Assoc. Prof. Ivan Lambev (e-mail: [email protected])
Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology
•Antidepressants•Mood stabilizers•Psychostimulants•Nootropic drugs•CNS stimulants
(Abstract)
Depression is a heterogeneous disorder. A simplified classification based on presumed origin is as follows:
(1) brief reactive or secondary depression (most common), occurring in response to real stimuli such as grief, illness, etc;(2) major depression (melancholic and recurrent depression) a genetically determined biochemical disorder manifested by an inability to experience ordinary pleasure or to cope with ordinary life events;(3) manic-depressive depression (depression associated with bipolar affective disorder)Pharmacologic treatment of depressions is very important, althougha continuing role for electroconvulsive therapy for severe forms oflife-threatening depression is also noted.
Depression is one of the most common psychiatric disorders. At any given moment, about 3–5% of the population is depressed,and an estimated 10% of people may become depressed during their lives. The symptoms of depression are often subtle and unrecognized both by patients and by physicians. Patients withvague complaints that resist explanation as manifestations ofsomatic disorders and those who might be simplistically describedas "neurotic" should be suspected of being depressed. Soon after the introduction of reserpine in the early 1950s, it becameapparent that the drug could induce depression by inhibiting the neuronal storage of amine neurotransmitters such as 5-HT and NE.Reserpine induced depression and depleted stores of amine neuro-transmitters. It was reasoned, depression must be associatedwith decreased functional amine-dependent synaptic transmission.
NA (noradrenaline) = NE (norepinephrine
Rauwolfia serpentina Benth.(a small indian shrub)
•Reserpine•Ajmaline
Pathogenesis of depression. Mechanism of action of antidepressants
The idea that depression must be associated with decreasedfunctional amine-dependent synaptic transmissionprovided the basis for what became known as the amine hypothesis of depression. By extension, drugs thatincreased amine function in appropriate synaptic areas wouldrelieve depression. The amine hypothesis has provided the majorexperimental models for the discovery of new antidepressants.All currently available antidepressants, except bupropion,are classified as having their primary actions on the metabolism, reuptake, or selective receptor antagonismof 5-HT, NE, or both.
The effects of DA, 5-HT and NE on the brain functions
(NE)
(DA)
(5-HT)
Raised neurotransmitter concentrations produceimmediate alterations in postsynaptic receptoractivation, leading to changes in second messenger(intracellular) systems and to gradual modificationsin cellular protein expression. Antidepressantsincrease a cyclic AMP response-element binding(CREB) protein which in turn is involved inregulating the transcription of genes that influencesurvival of other proteins including brain derivedneurotrophic factor (BDNF) which exerts effects onneuronal growth. The role of BDNF in depressionis supported by the observation that stress bothreduces its expression and impairs neurogenesis.
The monoamine hypothesis of depressionis an oversimplification of a complicated picture.Other systems that are implicated in the etiologyof depression (and which provide potential targetsfor drug therapy) include the hypothalamopituitary-thyroid axis and the hypothalamopituitary-adrenalaxis (HPA). The finding that 50% of depressedpatients have elevated plasma cortisol concentra-tions constitutes evidence that depression may beassociated with increased HPA drive.
Sites of action of
antidepressants
NE – norepinephrineNERIs – norepinephrinereuptake inhibitors5-HT – serotoninSSRIs – selectiveserotonin reuptake inhibitorsTCAs – tricyclic antideperssantMAO – monoamino-oxidase
The evolution of antidepressants and classification by mechanism of action
Structural relationships betweenvarious tricyclic antidepressants (TCAs).Their structures are similar to phenothiazines.
Selective serotonin reuptake inhibitors (SSRIs).
Pharmacokinetics
The antidepressants are generally well absorbed afteroral administration. Steady-state plasma concen-trations of TCAs show great individual variation butcorrelate with therapeutic effect.Antidepressants in general are inactivated princi-pally by metabolism by hepatic cytochrome P450enzymes (CYP 2D6 and CYP 3A4 etc.). Other P450 enzymes are CYP 1A2 inhibited by the SSRIfluvoxamine, and induced by cigarette smoking,substrates include caffeine and the atypical psychotics (clozapine and olanzapine).
