книги студ / Color Atlas of Pharmacology

Parasympathomimetics

Acetylcholine (ACh) is too rapidly hydrolyzed and inactivated by acetylcholinesterase (AChE) to be of any therapeutic use; however, its action can be mimicked by other substances, namely direct or indirect parasympathomimetics.

Direct Parasympathomimetics.

The choline ester, carbachol, activates M-cholinoceptors, but is not hydrolyzed by AChE. Carbachol can thus be effectively employed for local application to the eye (glaucoma) and systemic administration (bowel atonia, bladder atonia). The alkaloids, pilocarpine (from Pil- ocarpus jaborandi) and arecoline (from

Areca catechu; betel nut) also act as direct parasympathomimetics. As tertiary amines, they moreover exert central effects. The central effect of muscarinelike substances consists of an enlivening, mild stimulation that is probably the effect desired in betel chewing, a widespread habit in South Asia. Of this group, only pilocarpine enjoys therapeutic use, which is limited to local application to the eye in glaucoma.

Indirect Parasympathomimetics.

AChE can be inhibited selectively, with the result that ACh released by nerve impulses will accumulate at cholinergic synapses and cause prolonged stimulation of cholinoceptors. Inhibitors of AChE are, therefore, indirect parasympathomimetics. Their action is evident at all cholinergic synapses. Chemically, these agents include esters of carbamic acid (carbamates such as physostig- mine, neostigmine) and of phosphoric acid (organophosphates such as paraoxon = E600 and nitrostigmine = parathion = E605, its prodrug).

Members of both groups react like ACh with AChE and can be considered false substrates. The esters are hydrolyzed upon formation of a complex with the enzyme. The rate-limiting step in ACh hydrolysis is deacetylation of the enzyme, which takes only milliseconds, thus permitting a high turnover rate and activity of AChE. Decarbaminoyla- tion following hydrolysis of a carba-

mate takes hours to days, the enzyme remaining inhibited as long as it is carbaminoylated. Cleavage of the phosphate residue, i.e. dephosphorylation, is practically impossible; enzyme inhibition is irreversible.

Uses. The quaternary carbamate neostigmine is employed as an indirect parasympathomimetic in postoperative atonia of the bowel or bladder. Furthermore, it is needed to overcome the relative ACh-deficiency at the motor endplate in myasthenia gravis or to reverse the neuromuscular blockade (p. 184) caused by nondepolarizing muscle relaxants (decurarization before discontinuation of anesthesia). The tertiary carbamate physostigmine can be used as an antidote in poisoning with parasympatholytic drugs, because it has access to AChE in the brain. Carbamates (neostigmine, pyridostigmine, physostigmine) and organophosphates (paraoxon, ecothiopate) can also be applied locally to the eye in the treatment of glaucoma; however, their long-term use leads to cataract formation. Agents from both classes also serve as insecticides. Although they possess high acute toxicity in humans, they are more rapidly degraded than is DDT following their emission into the environment.

Tacrine is not an ester and interferes only with the choline-binding site of AChE. It is effective in alleviating symptoms of dementia in some subtypes of Alzheimer’s disease.

Parasympatholytics

Excitation of the parasympathetic division of the autonomic nervous system causes release of acetylcholine at neuroeffector junctions in different target organs. The major effects are summarized in A (blue arrows). Some of these effects have therapeutic applications, as indicated by the clinical uses of parasympathomimetics (p. 102).

Substances acting antagonistically at the M-cholinoceptor are designated parasympatholytics (prototype: the alkaloid atropine; actions shown in red in the panels). Therapeutic use of these agents is complicated by their low organ selectivity. Possibilities for a targeted action include:

•local application

•selection of drugs with either good or poor membrane penetrability as the situation demands

•administration of drugs possessing receptor subtype selectivity.

Parasympatholytics are employed for the following purposes:

1. Inhibition of exocrine glands

Bronchial secretion. Premedication with atropine before inhalation anesthesia prevents a possible hypersecretion of bronchial mucus, which cannot be expectorated by coughing during intubation (anesthesia).

Gastric secretion. Stimulation of gastric acid production by vagal impulses involves an M-cholinoceptor subtype (M1-receptor), probably associated with enterochromaffin cells. Pirenzepine (p. 106) displays a preferential affinity for this receptor subtype. Remarkably, the HCl-secreting parietal cells possess only M3-receptors. M1-receptors have also been demonstrated in the brain; however, these cannot be reached by pirenzepine because its lipophilicity is too low to permit penetration of the bloodbrain barrier. Pirenzepine was formerly used in the treatment of gastric and duodenal ulcers (p. 166).

