Transcript Side effects

Medical University of Sofia, Faculty of Medicine
Department of Pharmacology and Toxicology
•Antidepressants
•Mood stabilizers
•Psychostimulants
•Nootropic drugs
•CNS stimulants
(Abstract)
Assoc. Prof. Ivan Lambev (e-mail: [email protected])
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, although
a continuing role for electroconvulsive therapy for severe forms of
life-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 with
vague complaints that resist explanation as manifestations of
somatic disorders and those who might be simplistically described
as "neurotic" should be suspected of being depressed. Soon after
the introduction of reserpine in the early 1950s, it became
apparent 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 neurotransmitters. It was reasoned, depression must be associated
with 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 decreased
functional amine-dependent synaptic transmission
provided the basis for what became known as the
amine hypothesis of depression. By extension, drugs that
increased amine function in appropriate synaptic areas would
relieve depression. The amine hypothesis has provided the major
experimental 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 antagonism
of 5-HT, NE, or both.
(5-HT)
(NE)
(DA)
The effects of DA, 5-HT and NE on the brain functions
Raised neurotransmitter concentrations produce
immediate alterations in postsynaptic receptor
activation, leading to changes in second messenger
(intracellular) systems and to gradual modifications
in cellular protein expression. Antidepressants
increase a cyclic AMP response-element binding
(CREB) protein which in turn is involved in
regulating the transcription of genes that influence
survival of other proteins including brain derived
neurotrophic factor (BDNF) which exerts effects on
neuronal growth. The role of BDNF in depression
is supported by the observation that stress both
reduces its expression and impairs neurogenesis.
The monoamine hypothesis of depression
is an oversimplification of a complicated picture.
Other systems that are implicated in the etiology
of depression (and which provide potential targets
for drug therapy) include the hypothalamopituitarythyroid axis and the hypothalamopituitary-adrenal
axis (HPA). The finding that 50% of depressed
patients have elevated plasma cortisol concentrations constitutes evidence that depression may be
associated with increased HPA drive.
Sites of
action of
antidepressants
NE – norepinephrine
NERIs – norepinephrine
reuptake inhibitors
5-HT – serotonin
SSRIs – selective
serotonin reuptake
inhibitors
TCAs – tricyclic
antideperssant
MAO – monoaminooxidase
The evolution of antidepressants and classification by mechanism of action
Structural relationships between
various tricyclic antidepressants (TCAs).
Their structures are similar to phenothiazines.
Selective serotonin reuptake inhibitors (SSRIs).
Pharmacokinetics
The antidepressants are generally well absorbed after
oral administration. Steady-state plasma concentrations of TCAs show great individual variation but
correlate with therapeutic effect.
Antidepressants in general are inactivated principally by metabolism by hepatic cytochrome P450
enzymes (CYP 2D6 and CYP 3A4 etc.). Other P450
enzymes are CYP 1A2 inhibited by the SSRI
fluvoxamine, and induced by cigarette smoking,
substrates include caffeine and the atypical
psychotics (clozapine and olanzapine).
Several of these drugs produce active metabolites
which prolong their action (e.g. fluoxetine is
metabolized to norfluoxetine, t1/2 200 h). The metabolic products of certain TCAs are antidepressants
in their own right, e.g. nortriptyline (from amitriptyline), desipramine (from imipramine).
Half-lives of TCAs and SSRIs are long (> 15 h).
Around 7% of the Caucasian population have
very limited CYP 2D6 enzyme activity. Such “poor
metabolizers” may find standard doses of tricyclic
antidepressants intolerable and it is often worth
starting 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 (panic
disorder, 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 than
are required for depression). This effect is independent of that
on depression (which may co-exist) and may therefore involve
action on transmitter systems other than those involved in
modulating 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)
Mode of use
The action of TCAs in ameliorating mood is usually
absent in the first 2 weeks of therapy and at least 4
weeks must elapse to constitute an adequate trial.
Where a minimal response is noted in this period, it
is reasonable to extend the trial to 6 weeks to see
if further benefit is achieved. Dose titration is often
necessary. By contrast, patients may
experience unwanted drug effects immediately
on starting treatment (and they should be warned),
but such symptoms often diminish with time.
TCAs are given either in divided doses or, for the
more sedative compounds, as a single evening dose.
SSRIs have advantages over tricyclics in simplicity
of introduction and use. Dose titration is often
unnecessary since the minimum therapeutic dose
can usually be tolerated as a starting dose. Divided
doses are not required and administration is by a
single morning or evening dose. Evidence suggests
that patients commencing treatment on SSRIs are
more likely to reach an effective dose than those
starting on TCAs.