Several of these drugs produce active metaboliteswhich prolong their action (e.g. fluoxetine ismetabolized to norfluoxetine, t1/2 200 h). The meta-bolic products of certain TCAs are antidepressantsin their own right, e.g. nortriptyline (from ami-triptyline), desipramine (from imipramine).Half-lives of TCAs and SSRIs are long (> 15 h).Around 7% of the Caucasian population havevery limited CYP 2D6 enzyme activity. Such “poormetabolizers” may find standard doses of tricyclicantidepressants intolerable and it is often worthstarting at a very low dose.
Clinical indications for antidepressants
The major indication is to treat depression, but a number of other uses have been established by clinical experience.Antidepressants may benefit most forms of anxiety disorder (panicdisorder, generalized anxiety disorder, post-traumatic stress,obsessive-compulsive disorder and social phobia), migraine.SSRIs are effective in milder cases of the eating disorder bulimia nervosa, particularly fluoxetine (in higher doses thanare required for depression). This effect is independent of thaton depression (which may co-exist) and may therefore involveaction on transmitter systems other than those involved inmodulating depression. Antidepressants appear to be ineffective in anorexia nervosa.
SSRIs (selective serotonin reuptake inhibitors) are used in:
•chronic anxiety•depression•bulimia neurosa(fluoxetine – in higher doses)
Schematic representation of the time course of panic treatments
Adapted from Bennett and Brown (2003)Adapted from Bennett and Brown (2003)
Mode of use
The action of TCAs in ameliorating mood is usuallyabsent in the first 2 weeks of therapy and at least 4weeks must elapse to constitute an adequate trial.Where a minimal response is noted in this period, itis reasonable to extend the trial to 6 weeks to seeif further benefit is achieved. Dose titration is oftennecessary. By contrast, patients mayexperience unwanted drug effects immediatelyon starting treatment (and they should be warned), but such symptoms often diminish with time.TCAs are given either in divided doses or, for themore sedative compounds, as a single evening dose.
SSRIs have advantages over tricyclics in simplicityof introduction and use. Dose titration is oftenunnecessary since the minimum therapeutic dosecan usually be tolerated as a starting dose. Divideddoses are not required and administration is by asingle morning or evening dose. Evidence suggeststhat patients commencing treatment on SSRIs aremore likely to reach an effective dose than thosestarting on TCAs.Venlafaxine is licensed for treatment-resistant de-pression by gradual titration from 75 to 375 mg/day.There is some need for dose titration when usingMAOIs although recommended starting doses may be effective.
When changing between SSRIs and/or TCAs, dosesshould be reduced progressively over 2–4 weeks.Where a new drug is to be introduced its dose shouldbe gradually increased as that of the substituted drugis reduced. Changes to or from MAOIs must behandled with great caution due to the dangers of un-wanted interactions between antidepressants: MAOIscannot safely be introduced within 2 weeks of stop-ping paroxetine, sertraline or TCAs (3 weeks).When a patient achieves remission, the antidepres-sant should be continued for at least 9 months at thedose which returned mood to normal.When ceasing use of an antidepressant, the doseshould be reduced over at least 6 weeks to avoida discontinuation syndrome.
Side effects of TCAs
Anticholinergic (atropine-like): dry mouth, blurred vision, accommodation disturbances, increased ocular pressure, con-stipation, urinary retention, sweating, adynamic ileus (very rare).CNS: dizziness, tiredness, confusion, tremor, insomnia,seizures, sudden falls, exacerbation of psychotic symptoms.CVS: hypotension, sinus tachycardia, arrhythmia, impaired AVconduction.Blood: leucopenia, agranulocytosis, thrombocytopenia, hemolyticanemia. Other side-effects: hypo- or hyperthermia, impaired respiration,libido changes, exanthema, tinnitus, GI complaints, liver functiondisturbances, increased body weight, neurological symptoms.
TCAs – Interactions Potential results
MAOIs hyperthermia, palpitations, excitation
Adrenomimetics hypertension, hyperthermia, tachycardia
Alcohol effect of alcohol may be increased
Clonidine, Methyldopa decreased hypotensive effects
T3, T4 enhanced potential for CV toxicity
Physostigmine antagonism
Anticholinergics additional anticholinergic activity
Neuroleptics inhibition of metabolism of antidepressants
Levodopa overreaction of levodopa
Lithium the therapeutic response is increased in some cases and suppressed in others
Precautions: close supervision, especially in early phase oftreatment (suicide risk of TCAs). The possibility of unmaskinga latent psychosis should be considered. A switch into a manicor hypomanic condition may occur (“switch process”).Caution in CVD, history of urinary retention, narrow-angleglaucoma and in thyroid disease.
