GENERAL MECHANISMS OF DRUG ACTION IN THE NERVOUS SYSTEM.

GENERAL MECHANISMS OF DRUG ACTION IN THE NERVOUS SYSTEM.

ADRENERGIC AGONISTS

Chemistry

1. Direct-acting adrenergic agonists interact directly with adrenergic receptors to elicita response. These agonists include norepinephrine and epinephrine, which are endogenous or naturally occur ring catecholamines. The catecholamines are biosynthesized from tyrosine, an amino acid. Examples of other directacting adrenergic agonists include naphazoline, terbutaline, and dobutamine.

a. The ethylamine chain common to these agonists is essential to their adrenergic activity.

b. N-substitution alters drug activity. Small substituents (e.g., hydrogen, α-methyl group) produce α- receptor activity, as with norepinephrine; larger substituents (e.g., isopropyl group) produce β- receptor activity, as with isoproterenol .

c. Removal of the para (4) hydroxyl group leaves only α- receptor activity, as with phenylephrine.

d. The meta (3) hydroxyl group is essential for direct α- and β-activity. However , drugs in which the meta hydroxyl is replaced by a methoxy group (e.g., methoxamine) retain α-activity.

e. Catecholamines are inactivated by methylation of the meta hydroxyl group (catalyzed by catechol O-methyl transferase [COMT] ) and by oxidat ive deamination (catalyzed by monoamine oxidase [MAO]).

2. Indirect -acting adrenergic agonists are chemically related to the catecholamines, but they do not significantly interact directly with adrenergic receptors. These mostly synthetic compounds induce their pharmacological effects by enhancing the release of the endogenous neurotransmitters. Physiologically, therefore, they have effects similar to the catecholamine neurotransmitters, hence their nickname of sympathomimetic amines. Examples include amphetamine, ephedrine, phenylephrine, and tyramine.

a. Indirect -acting sympathomimetic amines may have two, one, or no hydroxyl groups. The fewer the hydroxyl groups, the higher the lipophilicity, and the greater the absorption and the duration of activity after oral administration. Faster and greater absorption also implies less intestinal destruction of the drug.

b. Alkyl substitution at the α-carbon (adjacent to the amino group) retards destruction of phenol and phenyl compounds and increases lipophilic character, contributing to prolonged activity.

c. N-substitution with bulky groups increases direct β-receptor activity, as with the directacting agents.

Pharmacology

1. Adrenergic peripheral responses are mediated by both α- and β-adrenoceptors. Adrenergic (and other ANS) receptors may be located at the cell membranes of nerve terminals (prejunctional receptors) or at the membranes of post junctional cells which receive the neural input from the nerve terminals. Prejunctional and post junctional receptors are also called presynaptic and postsynaptic receptors, respectively, where both the prejunctional cell and the post junct ional cell are nerve cel ls separated by a synaptic space.

a. α-Receptors fall into two main groups.

(1) Post-junctional α₁ -adrenergic receptors are found in the radial smooth muscle of the iris; in the arteries, arterioles, and veins; in the pilomotor smooth muscle of hair follicles; in the heart; and in the sphincters of the gastrointestinal tract (GIT). Drugs that are α₁ -selective agonists cause excitatory responses such as vasoconstriction and smooth muscle contraction, and include phenylephrine and methoxamine.

(2) Prejunctional α₂ -adrenergic receptors mediate the inhibition of adrenergic neurotransmitter release. Drugs that are α₂ -select ive agonists also inhibit lipolysis in fat cells and promote platelet aggregat ion. Examples of such drugs include clonidine and guanabenz.

b. β-Receptors fall into three main groups.

(1) Post junctional β₁ -adrenergic receptors are found mainly in the myocardium, where their stimulation increases myocaridal conduction speed (dromotropic effect) and the force (inotropic effect) and rate (chronotropic effect) of myocardial contraction. Drugs that are β₁ -selective agonists include xamoterol and to some extent dobutamine.

(2) Post junctional β₂ -adrenergic receptors are found in the smooth muscle of the vasculature, bronchioles, and uterus; stimulation of these receptors causes smoothmuscle relaxation. Drugs that are β2 -selective agonists include albuterol and terbutaline.

(3) Post junctional β₃-adrenergic receptors are expressed on fat cells, and their stimulation causes lipolysis. A number of β₃-agonists are under development as potential treatments for obesity, non- insulin-dependent diabetes mellitus, and frequent urination.