Venlafaxine is licensed for treatment-resistant depression by gradual titration from 75 to 375 mg/day.
There is some need for dose titration when using
MAOIs although recommended starting doses
may be effective.
When changing between SSRIs and/or TCAs, doses
should be reduced progressively over 2–4 weeks.
Where a new drug is to be introduced its dose should
be gradually increased as that of the substituted drug
is reduced. Changes to or from MAOIs must be
handled with great caution due to the dangers of unwanted interactions between antidepressants: MAOIs
cannot safely be introduced within 2 weeks of stopping paroxetine, sertraline or TCAs (3 weeks).
When a patient achieves remission, the antidepressant should be continued for at least 9 months at the
dose which returned mood to normal.
When ceasing use of an antidepressant, the dose
should be reduced over at least 6 weeks to avoid
a discontinuation syndrome.
Side effects of TCAs
Anticholinergic (atropine-like): dry mouth, blurred vision,
accommodation disturbances, increased ocular pressure, constipation, 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 AV
conduction.
Blood: leucopenia, agranulocytosis, thrombocytopenia, hemolytic
anemia.
Other side-effects: hypo- or hyperthermia, impaired respiration,
libido changes, exanthema, tinnitus, GI complaints, liver function
disturbances, 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 of
treatment (suicide risk of TCAs). The possibility of unmasking
a latent psychosis should be considered. A switch into a manic
or hypomanic condition may occur (“switch process”).
Caution in CVD, history of urinary retention, narrow-angle
glaucoma and in thyroid disease.
Side-effects of SSRIs
(mainly during the 1st and 2nd weeks of treatment): CNS: headache, restleness; CVS: bradycaria; GIT: nausea, diarrhoea
The serotonin syndrome is a rare but dangerous complication
and features restlessness, tremor, convulsions, coma
and 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 reactions
CVS: hypertension (at high doses).
Side-effects of MAOIs
General: 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 & NERIs
Venlafaxine produces some unwanted effects that
resemble those of SSRIs with a higher incidence of
nausea. Sustained hypertension (due to blockade
of noradrenaline reuptake) is a problem in a small
percentage of patients at high dose and blood
pressure should be monitored when > 200 mg/day
is taken.
Side-effects of presynaptic alpha-2-blockers
Mirtazapine also has benefits in rarely being associated with sexual dysfunction and in improving
sleep independent of mood but like TCAs it may
cause unwanted sedation and weight gain.
Trazodone has structural similarities with TCAs
but probably acts by antagonism of central
presynaptic alpha-2-adrenoceptors.
It is an option for depressed patients where heavy
sedation is required. Trazodone also has the advantages of lacking antimuscarinic effects and being
relatively safe in overdose. Males should be warned
of the possibility of priapism (painful penile
erections), attributable to the drug's blockade of
periferal apha-1-adrenoceptors.
Mianserin has the advantages of lacking
antimuscarinic effects too, but this antidepressant
rarely used due to associations with aplastic anaemia.
St John's Wort
(Hypericum perforatum)
St John's Wort
Many patients with mild to moderate depression are
aware of the benefits of the herbal remedy St. John's
Wort. The active ingredients in the hypericum extract
have yet to be identified and their mode of action is
unclear, although it has been postulated that several
of the known mechanisms of existing antidepressants
are incorporated (inhibition of monoamine reuptake
and the monoamine oxidase enzyme, as well as
a stimulation of GABA receptors).
A large multicentre trial found only limited
evidence of benefit for St. John's Wort over
placebo in significant major depression.
Use of St. John's Wort is complicated by the
lack of standardization of the ingredients. Those
who wish to take St. John's Wort should be made
aware 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 the
plasma concentration and therapeutic efficacy of
warfarin, oral contraceptives, some anticonvulsants,
antipsychotics and HIV protease/reverse transcriptase
inhibitors are reduced. Concomitant use of tryptophan and St John's Wort may cause serotoninergic
effects including nausea and agitation.
Electroconvulsive therapy (ECT) involves the
passage of a small electric charge across the brain by electrodes
applied to the frontotemporal aspects of the scalp with the aim of
inducing a tonic-clonic seizure. ECT requires the patient to be
receiving a general anaesthetic, carrying the small risks equivalent to those associated with general anaesthesia in minor
surgical operations. It may cause memory deficits although this is
generally transient. ECT is usually reserved for psychiatric illness
where pharmacotherapy have been unsuccessful for instance
the severely depressed patient who has stopped eating or
drinking. Modern-day ECT is a safe and effective alternative
to pharmacotherapy and remains a first-line option in clinical
circumstances where rapid, response is desired, when it can
be life-saving.