Side-effects of SSRIs(mainly during the 1st and 2nd weeks of treatment): CNS: head-ache, restleness; CVS: bradycaria; GIT: nausea, diarrhoeaThe serotonin syndrome is a rare but dangerous complicationand features restlessness, tremor, convulsions, comaand death. Risk is increased by co-administration with MAOIs, the antimigraine drug sumatriptan and St. John's Wort.
Side-effects of SNERIs (Reboxetine)Dermatological: skin reactionsCVS: hypertension (at high doses).
Side-effects of MAOIsGeneral: headache, perspiration, anorexia, hypotension, neuritis. CNS: insomnia, agitation, restlessness, confusion, dizziness.CVS: arrhythmia, tachycardia, palpitations.Other effects: leucopenia, agranulocytosis, icterus (small risk).Following foods and beverages should be avoided: Tyramine containing nutrition: maturated cheese (“cheese syndrome”), broad beans, smoked or pickled fish, meat extracts containing brewer's yeast, fermented sausages (e.g. salami);red wine, sherry, beer and excessive amounts of alcohol.
Side-effects of 5-HT & NERIsVenlafaxine produces some unwanted effects thatresemble those of SSRIs with a higher incidence ofnausea. Sustained hypertension (due to blockadeof noradrenaline reuptake) is a problem in a smallpercentage of patients at high dose and bloodpressure should be monitored when > 200 mg/dayis taken.
Side-effects of presynaptic alpha-2-blockersMirtazapine also has benefits in rarely being asso-ciated with sexual dysfunction and in improvingsleep independent of mood but like TCAs it maycause unwanted sedation and weight gain.
Trazodone has structural similarities with TCAsbut probably acts by antagonism of central presynaptic alpha-2-adrenoceptors. It is an option for depressed patients where heavysedation is required. Trazodone also has the advan-tages of lacking antimuscarinic effects and beingrelatively safe in overdose. Males should be warnedof the possibility of priapism (painful penileerections), attributable to the drug's blockade ofperiferal apha-1-adrenoceptors.Mianserin has the advantages of lacking antimuscarinic effects too, but this antidepressantrarely used due to associations with aplastic anaemia.
St John's Wort(Hypericum perforatum)
St John's Wort
Many patients with mild to moderate depression areaware of the benefits of the herbal remedy St. John'sWort. The active ingredients in the hypericum extracthave yet to be identified and their mode of action is unclear, although it has been postulated that severalof the known mechanisms of existing antidepressantsare incorporated (inhibition of monoamine reuptakeand the monoamine oxidase enzyme, as well asa stimulation of GABA receptors). A large multicentre trial found only limitedevidence of benefit for St. John's Wort overplacebo in significant major depression.
Use of St. John's Wort is complicated by thelack of standardization of the ingredients. Thosewho wish to take St. John's Wort should be madeaware that it may cause dry mouth, dizziness,sedation, GI disturbance and confusion.Importantly also, it induces hepatic P450 enzymes(CYP 1A2 and CYP 3A4) with the result that theplasma concentration and therapeutic efficacy ofwarfarin, oral contraceptives, some anticonvulsants,antipsychotics and HIV protease/reverse transcriptaseinhibitors are reduced. Concomitant use of trypto-phan and St John's Wort may cause serotoninergiceffects including nausea and agitation.
Electroconvulsive therapy (ECT) involves thepassage of a small electric charge across the brain by electrodesapplied to the frontotemporal aspects of the scalp with the aim ofinducing a tonic-clonic seizure. ECT requires the patient to bereceiving a general anaesthetic, carrying the small risks equi-valent to those associated with general anaesthesia in minorsurgical operations. It may cause memory deficits although this isgenerally transient. ECT is usually reserved for psychiatric illnesswhere pharmacotherapy have been unsuccessful for instancethe severely depressed patient who has stopped eating ordrinking. Modern-day ECT is a safe and effective alternativeto pharmacotherapy and remains a first-line option in clinicalcircumstances where rapid, response is desired, when it canbe life-saving.