2. Direct acting adrenergic agonists (e.g., norepinephrine, phenylephrine, clonidine, terbutaline) produce their effects primarily by direct stimulation of adrenergic receptors. They may be receptor-selective, as with the drugs listed previously, or they may be nonselective. For example, the adrenergic

neurotransmit ternorepinephrine affects all adrenergic receptors, especially α₁-, α₂-, and β₁- receptors, whereas the adrenal medullary hormone epinephrine affects α₁ -, α₂ -, β₁-, and β₂- receptors. Isoproterenol affects both β₁- and β₂- receptors but not α- receptors.

3. Indirect acting adrenergic agonists work through other primary mechanisms, which ultimately lead to receptor effects. For example, tyramine acts by releasing norepinephrine from storage sites in adrenergic neurons, while cocaine blocks the reuptake of norepinephrine, thereby increasing the duration and activity of the transmitter at the synapse.

4. Certain agonists (e.g., ephedrine, metaraminol, mephentermine) produce their effects through both direct and indirect mechanisms.

ADRENERGIC ANTAGONISTS

A. Chemistry

1. α-Adrenergic antagonists (α-blockers) have varied s ructures and bear little resemblance to the adrenergic agonists. Antagonists include the ergot alkaloids (e.g., ergotamine), the dibenzamines (e.g., phenoxybenzamine), the benzolines (e.g., tolazoline), and the quinazolines (e.g., prazosin).

2. β-Adrenergic antagonists (β-blockers) are structurally similar to β-agonists. The catecholring can be replaced by a variety of other ring systems without loss of antagonistic activity. The length of the side chain is important and the side chain hydroxyl, as well as a propyl or other bulky substitution on the chain nitrogen, are essential for interaction with β- receptors.

Pharmacology

1. Adrenergic antagonists inhibit or block adrenergic receptor -mediated responses.

2. α-Adrenergic antagonists may be α₁- selective (e.g., prazosin) or nonselective (e.g., phenoxybenzamine). Phenoxybenzamine is an irreversible antagonist because it forms covalent bonds with α- receptors, thereby inactivating the receptors.

3. β-Adrenergic antagonists may be β1 -selective (e.g., metoprolol) or nonselective (e.g., propranolol). Generally, however, β1 -selective agents may lose their selectivity at higher doses and thus block β₂ - receptors as well (a potential problem in asthmatics).

CHOLINERGIC AGONISTS

A. Chemistry

1. Acetylcholine, the natural endogenous mediator and the most potent cholinergic agonist, is an ester of acetic acid and choline a quaternary amino alcohol. Acetylcholine in the blood is unstable as it is quickly inactivated through hydrolysis by acetylcholinesterase. Thus, it is extremely short acting and usually is not a satisfactory therapeutic agent.

2. Therapeutically useful cholinergic agonists may be direct acting or indirect acting.

a. Direct acting agonists may be produced by replacing the acetyl group of acetylcholine with a carbamoyl group or by substituting a methyl group of the β-carbon. These substitutions produce compounds that are more resistant to acetylchol inesterase and thus have longer durations of action. Such stable agonists include methacholine (Provochol ine) and bethanechol (Urecholine).

b. Indirect acting agonists are generally acetylcholinesterase inhibitors and are divided into two major classes.

(1) Reversible (short-acting) agents are principally carbamates (carbamic acid esters), such as physostigmine (Eserine), neostigmine, and ambenonium (Metylase).

(2) Irreversible (long-acting) agents are principally organophosphate esters, such as echothiophate (Phospholine).

Pharmacology

1. Cholinergic responses are mediated by both muscarinic and nicotinic receptors.

a. PNS muscarinic receptors are present at parasympathetic post junctional neuroeffector sites.

b. PNS nicotinic receptors are present at the ganglia of both the parasympathetic and sympathetic branches of the ANS and also at the neuromuscular junctions of the somatic nervous system.

2. Cholinergic agonists act by mimicking the activity of endogenous acetylcholine at muscarinic and nicotinic receptor sites.

a. Direct acting agonists interact directly with these receptors.

b. Indirect acting agonists inhibit or block the activity of cholinesterase enzymes (e.g., acetylcholinesterase, butyrylcholinesterase), which break down endogenous acetylcholine to inactive metabolites. Thus, following physiological release of acetylcholine from nerve terminals, these agents allow the neurotransmitter to accumulate at cholinergic synapses, thereby enhancing cholinergic receptor stimulation. Organophosphate cholinesterase inhibitors, such as certain agricultural insecticides and the so-called nerve gases, can be extremely toxic as they bind to the enzyme to form an irreversible or long-lasting enzyme inhibitor complex.

