Analeptic Stimulants

ANALEPTIC STIMULANTS

Chemistry and Pharmacokinetics

The analeptic stimulants are a diverse chemical class of agents ranging from plant alkaloids, such as picrotoxin and strychnine, to synthetic compounds, such as pentylenetetrazol and doxapram. The wide range of chemical structures makes this particular class some-what difficult to categorize with respect to absorption, distribution, and metabolism. However, most analeptic stimulants can be absorbed orally and have short dura-tions of action. The pharmacological effect of most of these compounds is terminated through hepatic metab-olism rather than renal excretion of unchanged drug.

Mechanism of Action

Perhaps the most unifying concept concerning the mode of action of these agents comes from studies of the - aminobutyric acid (GABA) receptor–chloride ionophore interaction. It has long been recognized that the in-hibitory action of many amino acid neurotransmitters (e.g., GABA) involves an increase in chloride conduc-tance. Thus, GABA and other inhibitory amino acids ac-tively promote an increase in chloride influx by activation of the chloride channel in the neuronal membrane.An in-crease in chloride conductance generally leads to mem-brane hyperpolarization and a reduction in the probabil-ity of action potential generation (i.e., inhibition of neu-ronal activity). With GABA in particular, the interaction appears to occur through specific membrane-associated GABA_A-receptors that form an integral part of the chlo-ride channel . The chloride channel ap-pears to contain other regulatory sites with high affinity for such agents as the benzodiazepines, picrotoxin, alco-hol, neuroactive steroids, and the barbiturates.

Chloride movement across neuronal membranes can be regulated at this ion channel by at least three distinct molecular entities: (1) a GABA-binding site, (2) a benzo-diazepine-binding site, and (3) a picrotoxin-binding site. GABA and other agonists open the chloride channel (i.e., increase chloride conductance). Benzodiazepine-induced facilitation of GABA-mediated increases in chloride conduction are antagonized by pentylenetetra-zol and possibly by the methylxanthines, while picrotoxin closes the chloride channel. Other agents that appear to promote chloride conductance through this channel in-clude the barbiturates and alcohol.

The existence of the chloride channel as a major site of drug action permits a single molecular event (control of chloride ion movement) to be involved in the mech-anism of action of a diverse class of agents. Strychnine is an analeptic stimulant with a well-defined mechanism of action that is unrelated to inter-action with GABA receptors or other sites that modu-late the activity of the chloride ionophore. Strychnine appears to be a specific competitive postsynaptic antag-onist of glycine. Glycine, like GABA, is a known in-hibitory transmitter in the mammalian CNS. Whereas GABA is likely to be more important in the brain, glycine is more important in the spinal cord. Glycine me-diates inhibition of spinal cord neurons and is intimately involved in the regulation of spinal cord and brainstem reflexes. Strychnine directly antagonizes this inhibition, allowing excitatory impulses to be greatly exaggerated.

Clinical Uses

As indicated, most of the analeptic stimulants were used as pharmacological treatments for overdosage of CNS depressants. Doxapram (Dopram) is sometimes used to counteract postanesthetic respiratory depression and as an aid in chronic obstructive pulmonary disease. Pentylenetetrazol (Metrazol) was used experimentally on rare occasions to “activate” the electroencephalo-gram. Strychnine is used almost exclusively in animal studies as a tool for studying CNS mechanisms because it is a relatively specific glycine antagonist.

Adverse Effects

Most of the CNS stimulants produce adverse reactions that are extensions of their therapeutic effect. These agents produce convulsions that can be followed by coma and death. Convulsions produced by this class of agents (with the exception of strychnine) are usually tonic–clonic and are uncoordinated. In some cases, the convulsions are preceded by marked stimulation of res-piration, tachycardia, and excessive pressor effects.

The uncontrolled excitation that occurs after acci-dental or intentional strychnine ingestion (in the ab-sence of normal inhibition) results in characteristic con-vulsions. In humans, in whom extensor muscles are normally dominant, tonic extension of the body and all limbs is observed. This hyperextension is known as opisthotonos; at its extreme, it consists of a characteris-tic posture in which the back is arched and only the back of the head and the heels are touching the surface on which the victim is lying. Figure 29.1 illustrates a pa-tient in opisthotonos. Under the influence of strychnine, all sensory stimuli produce exaggerated responses. The primary therapeutic consideration after strychnine poi-soning is to prevent convulsions, which may be fatal. Diazepam and clonazepam  appear to be moderately effective in preventing strychnine con-vulsions, and either of these is the agent of choice. Barbiturates are often used to treat overdoses of all of the analeptic stimulants. Generally, however, antidotal therapy is not required.