Mood stabilizers
In bipolar affective disorder patients suffer episodes
of mania, hypomania and depression, classically
with periods of normal mood in between. Manic
episodes involve greatly elevated mood, often
interspersed with periods of irritability or undue
excitement, accompanied by biological symptoms
(increased energy, restlessness, decreased need for
sleep, increased sex drive), loss of social inhibitions,
irresponsible behaviour and grandiosity. Psychotic
features may be present, particularly disordered
thinking manifested by grandiose delusions and
“flight of ideas” with rapid speech.
Hypomania is a less dramatic and dangerous
presentation but retains the features of elation or
irritability and the biological symptoms, abnormalities
in speech and in social conduct to overfamiliarity
and mild recklessness.
Depressive episodes include depressive symptoms
described before and may include psychotic features.
Lithium salts are ineffective for prophylaxis of
bipolar affective disorder in around 35% of patients
and cause several unwanted effects. The search
for alternatives has produced drugs that are more
familiar as anticonvulsants, notably carbamazepine
and sodium valproate, and possibly lamotrigine.
The mode of action is not fully understood. The
main effect of lithium is probably to inhibit hydrolysis of inositol phosphate, so reducing the recycling
of free inositol for synthesis of phosphatidylinositides. These intracellular molecules are part of the
transmembrane signaling system that is important
in regulating intracellullar calcium ion concentration, which subsequently affects neurotransmitter
release. Other putative mechanisms involve the
cyclic AMP “second messenger” system and monoaminergic 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, mobilization
of intracellular Ca2+, etc.) Lithium, by inhibiting the recycling of inositol
substrates, 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 the
toxic concentration (low therapeutic index). Lithium
is a small ion that, given orally, is rapidly absorbed
throughout the gut. High peak plasma concentrations are avoided by using sustained-release formulations which deliver the peak plasma lithium
concentrations 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 unnecessary
fluctuation (peak and trough concentrations) and
maintain a plasma concentration just below the toxic
level. 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 weeks
to develop, lithium is generally used in combination
with lorazepam or diazepam (or with a neuroleptics
where there are also psychotic features).
For prophylaxis, lithium is indicated when there
have been two episodes of mood disturbance in
two years, although in some cases it is advisable
to continue with prophylactic use after one severe
episode. When an adequate dose of lithium is
taken consistently, around 65% of patients achieve
improved control of their illness.
Lithium is also used to augment the action of
antidepressants in treatment-resistant depression.
Monitoring. The difference between therapeutic
and toxic doses is narrow and therapy must be
guided by monitoring of the plasma concentration
once a steady state is reached. Increments are
made at weekly intervals until the concentration
lies within the required range of 0.4–1 mmol/L
(maintenance at the lower level is preferred for
elderly patients). The plasma concentration should
be checked every three months. Thyroid function
and renal function (plasma creatinine and
electrolytes) should be measured before initiation
and 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, epileptic
seizures, 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 or
valproic acid supplemented with high-potency
benzodiazepines (eg, lorazepam or clonazepam)
may suffice in milder cases.
Recent controlled trials support the efficacy of
monotherapy with atypical antipsychotics in the
acute phase (up to 4 weeks) of mania, and
olanzapine has been approved for this indication.
Psychostimulants
Psychostimulants have predominant cortical action. Their psychic
effects are more important then those on medullary vital centres.
(1) Methylxanthines
Three methylxanthines are pharmacologically
important: caffeine, theophylline, and theobromine.
All of them occur naturally in certain plants.
Only caffeine is used as a CNS stimulants. It is widely
consumed in the form of beverages, including as
infusions or decoctions, derived from these plants.
Methylxanthines (purine alkaloids)
Caffeine, Theophylline, Theobromine
Coffea
arabica (seeds)
In an average
cup of coffee:
Caffeine 75 mg
Theobroma
Cola acuminata
cacao (cocoa) (Guru nuts)
In an average
In 200 ml bottle
cup of cocoa:
of cola drink:
Caffeine 4 mg Caffeine 30 mg
Theobromine 200 mg
Thea sinensis
(leaves)
In an average
cup of tea:
Caffeine 50 mg
Theophylline 1 mg
Actions of methylxanthines
They block adenosine-1-receptors. Adenosine acts as a local
mediators in CNS, CVS and other organs. Adenosine contracts
bronchial muscles, dilates cerebral blood vessels, depressed
cardiac pacemaker and inhibits gastric secretions.