CHOLINERGIC ANTAGONISTS

A. Chemistry

1. Atropine, an alkaloid extracted from the belladonna plant, is the prototypical

cholinergic antagonist (anticholinergic agent). A portion of the atropine molecule is st ructurally simi lar to acetylcholine, permitting the molecule to bind to postjunctional receptors. However, the molecule has no intrinsic activity and its bulky shape prevents acetylcholine from binding to the receptor .

2. Synthetic anticholinergic agents (e.g., dicyclomine [Bentyl], glycopyrrolate [Robinul], propanthel ine [Pro-Banthine], pirenzepine and tropicamide) are also available. These agents, like atropine, are bulky analogues of acetylcholine.

3. An important factor that determines the pharmacologic spectrum of anticholinergic agents is the presence of a quaternary nitrogen (as in propantheline, glycopyrrolate, and ipratropium), which reduces passage across the blood-brain barrier, or atertiary nitrogen (as in dicyclomine, pirenzepine, tropicamide, and benztropine), which permits a broader volume of distribution (or accessibility to a wider range of tissues).

Pharmacology

1. Cholinergic antagonists competitively inhibit the activity of endogenous acetylcholine.

2. Antagonists that inhibit muscarinic receptor -mediated responses are called antimuscarinic agents; those that inhibit nicotinic receptor -mediated responses at the ganglia are called ganglionic-blocking agents, whereas those that inhibit nicotinic receptor -mediated responses at the neuromuscular junction are called neuromuscular -blocking agents.

NEUROMUSCULAR BLOCKING AGENTS

A. Chemistry

1. Neuromuscular blocking agents can be compet it ive (as wi th the prototypical curare alkaloids) or depolarizing (as wi th succinylcholine). Members of either category ultimately prevent the action of acetylcholine at nicotinic receptors located in the nerve-muscle junction.

2. The competitive nondepolarizing agents include the naturally occurring alkaloids of curare, which are bulky and rigid molecules, as well as several synthetic analogues.

a. The principal active alkaloid in curare is tubocurarine. A closely related trimethylate derivative is metocurine (Metubine). Their most important structural feature is the presence of a tertiary-quaternary amine in which the distance between the two cations is rigidly fixed at about twice the length of the critical receptor -binding moiety of acetylcholine.

b. A number of potent synthetic analogues have been developed. These include the structurally similar isoquinolines at racurium (Tracrium), doxacurium (Nuromax), and mivacurium (Mivacron), as well as the steroid derivatives pancuronium (Pavulon), vecuronium (Norcuron), and pipecuronium (Arduan).

3. The noncompetitive depolarizing agents include succinylcholine (Anectine) and gallamine (Flaxedil).

a. Unlike the large, bulky competitive agents, noncompetitive agents are slender aliphatic molecules.

b. Succinylchoine has a short duration of action compared with the other neuromuscular blocking agents. This results from its simple ester functional group, which is rapidly hydrolyzed by plasma and liver pseudochol inesterase (butyrylchol inesterase). Its action may be prolonged, however, in patients with an abnormal genetic variant of pseudocholinesterase, which has only about 20% the activity of normal pseudocholinesterase.

Pharmacology

1. The competitive nondepolarizing agents compete with acetylcholine for nicotinic receptors at the neuromuscular junction. These agents decrease the endplate potential so that the depolarization threshold is not reached. Competitive nondepolarizing agents produce a surmountable blockade of neuromuscular transmission in that administration of cholinesterase inhibi tors or prejunctional release of a large quantity of acetylcholine can relieve the blockade.

2. The noncompetitive depolarizing agents desensitize the nicotinic receptors at the neuromuscular junction. These agents react with the nicotinic receptors, decreasing receptor sensitivity in a manner similar to that of excess released acetylcholine. They depolarize the excitable membrane for a prolonged period (2-3 minutes); the membrane then becomes unresponsive (desensitized).

GENERAL ANESTHETICS

A. Chemistry

1. Volatile or inhalation anesthetics are drugs inhaled as gases or vapors. These diverse drugs are relatively simple lipophilic molecules. They include the inorganic agent nitrous oxide (N₂O) and the nonflammable halogenated hydrocarbons (e.g., halothane) and ethers (e.g., methoxyflurane, isoflurane, desflurane, sevoflurane) .

