexamethonium and mecamylamine.

Those acting on the end-plate nicotinic receptors (NM) are tubocurarine, atracurium, and succinylcholine. Those acting on muscarinic (M) receptors include atropine, benztropine, and scopolamine.

λAll M-receptor activators are nonspecific (they act on M1–3), and, in general, M-receptor activation decreases cardiovascular function and increases secretions and smooth muscle contraction. Table II-2-1 shows the type of M receptor involved and specific end-organ responses to M-receptor activators.

λTable II-2-2 summarizes the effects of nicotinic receptor activation on the adrenal medulla, the autonomic ganglia, and the neuromuscular junction.

The effect of autonomic ganglia stimulation depends upon the transmission system used to connect the ganglia to the end organ. Blood vessels are innervated by SANS, resulting in vasoconstriction. PANS innervates the gut, the end result being increased motility and secretion.

λTable II-2-3 summarizes the receptor mechanisms used by the various receptor types.

λTable II-2-4 summarizes the activity, properties, and clinical uses for the direct-acting cholinomimetics, and Table II-2-5 does the same for the indirect-acting ones.

λLong-acting AChE inhibitors are commonly used as insecticides. Although these are less toxic for humans, they still provide a hazard, causing poisoning with both acute and chronic symptoms caused by both muscarinic and nicotinic hyperactivity (“dumbbeelss”).

λTherapy for acute poisoning by AChE inhibitors includes administration of M blockers (atropine) and pralidoxime (2-PAM), which helps reactivate AChE.

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Chapter 2 λ Cholinergic Pharmacology

Chapter Summary (cont’d )

λAtropine is the prototype of muscarinic receptor antagonist drugs. In simple terms, increasing doses of atropine progressively decreases secretions and causes mydriasis, blurred vision, tachycardia, constipation, and urinary retention. Overdoses of over-the-counter medications containing M blockers are common causes of toxicity. Management is largely symptomatic, although physostigmine may be useful because it helps counteract both central and peripheral effects. The clinical uses and properties of the M-blocking drugs are summarized in Table II-2-6.

λThe NN antagonists act as ganglionic blockers, so they will affect both the SANS and PANS tracts.

λGanglionic blockade prevents ANS reflexes. Table II-2-7 summarizes specific effects of ganglionic blocking agents and the transmission system employed for various specific organs.

λFigure II-2-4 summarizes the effects of ganglionic blockers on drugs that modify blood pressure, causing a reflex change in heart rate, and on drugs that act directly at the SA node to change the heart rate.

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Learning Objectives

Answer questions about catecholamine synthesis, action, and degradation

Explain information related to direct-acting adrenoceptor agonists and indirect-acting adrenergic receptor agonists

Differentiate between alpha receptor antagonists and beta receptor antagonists

CATECHOLAMINE SYNTHESIS, ACTION, AND

DEGRADATION

The important aspects of the adrenergic neuroeffector junction are summarized in

Figure II-3-1.

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Junction

Tyrosine is actively transported into nerve endings and is converted to dihydroxyphenylalanine (DOPA) via tyrosine hydroxylase (1). This step is rate limiting in the synthesis of NE. DOPA is converted to dopamine (DA) via L-aromatic amino acid decarboxylase (DOPA decarboxylase). DA is taken up into storage vesicles where it is metabolized to NE via DA beta hydroxylase (6). Inactivation of NE via monoamine oxidase A (MAO-A) (2) may regulate prejunctional levels of transmitter in the mobile pool (3) but not the NE stored in granules.

Presynaptic membrane depolarization opens voltage-dependent Ca2+ channels. Influx of this ion causes fusion of the synaptic granular membranes, with the presynaptic membrane leading to NE exocytosis into the neuroeffector junction

(7). NE then activates postjunctional receptors (8), leading to tissue-specific responses depending on the adrenoceptor subtype activated.

Termination of NE actions is mainly due to removal from the neuroeffector junction back into the sympathetic nerve ending via an NE reuptake transporter system

(4). At some sympathetic nerve endings, the NE released may activate prejunctional

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Section II λ Autonomic Pharmacology

Table II-3-2. Mechanisms Used by Adrenergic Receptors

DIRECT-ACTING ADRENOCEPTOR AGONISTS

α1 Agonists

• α1: ↑ TPR, ↑ BP

• Potential reflex bradycardia

• No change in pulse pressure

α1 activation (e.g., Phenylephrine)

Figure II-3-2. Effect of Alpha Activators on Heart Rate and Blood Pressure

λSystemically, ↑ mean blood pressure via vasoconstriction

λ↑ BP may elicit a reflex bradycardia

λCardiac output may be ↓ but also offset by ↑ venous return

λDrugs and uses:

−Phenylephrine: nasal decongestant and ophthalmologic use (mydriasis without cycloplegia), hypotensive states

α2 Agonists

Stimulate prejunctional receptors in the CNS to decrease sympathetic outflow. Primary use is in mild to moderate HTN.

λDrugs and uses: clonidine and methyldopa (mild to moderate hypertension)

λSee Cardiovascular section.

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