Mazindol
A white to off-white crystalline powder, having not more than
a faint odour. Practically insoluble in water: slightly soluble
in methyl alcohol and in chloroform. Store in airtight con-
tainers.
Adverse Effects, Treatment, and Precautions
As for Dexamphetamine Sulphate.
Effects on the testicles. A report of 8 men who developed
testicular pain after taking mazindol.
Interactions
As for Dexamphetamine Sulphate.
Dexamphetamine sulphate : adverse effects, precautions & interactions :-
Adverse Effects
The side-effects of dexamphetamine are commonly symp-
toms of over stimulation of the CNS and include insomnia.
night terrors, nervousness, restlessness, irritability, and euphoria that may be followed by fatigue and depression. There may be dryness of the mouth, anorexia, abdominal cramps
and other gastro-intestinal disturbances, headache, dizziness.
tremor, sweating, tachycardia, palpitations, increased or
sometimes decreased blood pressure, altered libido, and im-
potence. Psychotic reactions have occurred as has muscle
damage with associated rhabdomyolysis and renal complica-
tions. Rarely, cardiomyopathy has occurred with chronic use.
In children, growth retardation may occur during prolonged
treatment
In over dosage, the adverse effects are accentuated and
may be accompanied by hyperpyrexia. mydriasis. hyper-
reflexia. chest pain, cardiac arrhythmias, confusion, panic
states, aggressive behavior, hallucinations, delirium, convulsions, respiratory depression, coma, circulatory collapse, and death. Individual patient response may vary widely and toxic manifestations may occur at relatively low overdoses.
Tolerance can develop to some of dexamphetamine's central
effects leading to increased doses and habituation. Abrupt
cessation after prolonged treatment or abuse of amphetamines
has been associated with extreme fatigue, hyperphagia. and
depression. However, it is generally accepted that the amphetamines, although widely abused, are not associated with substantial physical dependence.
Amphetamines are abused for their euphoriant effects. Abuse
has resulted in personality changes, compulsive and stereo
typed behavior, and may induce a toxic psychosis with audi
tory and visual hallucinations and paranoid delusions.
Abuse: Abuse of amphetamines can lead to toxicity affecting
many organs or body systems. There have been reports of in-
tracerebral haemorrhage and of cardiomyopathy.
Kendrick et al described a syndrome characterised by circu-
latory collapse, fever, leukaemoid reaction, disseminated in-
travascular coagulation, and rhabdomyolysis with diffuse
myalgias and muscle tenderness in 5 drug abusers who had
administered amphetamines or phenmetrazine intravenously.
Scandling and Spiral" reported a 30-year-old man who had
ingested 50 amphetamine sulphate tablets and developed
rhabdomyolysis and myoglobinuric renal failure, possibly
secondary to a crush syndrome, but in the absence of pro
longed coma or other major myotoxic factors. In contrast,
Foley et at' reported a patient who developed acute infersti
tial nephnritis and acute renal failure after oral amphetamine abuse without the associated factors of rhabdomyolysis,hyperpyrexia, or necrotising angiitis. In an earlier study. Citron et al had found necrolising angitis to be associated with intravenous methylamphetamine abuse.
Chronic use may result in adverse effects such as hallucina
lions, a delusional disorder resembling paranoid schizophre
nia, stereotyped behaviour, and movement disorders.
Although chronic intoxication is the most common precondi-
tion for psychosis, individual sensitivities are an important aspect of the drug reaction.
Increased serum concentrations of thyroxine have been asso-
ciated with heavy amphetamine abuse in 4 psychiatric pa-
tients.
Abrupt cessation after prolonged treatment or abuse of am
phetamines may cause extreme fatigue, hyperphagia, and de
pression. Depressive stupor has been reported in 3 longterm
abusers of amphetamine after sudden withdrawal.
Effects on growth. The Pediatric Subcommittee of the
Psychopharmacologic Drugs Advisory Committee revealed
the growth-suppressing effects of stimulant medication
in hyperkinetic children.' There was reasonable evidence
that stimulant drugs, particularly in higher doses, moderately
suppressed growth in weight and might have a minor suppressing
effect on growth in stature. There were indications that some
growth caught up during drug holidays, and that early growth
suppression was not evident in adulthood. Careful monitoring
during treatment was recommended.
Treatment of Adverse Effects
In general the management of overdosage with amphetamines
involves supportive and symptomatic therapy. Sedation is
usually sufficient. Forced acid diuresis has been advocated to
increase amphetamine excretion but is seldom necessary and
should only be considered in severely poisoned patients; it
requires close supervision and monitoring
Precautions
Dcxamphetamine is contra-indicated in patients with cardio-
vascular disease including moderate to severe hypertension,
and in patients with hyperthyroidism, glaucoma, hyperexcit-
ability, or agitated states. It should not be given to patients
with a history of drug abuse and it should be avoided in preg-
nant women or breast-feeding mothers. It should be given
with caution to patients with mild hypertension, impaired kid-
ney function or unstable personality. Height and weight in
children should be monitored as growth retardation may oc-
cur. Prolonged high doses may need gradual withdrawal as
abrupt cessation may produce fatigue and mental depression.
Care may be needed in certain patients predisposed to tics or
Tourette's syndrome as symptoms may be provoked. Dexam
phetamine is likely to reduce the convulsive threshold; cau-
tion is therefore advised in patients with epilepsy. However, it
appears that in some countries amphetamines are included in
antiepileptic preparations containing phenytoin or phenobar-
bitone in an attempt to increase their antiepileptic action. Am-
phetamines may impair patients' ability to drive or to operate
machinery.
Diabetic control should be monitored when central stimulants
are used for the control of obesity.
Abuse. Dexamphetamine is subject to extensive abuse and
for this reason its availability needs to be severely curtailed.