2. Relaxation of smooth musculature

Bronchodilation can be achieved by the use of ipratropium in conditions of increased airway resistance (chronic obstructive bronchitis, bronchial asthma). When administered by inhalation, this quaternary compound has little effect on other organs because of its low rate of systemic absorption.

Spasmolysis by N-butylscopolamine in biliary or renal colic (p. 126). Because of its quaternary nitrogen, this drug does not enter the brain and requires parenteral administration. Its spasmolytic action is especially marked because of additional ganglionic blocking and direct muscle-relaxant actions.

Lowering of pupillary sphincter tonus and pupillary dilation by local administration of homatropine or tropicamide (mydriatics) allows observation of the ocular fundus. For diagnostic uses, only short-term pupillary dilation is needed. The effect of both agents subsides quickly in comparison with that of atropine (duration of several days).

3. Cardioacceleration

Ipratropium is used in bradycardia and AV-block, respectively, to raise heart rate and to facilitate cardiac impulse conduction. As a quaternary substance, it does not penetrate into the brain, which greatly reduces the risk of CNS disturbances (see below). Relatively high oral doses are required because of an inefficient intestinal absorption.

Atropine may be given to prevent cardiac arrest resulting from vagal reflex activation, incident to anesthetic induction, gastric lavage, or endoscopic procedures.

4. CNS-dampening effects

Scopolamine is effective in the prophy- laxis of kinetosis (motion sickness, sea sickness, see p. 330); it is well absorbed transcutaneously. Scopolamine (pKa = 7.2) penetrates the blood-brain barrier faster than does atropine (pKa = 9), because at physiologic pH a larger proportion is present in the neutral, mem- brane-permeant form.

In psychotic excitement (agitation), sedation can be achieved with scopolamine. Unlike atropine, scopolamine exerts a calming and amnesiogenic action that can be used to advantage in anesthetic premedication.

Symptomatic treatment in parkinsonism for the purpose of restoring a dopaminergic-cholinergic balance in the corpus striatum. Antiparkinsonian agents, such as benzatropine (p. 188), readily penetrate the blood-brain barrier. At centrally equi-effective dosage, their peripheral effects are less marked than are those of atropine.

Contraindications for parasympatholytics

Glaucoma: Since drainage of aqueous humor is impeded during relaxation of the pupillary sphincter, intraocular pressure rises.

Prostatic hypertrophy with impaired micturition: loss of parasympathetic control of the detrusor muscle exacerbates difficulties in voiding urine.

Atropine poisoning

Parasympatholytics have a wide therapeutic margin. Rarely life-threatening, poisoning with atropine is characterized by the following peripheral and central effects:

Peripheral: tachycardia; dry mouth; hyperthermia secondary to the inhibition of sweating. Although sweat glands are innervated by sympathetic fibers, these are cholinergic in nature. When sweat secretion is inhibited, the body loses the ability to dissipate metabolic heat by evaporation of sweat (p. 202). There is a compensatory vasodilation in the skin allowing increased heat

exchange through increased cutaneous blood flow. Decreased peristaltic activity of the intestines leads to constipa- tion.

Central: Motor restlessness, progressing to maniacal agitation, psychic disturbances, disorientation, and hal- lucinations. Elderly subjects are more sensitive to such central effects. In this context, the diversity of drugs producing atropine-like side effects should be borne in mind: e.g., tricyclic antidepressants, neuroleptics, antihistamines, antiarrhythmics, antiparkinsonian agents.

Apart from symptomatic, general measures (gastric lavage, cooling with ice water), therapy of severe atropine intoxication includes the administration of the indirect parasympathomimetic physostigmine (p. 102). The most common instances of “atropine” intoxication are observed after ingestion of the berry-like fruits of belladonna (children) or intentional overdosage with tricyclic antidepressants in attempted suicide.

Ganglionic Transmission

Whether sympathetic or parasympathetic, all efferent visceromotor nerves are made up of two serially connected neurons. The point of contact (synapse) between the first and second neurons occurs mainly in ganglia; therefore, the first neuron is referred to as pregan- glionic and efferents of the second as postganglionic.

Electrical excitation (action potential) of the first neuron causes the release of acetylcholine (ACh) within the ganglia. ACh stimulates receptors located on the subsynaptic membrane of the second neuron. Activation of these receptors causes the nonspecific cation channel to open. The resulting influx of Na+ leads to a membrane depolarization. If a sufficient number of receptors is activated simultaneously, a threshold potential is reached at which the membrane undergoes rapid depolarization in the form of a propagated action potential. Normally, not all preganglionic impulses elicit a propagated response in the second neuron. The ganglionic synapse acts like a frequency filter (A). The effect of ACh elicited at receptors on the ganglionic neuronal membrane can be imitated by nicotine; i.e., it involves nic- otinic cholinoceptors.