Mood stabilizersIn bipolar affective disorder patients suffer episodesof mania, hypomania and depression, classicallywith periods of normal mood in between. Manicepisodes involve greatly elevated mood, ofteninterspersed with periods of irritability or undueexcitement, accompanied by biological symptoms(increased energy, restlessness, decreased need forsleep, increased sex drive), loss of social inhibitions,irresponsible behaviour and grandiosity. Psychoticfeatures may be present, particularly disorderedthinking manifested by grandiose delusions and“flight of ideas” with rapid speech.
Hypomania is a less dramatic and dangerouspresentation but retains the features of elation orirritability and the biological symptoms, abnormalitiesin speech and in social conduct to overfamiliarity and mild recklessness.Depressive episodes include depressive symptomsdescribed before and may include psychotic features.
Lithium salts are ineffective for prophylaxis ofbipolar affective disorder in around 35% of patientsand cause several unwanted effects. The searchfor alternatives has produced drugs that are morefamiliar as anticonvulsants, notably carbamazepineand sodium valproate, and possibly lamotrigine.
The mode of action is not fully understood. Themain effect of lithium is probably to inhibit hydro-lysis of inositol phosphate, so reducing the recyclingof free inositol for synthesis of phosphatidylino-sitides. These intracellular molecules are part of thetransmembrane signaling system that is importantin regulating intracellullar calcium ion concentra-tion, which subsequently affects neurotransmitterrelease. Other putative mechanisms involve thecyclic AMP “second messenger” system and mono-aminergic and cholinergic neurotransmitters.
Effect of lithium on the IP3 and DAG second-messenger system. The schematic diagram shows the synaptic membrane of a neuron. (PIP2, phosphatidylinositol-4,5-bisphosphate; PLC, phospholipase-C; G, coupling protein; EFFECTS, activation of protein kinase C, mobilizationof intracellular Ca2+, etc.) Lithium, by inhibiting the recycling of inositolsubstrates, may cause depletion of the second-messenger source PIP2
and therefore reduce the release of IP3 and DAG.
Knowledge of pharmacokinetics of lithium is important for successful use since the therapeutic plasma concentration is close to thetoxic concentration (low therapeutic index). Lithiumis a small ion that, given orally, is rapidly absorbedthroughout the gut. High peak plasma concentra-tions are avoided by using sustained-release formu-lations which deliver the peak plasma lithiumconcentrations in about 5 h. With chronic use the plasma t1/2 of lithium is 15–30 h.Lithium is usually given 12-hourly to avoid unnecessaryfluctuation (peak and trough concentrations) and maintain a plasma concentration just below the toxiclevel. A steady-state plasma concentration will be attained after about 5–6 days (i.e. 5 x t1/2).
Lithium carbonate is effective treatment in > 75%of episodes of acute mania or hypomania. Because its therapeutic action takes 2–3 weeksto develop, lithium is generally used in combinationwith lorazepam or diazepam (or with a neurolepticswhere there are also psychotic features).For prophylaxis, lithium is indicated when therehave been two episodes of mood disturbance intwo years, although in some cases it is advisableto continue with prophylactic use after one severeepisode. When an adequate dose of lithium istaken consistently, around 65% of patients achieveimproved control of their illness.
Lithium is also used to augment the action ofantidepressants in treatment-resistant depression.Monitoring. The difference between therapeuticand toxic doses is narrow and therapy must beguided by monitoring of the plasma concentrationonce a steady state is reached. Increments aremade at weekly intervals until the concentrationlies within the required range of 0.4–1 mmol/L(maintenance at the lower level is preferred forelderly patients). The plasma concentration shouldbe checked every three months. Thyroid function and renal function (plasma creatinine andelectrolytes) should be measured before initiationand every 3 months during therapy.
Side-effects of Lithium
General reactions: in case of overdose: nausea, thirst.CNS: ataxia, dysarthia, choreotetoid disturbances, extrapyrimidal symptoms, confusion, tremor, epilepticseizures, spasms, stupor, sedation, lethargy.CVS: arrhythmia, hypertension, circulatory collaps.Other effects: weight increase, muscular hypotonia,anorexia, nausea, vomiting, rash, acneiform eruptions,incontinence, dehydration, dry mouth, polyuria,albuminurea, glycosuria, myxoedema, fatigue,leucocytosis, hyperthyroidism.