For adverse effects associated with abuse, see above.
Porphyria: Amphetamines were considered to be unsafe in
patients with acute porphyria although there is conflicting ex-
perimental evidence on porphyrinogenicity. Methylamphet-
amine has been associated with clinical exacerbations of
porphyria.
Pregnancy. No difference was found in the incidence of se-
vere congenital anomalies between 1824 children of mothers
prescribed amphetamines or pheninetrazine during pregnan-
cy and 8989 children of mothers who had not received these
drugs.' Though an excess of oral clefts was noted in the off
spring of mothers prescribed amphetamines, there was no ex-
cess of congenital heart diseased This was contrary to a
previous suggestion' in which congenital heart disease in 184
infants had been studied and a link to maternal dexampheta-
inine exposure postulated. There has been a report of a brady-
cardia followed by death in a fetus due to maternal
intravenous self-administration of 500 mg of amphetamine.
Tourette's syndrome. In a review of clinical reports, Sha-
piro and Shapiro' concluded that there was virtually no evi.
dence that central stimulants caused or provoked Tourette's
syndrome and weak or inadequate evidence that clinically ap-
propriate doses of central stimulants caused tics in previously
asymptomatic patients or exacerbated pre-existing symp-
toms. However, they suggested that there was evidence that
high or toxic doses might exacerbate or provoke tics in pre-
disposed patients. Lowe el al.' reported on 15 children who
developed Tourette's syndrome while receiving stimulant
medication for attention deficit disorders; 13 of these children
had either pre-existing tics or a family history of tics or of
Tourette's syndrome. They considered that stimulant therapy
for hyperactivity was contra-indicated in children with motor
tics or diagnosed Tourette's syndrome and should be used
with caution in children with a family history of these symp-
toms. In addition, they suggested that the development of mo-
tor tic symptoms in any child receiving stimulants should be
a clear indication for immediate discontinuation to minimise
the possibility of eliciting a full-blown Tourette's syndrome.
Interactions
Dexamphetamine is an indirect-acting sympathomimetic and
may interact with a number of other drugs. To avoid precipitating a hypertensive crisis, it should not be given to patients being treated with an MAOI or within 14 days of stopping such treatment. Concurrent use of beta blockers and amphetamines may produce severe hypertension. Dexamphetamine
may also diminish the effects of other antihypertensives, in-
cluding guanethidine and similar drugs, and concurrent use
should be avoided. Patients receiving amphetamines and tri-
cyclic antidepressants require careful monitoring as the risk
of cardiovascular effects including arrhythmias may he in-
creased. The urinary excretion of amphetamines is reduced by
urinary alkalinisers which may enhance or prolong their ef-
fects: excretion is increased by urinary acidifiers.
Amphetamines may delay the absorption of ethosuximide,
phenobarbitone, and phenytoin. The stimulant effects of am-
phetamines are inhibited by chlorpromazine, haloperidol, and
lithium, Disulfiram may inhibit the metabolism and excretion
of amphetamines.
Concurrent use of sympathomimetics with volatile liquid an
aesthetics such as halothane is associated with an increased
risk of cardiac arrhythmias.
Pharmacokinetics
Amphetamines are readily absorbed from the gastro-intesti
nal tract and are distributed in most body tissues with high
concentrations in the brain and CSF. They are partially metab-
olised in the liver but a considerable fraction may be excreted
in the urine unchanged. Urinary elimination is pH-dependent
and enhanced in acid urine. Amphetamines are distributed
into breast milk.
Uses and Administration
Dexamphetamine. the dextrorotatory isomer of ampheta
mine, is an indirect-acting sympathomimetic with alpha- and
beta-adrenergic agonist activity. It has a marked stimulant effect on the CNS, particularly the cerebral cortex.
Dexamphetamine is used in the treatment of narcolepsy
and as an adjunct in the management of refractory
hyperactivity disorders in children above the age of 6 year'
Dexamphetamine has been given in the treatment of obesity
although amphetamines are no longer recommended for this indication. Amphetamines have also been used to overcome fatigue but, again, such use is considered undesirable.
In some countries amphetamines have been included in antie
pileptic preparations but the practice is not recommended.
Dexamphetamine is used as the sulphate and is given by
mouth.
In the treatment of narcolepsy, the usual starting dose is 10 mg daily in divided doses, increased if necessary by 5
to 10 mg at weekly intervals to a maximum of 60 mg daily. The lower initial starting dose of 5 mg daily is suggested for
elderly and any weekly increments should also be restricted
to 5 mg in such patients.
In hyperactive children individualization of treatment is especially important: children aged 6 years and over usually start with a dose of 5 mg once or twice daily. Increased if necessary by 5 mg at weekly intervals to an upper limit of 20 mg daily.
though older children might require up to 40 mg daily.
Dexamphetamine has also been given as the saccharate.
Pharmacokinetics
Mazindol is readily absorbed from the gastro-intestinal tract
and is excreted in the urine, partly unchanged and partly as
metabolites.
Uses and Administration
Mazindol is a central stimulant with actions similar to those
of dexamphetamine , although structurally the two
compounds are unrelated. It appears to inhibit reuptake of
dopamine and noradrenaline. It has been used as an anorectic.
given by mouth in the treatment of obesity . The usu-
al initial dose is I mg once daily before food adjusted as re-
quired up to a maximum of 1 mg three limes a day.
Mazindol has been investigated in the treatment of Duchenne
muscular dystrophy.
Narcolepsy. Mazindol has been reported to be beneficial
in patients with narcolepsy . A wide range of doses
has been employed: 3 to 8 mg daily in one study. 1 mg weekly to 16 mg daily in another children have been given 1 to
2 mg daily.