2. Nonvolatile or intravenous anesthetics are administered intravenously or occasionally intramuscularly and come as aqueous solutions, aqueous propylene glycol solutions, or emulsions.

a. The water -soluble and relatively short-acting agents include ultra-short -acting barbiturates (e.g., thiopental, methohexital, thiamylal), cyclohexylamines (e.g., ketamine), benzo-diazepines (e.g., diazepam, midazolam), butyrophenones (e.g., droperidol), and opioid analgesics (e.g., morphine, fentanyl).

b. The imidazole, etomidate, is prepared as an aqueous propylene glycol solution, which is compatible with many preanesthetics.

c. The dialkylphenol, propofol, is administered as an emulsion, which should not be mixed with other therapeutic agents before administration.

Pharmacology

1. General anesthetics depress the CNS, producing a reversible loss of consciousness and loss of all forms of sensation.

2. Inhalational anesthetics are absorbed and primarily excreted through the lungs. Frequently, these drugs are supplemented with analgesics, a skeletal muscle relaxant, and an antimuscarinic agent.

a. Analgesics permit a reduction in the required concentration of inhalational anesthetic.

b. Skeletal muscle relaxants cause adequate muscle relaxat ion during surgery.

c. Ant imuscarinic agents decrease buccal and bronchiolar secretions.

3. Nonvolat i le anesthetics are usually administered intravenously (e.g., thiobarbiturates, benzodiazepines), but some agents may also be given intramuscularly (e.g., ketamine).

LOCAL ANESTHETICS

A. Chemistry. Most local anesthetics are structurally similar to the alkaloid cocaine. These drugs consist of a hydrophilic amino group linked through an ester or amide connecting group to a lipophilic aromatic moiety. A few phenols and aromatic alcohols also have local anesthetic activity.

1. Ester -type agents are generally shortacting due to rapid hydrolysis by plasma esterases. These agents include cocaine, procaine, chloroprocaine, benzocaine, butamben, and tetracaine.

2. Amide- type agents are generally longer acting and are metabolized in the liver.

Examples of the amide- type local anesthetics include lidocaine, dibucaine, prilocaine, mepivacaine, bupivacaine, and etidocaine.

3. The drug's pKa (or dissociation constant) influences its chemical state, which in turn determines the anesthetic effectiveness of the compound. The site of anesthetic action is at the inner surface of the cell membrane. At tissue pH, the drug is in the form of a lipophilic, uncharged, secondary or tertiary amine, and thus diffuses across connective tissue and cell membranes and enters nerve cells where

it is ionized to a charged ammonium cation. The cationic form of the drug is the active form of the drug that blocks the generat ion of action potentials at the membrane receptor complex. Also, because of its charged ammonium cation, the intracellular ionized molecule poorly penetrates the cell membrane and thus remains trapped within the cell, thereby enhancing its durat ion of action.

Pharmacology

1. Local anesthetics reversibly block nerve impulse conduction and produce reversible loss of sensation at their administration site. They do not produce a loss of consciousness.

a. Small, nonmyelinated nerve fibers, which conduct pain and temperature sensations, are affected first.

b. Local anesthetics appear to become entrapped within the nerve membrane or to bind to specific membrane sodium ion (Na+) channels, restricting Na+ permeability in response to partial depolarization.

2. Local anesthetic solutions frequently contain the vasoconstrictor epinephrine, which reduces vascular blood flow at the administration site. This prolongs the duration of action, and reduces systemic absorption, and hence systemic toxicity.

ANTIPSYCHOTICS.

A. Chemistry

1. Phenothiazines (e.g., chlorpromazine, triflupromazine, thioridazine, prochlorperazine, trifluoperazine, fluphenazine) must have a nitrogen-containing side-chain substituent on the ring nitrogen for antipsychotic activity.

The ring and side-chain nitrogens must be separated by a three-carbon chain; phenothiazines in which the ring and side-chain nitrogens are separated by a twocarbon chain have only antihistaminic or sedative activity.

a. The side chains are either aliphatic, piperazine, or piperidine derivatives. Piperazine side chains confer the greatest potency and the highest pharmacological selectivity.

b. Fluphenazine and long-chain alcohols form stable, highly lipophilic esters (e.g., enanthate, decanoate), which possess markedly prolonged activity.

2. Thioxanthenes (e.g., chlorprothixene, thiothixene) lack the ring nitrogen of phenothiazines and have a side chain attached by a double bond.

3. Butyrophenones (e.g., haloperidol) are chemically unrelated to phenothiazines but have similar activity.

4. Newer agents derive from diverse chemical classes and include clozapine, olanzapine, loxapine, pimozide, molindone, quetiapine, risperidone, remoxipride, ziprasidone and aripiprazole.