Ganglionic action of nicotine. If a small dose of nicotine is given, the ganglionic cholinoceptors are activated. The membrane depolarizes partially, but fails to reach the firing threshold. However, at this point an amount of released ACh smaller than that normally required will be sufficient to elicit a propagated action potential. At a low concentration, nicotine acts as a ganglionic stimulant; it alters the filter function of the ganglionic synapse, allowing action potential frequency in the second neuron to approach that of the first (B). At higher concentrations, nicotine acts to block ganglionic transmission. Simultaneous activation of many nicotinic cholinoceptors depolarizes the ganglionic cell membrane to such an extent that generation of action potentials

is no longer possible, even in the face of an intensive and synchronized release of ACh (C).

Although nicotine mimics the action of ACh at the receptors, it cannot duplicate the time course of intrasynaptic agonist concentration required for appropriate high-frequency ganglionic activation. The concentration of nicotine in the synaptic cleft can neither build up as rapidly as that of ACh released from nerve terminals nor can nicotine be eliminated from the synaptic cleft as quickly as ACh.

The ganglionic effects of ACh can be blocked by tetraethylammonium, hexamethonium, and other substances (gan- glionic blockers). None of these has intrinsic activity, that is, they fail to stimulate ganglia even at low concentration; some of them (e.g., hexamethonium) actually block the cholinoceptor-linked ion channel, but others (mecamylamine, trimethaphan) are typical receptor antagonists.

Certain sympathetic preganglionic neurons project without interruption to the chromaffin cells of the adrenal medulla. The latter are embryologic homologues of ganglionic sympathocytes. Excitation of preganglionic fibers leads to release of ACh in the adrenal medulla, whose chromaffin cells then respond with a release of epinephrine into the blood (D). Small doses of nicotine, by inducing a partial depolarization of adrenomedullary cells, are effective in liberating epinephrine (pp. 110, 112).

Effects of Nicotine on Body Functions

At a low concentration, the tobacco alkaloid nicotine acts as a ganglionic stimulant by causing a partial depolarization via activation of ganglionic cholinoceptors (p. 108). A similar action is evident at diverse other neural sites, considered below in more detail.

Autonomic ganglia. Ganglionic stimulation occurs in both the sympathetic and parasympathetic divisions of the autonomic nervous system. Parasympathetic activation results in increased production of gastric juice (smoking ban in peptic ulcer) and enhanced bowel motility (“laxative” effect of the first morning cigarette: defecation; diarrhea in the novice).

Although stimulation of parasympathetic cardioinhibitory neurons would tend to lower heart rate, this response is overridden by the simultaneous stimulation of sympathetic cardioaccelerant neurons and the adrenal medulla. Stimulation of sympathetic nerves resulting in release of norepinephrine gives rise to vasoconstriction; peripheral resistance rises.

Adrenal medulla. On the one hand, release of epinephrine elicits cardiovascular effects, such as increases in heart rate und peripheral vascular resistance.

On the other, it evokes metabolic responses, such as glycogenolysis and lipolysis, that generate energy-rich substrates. The sensation of hunger is suppressed. The metabolic state corresponds to that associated with physical exercise – “silent stress”.

Baroreceptors. Partial depolarization of baroreceptors enables activation of the reflex to occur at a relatively smaller rise in blood pressure, leading to decreased sympathetic vasoconstrictor activity.

Neurohypophysis. Release of vasopressin (antidiuretic hormone) results in lowered urinary output (p. 164). Levels of vasopressin necessary for vasoconstriction will rarely be produced by nicotine.

Carotid body. Sensitivity to arterial pCO2 increases; increased afferent input augments respiratory rate and depth.

Receptors for pressure, temperature, and pain. Sensitivity to the corresponding stimuli is enhanced.

Area postrema. Sensitization of chemoceptors leads to excitation of the medullary emetic center.

At low concentration, nicotine is also able to augment the excitability of the motor endplate. This effect can be manifested in heavy smokers in the form of muscle cramps (calf musculature) and soreness.

The central nervous actions of nicotine are thought to be mediated largely by presynaptic receptors that facilitate transmitter release from excitatory aminoacidergic (glutamatergic) nerve terminals in the cerebral cortex. Nicotine increases vigilance and the ability to concentrate. The effect reflects an enhanced readiness to perceive external stimuli (attentiveness) and to respond to them.

The multiplicity of its effects makes nicotine ill-suited for therapeutic use.