The manic phase in bipolar affective disorder often requires treatment with neuroleptics(chlorpromazine, haloperidol), though lithium orvalproic acid supplemented with high-potencybenzodiazepines (eg, lorazepam or clonazepam)may suffice in milder cases.
Recent controlled trials support the efficacy ofmonotherapy with atypical antipsychotics in theacute phase (up to 4 weeks) of mania, andolanzapine has been approved for this indication.
PsychostimulantsPsychostimulants have predominant cortical action. Their psychiceffects are more important then those on medullary vital centres.
(1) Methylxanthines
Three methylxanthines are pharmacologicallyimportant: caffeine, theophylline, and theobromine.All of them occur naturally in certain plants.
Only caffeine is used as a CNS stimulants. It is widelyconsumed in the form of beverages, including asinfusions or decoctions, derived from these plants.
Coffea arabica (seeds)In an averagecup of coffee:Caffeine 75 mg
Theobromacacao (cocoa)In an average cup of cocoa:Caffeine 4 mgTheobromine 200 mg
Cola acuminata(Guru nuts)In 200 ml bottleof cola drink:Caffeine 30 mg
Methylxanthines (purine alkaloids)Caffeine, Theophylline, Theobromine
Thea sinensis(leaves)In an average cup of tea:Caffeine 50 mgTheophylline 1 mg
Actions of methylxanthines
They block adenosine-1-receptors. Adenosine acts as a localmediators in CNS, CVS and other organs. Adenosine contractsbronchial muscles, dilates cerebral blood vessels, depressedcardiac pacemaker and inhibits gastric secretions.Methylxanthines inhibite phosphodiestarease which degradesintracelullarly cAMP. Theophylline-containing preparationsenhance cAMP accumulation. It results in bronchodilation,vasodilation and cardiac stimulation.
Caffeine and theophylline are CNS stimulants, primarily affect thehigher centres. Caffeine (150 to 250 mg) produces a sense ofwellbeing, alertness, beats boredom, allays fatigue; thinking
becomes clear, improves performance and increases motoractivity. As a CNS stimulant caffeine is more active than theo-phylline. In higher doses caffeine causes nervousness, rest-lesness, panic, insomnia and excitement. Still higherdoses produces tremor, arrhythmia, delirium and convulsions.Methylxanthines, especially caffeine, also stimulate medullaryvagal, respiratory and vasomotor centres (analeptic effect).Vomiting in high doses is due to both to gastric irritation and stimulation of chemoreceptor trigger zone.
Methylxanthines directly stimulates the heart and increase forceof myocardial contraction. They tend to increase heart rate bydirect action, but also decrease it by vagal stimulation. Net effectis variable. Tachycardia is more common with theophylline, but
caffeine generally decreases heart rate. Cardiac output isincreased. This action is more marked in CHF patients. At highdoses cardiac arrhythmias may produced.Methylxanthines, specially theophylline, dilate systemic bloodvessels, including coronaries. However, cranial vessels are const-ricted by caffeine: this is one of the bases of its use in migraine.Effect of blood pressure is variable and unpredictable. Usuallya rise in systolic and fall in diastolic BP is observed.
Antiasthmatic (bronchodilatation) effect of theophylline is morepotent then those of caffeine. Slow but sustained dose relatedbronchodilatation is produced and vital capacity is increased.
ATP 3’, 5’-AMPcAMP
Lipolysis
(–)
AC PD
Cholesterol synthesis
Caffeine > 300 mg/d:5–6 coffee cups daily
(+)
(+)
Hypercholesterolemia
Methylxanthines are mild diuretics. They act by inhibiting tubularreabsorption of Na+ and water. Theophylline and theobromineare more potent diuretics than caffeine.
At high dose caffeine enhances contractile power of skeletalmuscle: it increases release of Ca2+ from sarcoplasmatic reticu-lum by direct action. In addition, caffeine facilitates neuro-muscular transmission by increasing ACh release. Its centralaction relives fatigue and increases muscular work.
Methylxanthines enhance secretion of acid and pepsin in stomach,even on parenteral application. They are gastric irritants – theophylline more than caffeine.