Pharmacology

1. These agents have generally similar pharmacodynamic effects in the treatment of psychoticillness. Their antipsychotic action (i.e., improvement of cognitive and behavioral abnormalities) results primarily from their blockade of dopamine receptors in cortical and limbic areas of the brain, whereas their adverse ex rapyramidal effects such as parkinsonian reactions result from antagonism of dopamine receptors in the basal ganglia.

2. Other effects vary among the classes of antipsychotics. These include antiemetic activity and blockade of muscarinic, serotonergic, α₁- adrenergic, and H₁- histaminergic receptors.

3. The atypical antipsychotics (e.g., clozapine, aripiprazole) are newer agents that show strong antagonistic properties at serotonin receptors in addition to their blockade of dopamine receptors. Compared to the phenothiazines, butyrophenones, and other classic antipsychotic drugs, the atypical agents are effective in ameliorating a wider range of symptoms, including negative symptoms, and they also are less likely to induce extrapyramidal side effects.

ANTIDEPRESSIVE AND ANTIMANIC AGENTS

A. Chemistry

1. MAO inhibitors may be weakly potent hydralazines (e.g., phenelzine) or extremely potent phenylcyclopropylamines such as tranylcypromine which is a ring-closed amphetamine derivative.

2. Tricyclic antidepressants, which are used commonly, are secondary or tertiary amine derivatives of molecules that have a fused three- ring system.

a. The principal tricyclic antidepressants are derivatives of dibenzazepine (e.g., imipramine, desipramine, clomipramine, trimipramine) and dibenzocycloheptadiene (e.g., amitriptyline, nortriptyline, protriptyline).

b. Other closely related tricyclic antidepressants include doxepin, adibenzoxepine, and amoxapine.

3. Atypical antidepressants have varied structures ranging from the simple phenethylamine venlafaxine and the phenylpiperazine nefazodone to the aminoketone bupropion and the complex heterocyclics maprotiline and mirtazepine.

4. SSRIs have varied chemical structures and arerelated only by their pharmacologically common ability to inhibit the reuptake of serotonin from the synaptic cleft. These compounds include fluoxetine, paroxetine, sertraline, and fluvoxamine.

5. Lithium is an alkali metal that is used in the form of the carbonate salt in the treatment of manic depression or bipolar disease. Other agents in this therapeutic category include the organic compounds valproic acid and carbamazepine.

Pharmacology

1. MAO inhibitors appear to produce their antidepressant effects by blocking the intraneuronal oxidative deamination of brain biogenic amines (e.g., dopamine, norepinephrine, serotonin). This action increases the availability of biogenic amines at central aminergic synapses, and hence the probability of interaction with postsynaptic receptors to elicit the desired therapeutic effects. Other biochemical events (e.g., the down- regulation of central β-adrenergic and serotonergic receptors) that result from chronic inhibition of MAO and reuptake blockade can also explain the therapeutic action of antidepressants. This explanation is suggested by the latency period of MAO inhibitors, which take 2-4 weeks to become effective.

2. Tricyclic antidepressants appear to act principally by reducing CNS neuronal reuptake of the biogenic amines norepinephrine and serotonin. This prolongs the synaptic availability of biogenic amines and hence their action at central aminergic receptors.

3. SSRIs and atypical antidepressants have varying effects on reuptake of biogenic amines. The SSRIs selectively inhibit serotonin reuptake into the nerve terminal, thus prolonging the synaptic activity of the amine. Trazodone and other heterocyclics also inhibit amine transmitter reuptake. While bupropion appears to selectively inhibit dopamine reuptake, its mechanism may involve additional currently unknown actions since some other inhibitors of dopamine reuptake may not exhibit antidepressive effects.

4. Lithium appears to interfere with transmembrane Na+ exchange, alters the release of aminergic neurotransmitters, and blocks inositol metabolism, ultimately leading to depletion of cellular inositol and inhibition of phospholipase C-mediated signal transduction. The relevance of these actions to the mood-stabilizing effects of lithium, however, has not been established. Carbamazepine and valproic acid are known to interfere with ionic conductances in nerve cells, and to modulate other intracellular signaling cascades, but the contributions of these actions to their clinical effectiveness in bipolar disorder remain unclear.

ANXIOLYTICS AND SEDATIVE-HYPNOTICS.

