Chemical Properties

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 somewhat difficult to categorize with respect to absorption, distribution, and metabolism. However, most analeptic stimulants can be absorbed orally and have short durations of action. The pharmacological effect of most of these compounds is terminated through hepatic metabolism 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 inhibitory action of many amino acid neurotransmitters (e.g., GABA) involves an increase in chloride conductance. Thus, GABA and other inhibitory amino acids actively promote an increase in chloride influx by activation of the chloride channel in the neuronal membrane.An increase in chloride conductance generally leads to membrane membrane hyperpolarization and a reduction in the probability of action potential generation (i.e., inhibition of neuronal activity).With GABA in particular, the interaction appears to occur through specific membrane-associated GABA_A-receptors that form an integral part of the chloride channel. The chloride channel appears to contain other regulatory sites with high affinity for such agents as the benzodiazepines, picrotoxin, alcohol, 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 benzodiazepine- binding site, and (3) a picrotoxin-binding site. GABA and other agonists open the chloride channel (i.e., increase chloride conductance). Benzodiazepineinduced facilitation of GABA-mediated increases in chloride conduction are antagonized by pentylenetetrazol and possibly by the methylxanthines, while picrotoxin closes the chloride channel. Other agents that appear to promote chloride conductance through this channel include 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 mechanism of action of a diverse class of agents.
Strychnine is an analeptic stimulant with a welldefined mechanism of action that is unrelated to interaction with GABA receptors or other sites that modulate the activity of the chloride ionophore. Strychnine appears to be a specific competitive postsynaptic antagonist of glycine. Glycine, like GABA, is a known inhibitory 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 mediates 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 Use

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 electroencephalogram. Strychnine is used almost exclusively in animal studies as a tool for studying CNS mechanisms because it is a relatively specific glycine antagonist.

Side effects

Most of the CNS stimulants produce adverse reactions that are extensions of their therapeutic effect. These 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 respiration, tachycardia, and excessive pressor effects. The uncontrolled excitation that occurs after accidental or intentional strychnine ingestion (in the absence of normal inhibition) results in characteristic convulsions. 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 characteristic 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 patient in opisthotonos. Under the influence of strychnine, all sensory stimuli produce exaggerated responses. The primary therapeutic consideration after strychnine poisoning is to prevent convulsions, which may be fatal.
Diazepam and clonazepam appear to be moderately effective in preventing strychnine convulsions, 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.

Raw materials

Preparation Products