Caffeine is an alkaloid with pKb 0.8. It is rapidly absorbed afteroral administration. It is < 50% bound to plasma proteins. Itst1/2 is 4 h. Caffeine is nearly completely metabolized in liver bydemethylation and oxidation, and excreted in urine. Caffeine is tobe avoided in peptic ulcer patients. It is not contraindicated ingout because it is not converted in the body to uric acid. Moderatecoffee drinking does not contribute to development of hypertension.
Uses of caffeine• In analgesic drug combinations: caffeine benefits headache probably by allaying fatigue and boredom.• Migraine attacks: in combination with ergotamine. • To counteract hypnotic overdose, but its value is doubtful, better not use.
Amphetamines
Amphetamines are central adrenomimetics. Compared toamphetamine, higher central and peripheral activity ratio isexhibited by dextroamphetamine and methamphetamine. Amphetamine are indirect sympathomimetic and they stimulatemental than motor activity. Convulsive doses are much higher.Abuse potential of amphetamine is very high.
Methylphenidate is chemical and pharmacological similar toamphetamine. Both act by releasing NE and DA in the brain.Both produce increase in mental activity at doses which havelittle action on other central and peripheral functions. Methylphenidate is considered superior to amphetamine fortreatment of hyperkinetic children (attention deficit disorder)because it causes less tachycardia and growth retardation.Behaviour and learning ability are improved in 75% of cases.Methylphenenidate can also used for concentration and attentiondefect in adults, and for narcolepsy. It is well absorbed orally, metabolized and excreted in urine.It plasma t1/2 is 4 h.Side effects of methylphenidate are anorrhexia, insomnia,abdominal discomphort and bowel upset.
Cocaine is an alkaloid from leaves of Erythroxylon coca, a southAmerican plants. The native of Peru and Bolivia habitually chewthe these leaves. Cocaine use sometimes in ocular anesthesia aseyes drops. It should be never be injected because can causestissue necrosis.After system absorption cocaine produces prominent CNS stimu-lation with marked effect on mood and behaviour. It induces a sense of wellbeing, delays fatigue and increases power of endu-rance. In susceptible individuals it produces strong psychological,but not physical dependence. Cocaine is unique among drugs ofabuse, because it is not produce tolerance on reputed use.It also stimulate vagal, vasomotor, vomiting and thermoregulatorycentres. In periphery it blocks reuptake of NA and adrenalineand acts indirectly as a sympathomimetic.
Nootropic drugs (cognition enhancers)
Piracetam is a cyclic GABA derivative withoutGABA like activity. Piracetam selective improves efficiency of higher encephalic integrative activity by:
• Enhancement of learning and memory• Facilitation of interhemisphere information transfer• Increased tonic cortical control of subcortical areas• Improves ATP/ADP ratio in encephalon• Stimulate synaptic transmission etc.
The indications of piracetam are:• Senile dementia of Alzheimer type, multi infarct dementia etc.• Mental retardation and learning problems in children• Cerebrovascular accident: to hasten recovery• To reduce impairment of consciousness following brain trauma or brain surgery, memory impairment after electroconvulsive therapy, and central vertigo.The validity of evidence for drug induced cognition enhancementhas not been established. Side effects include: gastric discomfort,excitement, insomnia, dizziness, skin rash.
Pramiracetam has the similar properties and indications.
CNS Stimulants – classification
1. Psychostimulants• Caffeine, Amphetamines, Cocaine etc.
2. Analeptics (Respiratory stimulants)• Doxapram, Prethcamide
The analeptics stimulate respiration in subconvulsive doses, but margin of safety is narrow. The patients may getconvulsions while still in coma. Mechanical support torespiration and other measures to improve circulation aremore effective and safe.
3. Convulsants
Strychnine is an alkaloid from seeds of Strychnos nux vomica.It acts by blocking post-synaptic inhibition produced by the inhi-bitory transmitter glycine. Strychnine is a potent convulsant.The convulsions are tonic-clonic and symmetrical. There are novalid use of strychnine now.Picrtoxin is obtained from “fish berries” of East Indies Anamirtacocculis. It produces asymmetrical clonic convulsions by blockingpresynaptic inhibition mediated through GABA. Picrotoxin hasno therapeutic indication now.Bicucculline is a synthetic convulsant. It has picrotoxin like action.It is GABA-A blocker and used only as a research tool.Pentylenetetrazol is a powerful CNS stimulants, acting by directdepolarization of central neurones. It is commonly used convulsantfor testing anticonvulsive drugs in laboratory animals.