A. Chemistry- 1. Benzodiazepines (e.g., alprazolam, diazepam, chlordiazepoxide, clonazepam, clorazepate, lorazepam, and oxazepam) have varying durations of action, which can be correlated with their structures in some cases.

a. Agents with a 3-hydroxyl group are easily metabolized by phase II glucuronidation and are short acting.

b. Agents lacking a 3-hydroxyl group must undergo considerable phase I metabolism, including 3-hydroxylation. These agents are long acting. Most longacting agents form the intermediate metabolite desmethyldiazepam, which has a very long half -life. Thus, these agents can have a cumulative action.

c. Triazolobenzodiazepines (e.g., alprazolam) undergo a different pattern of metabolism and are intermediate in activity.

d. Agents lacking an amino side chain are not basic enough to form water-soluble salts with acids. For example, intravenous solutions of diazepam contain propylene glycol as a solvent . Precipitation can occur if these solutions are mixed with aqueous solutions.

2. Azaspirodecanediones or azapirones (e.g., buspirone, gepirone, ipsapirone, tiaspirone) are chemically unrelated to the benzodiazepines. Represented by buspirone, these agents have anxiolytic activity resembling that of the benzodiazepines. Unlike the benzodiazepines, buspirone lacks CNS depressant activity and is considered an atypical anxiolytic.

3. The imidazopyridine zolpidem is a nonbenzodiazepine sedative-hypnotic with actions generally resembling those of the benzodiazepines.

4. Barbiturates are 5,5-disubstituted derivatives of barbituric acid, a saturated triketopyr imidine.

a. Two side chains in position 5 are essential for sedative-hypnotic activity.

b. Long-acting agents have a phenyl and an ethyl group in position 5.

c. Branched side chains, unsaturated side chains, or side chains longer than an ethyl group increase lipophilicity and metabolism rate. Increased lipophilicity leads to a shorter onset of action, a shorter duration of action, and increased potency.

d. Replacement of the position 2 oxygen with sulfur produces an extremely lipophilic molecule that distributes rapidly into lipid tissues outside the brain.

(1) These ultra-short -acting barbiturates are not useful as sedative-hypnotics but are ef fective in facilitating the induction of anesthesia. The action of these drugs is terminated very quickly.

(2) The prototype ultra-short-acting barbiturate is thiopental (Pentothal), the 2-thioisostere of pentobarbital.

e. The barbiturates and many of their metabolites are weak acids, and changes in urinary pH greatly influence their excretion. This is particularly true with overdoses, when a relatively large amount of unchanged drug appears in the glomerular filtrate.

f . Phenobarbital is one of the most powerful and versatile agents that can induce certain enzyme systems (e.g., the cytochrome P-450 metabolic system). This increases the potential for drug interactions and includes interaction with any drug metabolized by this system. Other barbiturates have less enzyme- inducing effect, except when they are used continuously in higher - than-normal doses.

5. Piperidinediones (e.g., glutethimide, methyprylon) and aldehydes (e.g., paraldehyde, chloral hydrate) differ structurally and are used less commonly than the benzodiazepines as sedative-hypnotics.

Pharmacology

1. Benzodiazepines appear to produce their calming and hypnotic effects by depressing the limbic system and reticular formation through potentiation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).

a. Anxiolytic activity correlates with the drug's binding affinity to a macromolecular complex consisting of GABAA receptors and chloride channels.

b. The interaction of benzodiazepines with GABA causes an increase in the frequency of chloride channel opening events, leading to a facilitation of chloride ion conductance, membrane hyperpolarization, and ultimately synaptic inhibition.

c. In addition to their anxiolytic properties, most benzodiazepines have other significant CNS actions, including hypnotic, anesthetic, anticonvulsant, and muscle relaxant effects at appropriate doses.

d. Benzodiazepines increase the depressant effects of alcohol and other CNS depressant drugs.

2. Azaspirodecanediones have multiple biochemical actions, but their principal mechanism of anxiolytic effect is still unknown.

a. Buspirone binds to central dopamine and serotonin receptors rather than to GABA-chloride ionophore receptor complexes. Interactions of azapirones with serotonin receptors may be agonistic when acting at somatodendritic 5-HT1A autoreceptors or antagonistic when acting at postsynaptic 5-HT1A receptors.

b. Buspirone possesses no hypnotic or anticonvulsant properties and does not appear to enhance the depressant effects of alcohol or other CNS depressant drugs.

c. Buspirone has minimal abuse liability and does not produce rebound anxiety following abrupt discontinuation.