Methylxanthines inhibite phosphodiestarease which degrades
intracelullarly cAMP. Theophylline-containing preparations
enhance cAMP accumulation. It results in bronchodilation,
vasodilation and cardiac stimulation.
Caffeine and theophylline are CNS stimulants, primarily affect the
higher centres. Caffeine (150 to 250 mg) produces a sense of
wellbeing, alertness, beats boredom, allays fatigue; thinking
becomes clear, improves performance and increases motor
activity. As a CNS stimulant caffeine is more active than theophylline. In higher doses caffeine causes nervousness, restlesness, panic, insomnia and excitement. Still higher
doses produces tremor, arrhythmia, delirium and convulsions.
Methylxanthines, especially caffeine, also stimulate medullary
vagal, 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 force
of myocardial contraction. They tend to increase heart rate by
direct action, but also decrease it by vagal stimulation. Net effect
is variable. Tachycardia is more common with theophylline, but
caffeine generally decreases heart rate. Cardiac output is
increased. This action is more marked in CHF patients. At high
doses cardiac arrhythmias may produced.
Methylxanthines, specially theophylline, dilate systemic blood
vessels, including coronaries. However, cranial vessels are constricted by caffeine: this is one of the bases of its use in migraine.
Effect of blood pressure is variable and unpredictable. Usually
a rise in systolic and fall in diastolic BP is observed.
Antiasthmatic (bronchodilatation) effect of theophylline is more
potent then those of caffeine. Slow but sustained dose related
bronchodilatation is produced and vital capacity is increased.
Caffeine > 300 mg/d:
5–6 coffee cups daily
(–)
ATP
AC
cAMP
3’, 5’-AMP
Hypercholesterolemia
(+)
Lipolysis
PD
(+)
Cholesterol synthesis
Methylxanthines are mild diuretics. They act by inhibiting tubular
reabsorption of Na+ and water. Theophylline and theobromine
are more potent diuretics than caffeine.
At high dose caffeine enhances contractile power of skeletal
muscle: it increases release of Ca2+ from sarcoplasmatic reticulum by direct action. In addition, caffeine facilitates neuromuscular transmission by increasing ACh release. Its central
action 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 after
oral administration. It is < 50% bound to plasma proteins. Its
t1/2 is 4 h. Caffeine is nearly completely metabolized in liver by
demethylation and oxidation, and excreted in urine. Caffeine is to
be avoided in peptic ulcer patients. It is not contraindicated in
gout because it is not converted in the body to uric acid. Moderate
coffee 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 to
amphetamine, higher central and peripheral activity ratio is
exhibited by dextroamphetamine and methamphetamine.
Amphetamine are indirect sympathomimetic and they stimulate
mental than motor activity. Convulsive doses are much higher.
Abuse potential of amphetamine is very high.
Methylphenidate is chemical and pharmacological similar to
amphetamine. Both act by releasing NE and DA in the brain.
Both produce increase in mental activity at doses which have
little action on other central and peripheral functions.
Methylphenidate is considered superior to amphetamine for
treatment 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 attention
defect 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 south
American plants. The native of Peru and Bolivia habitually chew
the these leaves. Cocaine use sometimes in ocular anesthesia as
eyes drops. It should be never be injected because can causes
tissue necrosis.
After system absorption cocaine produces prominent CNS stimulation with marked effect on mood and behaviour. It induces a
sense of wellbeing, delays fatigue and increases power of endurance. In susceptible individuals it produces strong psychological,
but not physical dependence. Cocaine is unique among drugs of
abuse, because it is not produce tolerance on reputed use.
It also stimulate vagal, vasomotor, vomiting and thermoregulatory
centres. In periphery it blocks reuptake of NA and adrenaline
and acts indirectly as a sympathomimetic.
Nootropic drugs
(cognition enhancers)
Piracetam is a cyclic GABA derivative without
GABA 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 enhancement
has 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 get
convulsions while still in coma. Mechanical support to
respiration and other measures to improve circulation are
more 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 inhibitory transmitter glycine. Strychnine is a potent convulsant.
The convulsions are tonic-clonic and symmetrical. There are no
valid use of strychnine now.
Picrtoxin is obtained from “fish berries” of East Indies Anamirta
cocculis. It produces asymmetrical clonic convulsions by blocking
presynaptic inhibition mediated through GABA. Picrotoxin has
no 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 direct
depolarization of central neurones. It is commonly used convulsant
for testing anticonvulsive drugs in laboratory animals.