3. The imidazopyridines have strong sedative effects with minimal clinical anxiolytic actions.

a. Zolpidem is as effective as the benzodiazepines in shortening sleep latency and in prolonging total sleep time in patients with insomnia.

b. Zolpidem is rarely associated with physical dependence, rebound insomnia, or respiratory depression even in overdosage.

4. Barbiturates are less selective than benzodiazepines and produce generalized CNS depression.

a. Barbiturates bind to a site that is distinct from the benzodiazepine binding site on a macromolecular GABA-chloride ionophore receptor complex. Barbiturate binding induces an increase in the duration of channel opening events, and thus mimics or enhances the inhibitory actions of GABA.

b. Barbiturates have a wide range of dose-dependent pharmacological actions related to CNS depression, including sedation, hypnosis, and anesthesia. They also act as potent respiratory depressants and inducers of hepatic microsomal drug metabolizing enzyme activity.

5. Piperidinediones, aldehydes, and other nonbarbiturate sedative-hypnotics have similar pharmacological actions related to CNS depression.

a. Chloralhydrate is commonly used to induce sleep in pediatric or geriatric patients. Its low cost is the major factor accounting for its preferred usage in institutional settings.

b. Chloral hydrate is biotransformed to trichloroethanol, which is responsible for the pharmacological activity of the drug. Chloral hydrate induces hepatic microsomal

drug-metabolizing enzyme activity.

ANTIEPILEPTICS

A. Chemistry. Antiepileptics (anticonvulsants) vary widely in structure.

1. Older agents, which are still widely used, include derivatives of the long-acting barbiturates (e.g., phenobarbital, mephobarbital, metharbital, primidone), hydantoins (e.g., phenytoin, ethotoin), succinimides (e.g., ethosuximide, phensuximide), oxazolidinediones (e.g., trimethadione, dimethadione), and dialkylacetates (e.g., valproic acid).

2. Newer agents, which are more structurally diverse, include the iminostilbenes (e.g., carbamazepine), benzodiazepines (e.g., diazepam, clonazepam, clorazepate), GABA analogs (vigabatrin, gabapentin, pregabalin), and the miscellaneous agent’s lamotrigine, felbamate, levetiracetam, zonisamide, and topiramate which is actually a substituted monosaccharide.

Pharmacology

1. Antiepileptics prevent or reduce excessive discharge and reduce the spread of excitation from CNS seizure foci.

2. The mechanisms of action of antiepileptics appear to be alteration of Na+ neuronal concentrations by promotion of Na+ efflux (e.g., hydantoins) and restoration or enhancement of GABA-ergicinhibitory neuronal function (e.g., barbiturates, benzodiazepines, valproic acid).

ANTIPARKINSONIAN AGENTS

A. Chemistry. The principal antiparkinsonian agents are either dopaminergic agonists or cholinergic antagonists.

1. Some anticholinergic antiparkinsonian agents are structurally related to atropine (e.g., benztropine, trihexyphenidyl). Other antiparkinsonian anticholinergic agents include procyclidine (Kemadrin), orphenadrine (Norflex), and biperiden (Akineton).

2. The prototypical dopaminergic antiparkinsonian agent is the catecholamine levodopa, a prodrug that must be converted in-vivo to dopamine by dopadecarboxylase. Direct receptor-acting dopaminergics include ergolines such as bromocriptine (Par lodel) and pergolide (Permax) , the phenanthrene apomorphine, and the newer nonergoline dopamine agonists pramipexole (Mi rapex) and ropinirole (Requip) .

3. Several agents are available to improve the therapeutic efficacy and safety of levodopa.

a. Carbidopa, a levodopa analogue that does not cross the blood-brain barrier, is a decarboxylase inhibitor that diminishes the decarboxylation and subsequent inactivation of levodopa in peripheral tissues. When coadministered, more levodopa is preserved to enter the CNS. A combination of levodopa and carbidopa (Sinemet) is available for clinical use.

b. Selegiline (deprenyl) is a selective monoamine oxidase-B (MAO-B) inhibitor that inhibits the intracerebral degradation of endogenous or levodopa-derived dopamine.

c. Tolcapone or entacapone are selective inhibitors of COMT, thus reducing the conversion of levodopa to 3-O-methyldopa, an inactive metabolite that also inhibits levodopa uptake into the brain. Additionally, inhibition of dopamine breakdown by COMT may prolong the availability and action of the transmitter in the CNS.

Pharmacology.

Antiparkinsonian agents act by restoring the striatal balance of dopaminergic and cholinergic neurotransmission, which is deranged in parkinsonism as a result of degeneration of dopaminergic neurons that supply dopamine to the basal ganglia (caudate-putamen).

1. Levodopa, which can cross the blood-brain barrier, is the immediate precursor of the striatal neurotransmitter dopamine and is converted to dopamine in the body.

2. Amantadine, an antiviral agent, appears to stimulate the release of dopamine from intactstriatal terminals of remaining dopaminergic neurons. As the disease progresses and fewer dopaminergic neurons remain, amantadine becomes progressively ineffective.

3. Apomorphine, bromocriptine, pergolide, pramipexole, and ropinirole, which are direct dopaminergic receptor agonists, mimic the activity of dopamine in the caudate-putamen. Nevertheless, the drugs cannot reproduce the pulsatile rhythm of endogenous dopamine release.

4. Selegiline, an inhibitor of the central MAO-B isoenzyme, blocks the central catabolism of dopamine, increasing its avai lability in the caudate-putamen.

5. Antichol inergics, such as trihexyphenidyl, benztropine, and orphenadrine, block the excitatory cholinergic system, thus reducing the functional imbalance between dopamine and acetylcholine in the striatum.

6. The enzyme inhibitors, carbidopa and tolcapone, increase the transport and bioavailability of levodopa in the brain and are thus given as adjunctive treatments with levodopa.

OPIOID ANALGESICS and ANTAGONISTS.

A. Chemistry. The opiate alkaloids are derived from opium, which is considered the oldest drug on record. Opium (the dried exudate of the poppy seed capsule) contains about 25 different alkaloids. Of these, morphine is the most important, both quantitatively and pharmacologically.

1. Morphine's phenolic hydroxyl group is extremely important for activity; however, analgesic activity appears to depend on a p-phenyl -N-alkylpiperidine moiety, in which the piperidine ring is in the chair form and is perpendicular to the aromatic ring. The alkyl group is usually methyl. The morphine molecule can be altered in a variety of ways; related compounds also can be synthesized from other starting materials.

2. Natural or synthet ic opioids may be classified into four chemical groups:

a. Phenanthrenes (e.g., morphine and hydromorphone, codeine and hydrocodone, nalbuphine and buprenorphine, and nalorphine, naltrexone, and naloxone). Methylation of the phenolic (3)-hydroxyl group with or without modification of the 6-hydroxyl group of morphine yields agents with reduced agonist potency but enhanced oral bioavailability (e.g., codeine, hydrocodone, oxycodone).

b. Phenylheptylamines (e.g., methadone and propoxyphene) are bisphenyl derivatives of heptylamine that have strong (methadone) or moderate (propoxyphene) agonist potency and excellent oral bioavailability.

c. Phenylpiper idines include meperidine, fentanyl, and sufentanil, which are strong agonists that are more effective when given parenterally, and the moderate agonists diphenoxylate and loperamide.

d. The morphinan levorphanol is a strong agonist with high oral bioavailability.

3. Opioid antagonists are derived by replacing the methyl group on the nitrogen atom with more bulky substitutions. Thus, nalbuphine and buprenorphine are phenanthrene mixed agonist -antagonists; naltrexone and naloxone are phenanthrene pure antagonists; and butorphanol and levallorphan are morphinan derived antagonists.

4. Agents having both a free phenolic hydroxyl group and a tertiary amine function (e.g., morphine and nalbuphine) are chemically amphoteric. Amphotericity probably accounts for the erratic absorption of morphine when administered orally.

5. Some newer opioid analgesic agents, such as tramadol, are chemically unrelated to the natural, semisynthetic, and synthetic opiate derivatives.

6. Numerous analogues of endogenous opioid peptides have been synthesized and are being used in research.

Pharmacology

1. Opioid analgesics mimic the actions of endogenous opioid peptides at CNS opioid receptors, raising the pain threshold and increasing pain tolerance. The analgesic actions are mediated primarily through the μ-subtype of opioid receptors.

2. Other actions at tributable to stimulation of opioid receptors include induction of euphoria, sedation, cough suppression, and chemoreceptor trigger -zone stimulation leading to nausea and vomiting.

3. Tramadol appears to actvia a metabolite, which is selective for the μ-opioid receptor and also inhibits reuptake of norepinephrine and serotonin. Its nonopiate character appears to confer no clear benef its over the opiates.

4. Pure opioid antagonists such as naloxone block the actions of opioid agonists. Mixed agonist-antagonists such as nalbuphine, buprenorphine, butorphanol, and pentazocine block the actions of agonists at some receptors while directly stimulating other receptors to produce agonistic effects.