Drugs Acting On Central Nervous System
Drugs Acting On Central Nervous System
Drugs Acting On Central Nervous System
[1] ANALGESICS
Analgesics are drugs that relieve pain due to multiple causes. Drugs that
relieve pain due to a single cause, e.g. ergotamine (migraine), glyceryl
trinitrate (angina pectoris) are not classed as analgesics.
Non-opioid Analgesics
(analgesics- antipyretics)
Are the most powerful analgesics Are mild analgesics and effective in certain
that can relieve any type of pain types of pain as headache, toothache
except itching.
Act on the level of the thalamus and
Act mainly at the level of the cortex.
hypothalamus.
No addiction.
Used to lower
temperature.
the
elevated
body
NARCOTIC ANALGESICS
They are derived from opium alkaloids. Many alkaloids are isolated from
opium, but few of them are used clinically (Morphine, Codeine and
Papaverine).
OPIUM ALKALOIDS
I. Morphine
Absorption and Fate:
It is not addicting.
C. Bronchi:
Therapeutic doses of morphine do not cause bronchoconstriction in normal
individuals.
But it may precipitate bronchoconstriction in asthmatic patients due to
histamine release.
So, morphine is contraindicated in bronchial asthma due to:
(a) Bronchoconstriction.
(b) Release of histamine.
(c) Respiratory center depression.
D. Urinary Bladder:
Urine retention due to:
(1) Tone of urinary bladder sphincter.
(2) Depression of the micturition reflex.
(3) Urine formation is decreased due to central effect of the drug that
causes the release of ADH.
(IV) On Histamine:
Morphine is a histamine releaser.
Opioid Receptors:
Several types of opioid receptors have been identified at various sites in the
nervous system and other tissues.
Delta (
) receptors:
Supraspinal analgesia
analgesics.
Side Effects:
(A) Minor side effects:
1. Nausea and vomiting.
2. Constipation.
3. Itching, bronchoconstriction and hypotension due to histamine release.
4. Urine retention.
5. Increased intracranial tension.
(B) Major side effects:
1. Respiratory depression.
2. Addiction.
Contra-Indications:
1. Bronchial asthma due to:
Bronchoconstriction.
Release of histamine.
Respiratory depression.
Yawning.
Lacrimation.
Dilated pupils.
Vomiting.
Diarrhea.
Severe headache.
Excitement.
will occur, because the endogenous opioid is deficient and the receptor is
deprived from both the endogenous and the exogenous opioids.
Treatment:
Uses:
1. As cough depressant (for dry cough).
2. As analgesic with aspirin and paracetamol.
Uses:
Not used clinically except in severe pain of terminal stages of malignancy.
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Therapeutic Uses:
1. As analgesic instead of morphine.
2. In obstetrics to relieve labour pain.
3. As preanesthetic medication instead of morphine.
4. Better than morphine in renal and biliary colics (It has atropine and
papaverine-like actions).
II. Fentanyl
Analgesic potency is 80 times that of morphine.
Duration of action shorter than morphine and pethidine.
Uses:
1. As analgesic alone.
2. With a tranquillizer to produce Neuroleptanalgesia (a state of sedation
and analgesia) which is used in minor procedures e.g. bronchoscopy or
in obstetrics.
III. Methadone
A potent analgesic.
With long duration of action.
Depresses respiratory and cough centers.
Causes addiction but the withdrawal symptoms are milder than morphine.
Uses:
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1. Analgesic.
2. Treatment of opium (morphine) addiction.
IV. Loperamide
analgesic opioids, used for antimotility effect on the gut. They are constipating
agents. (refer to pharmacology of GIT)
Example:
Pentazocine is agonist on kappa receptors and is a weak antagonist at Mu
receptors.
OPIOID ANTAGONISTS
Nalorphine
It has antagonist action on Mu receptors, with a partial agonist action on delta
and Kappa receptors so it is considered as a partial antagonist.
Naloxone (Narcan)
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It is a pure narcotic antagonist at all opioid receptor sites with no morphine like
properties i.e. it is a pure antagonist. Therapeutic uses of naloxone are the
same of that of nalorphine. Naloxone is preferred since it lacks any agonistic
activity.
Naltrexone: has a longer duration of action than naloxone and a single oral
dose of naltrexone blocks the effects of injected heroin up to 24 hours.
Therapeutic Uses:
1. Treatment of acute morphine poisoning (it stimulates respiration, improves
miosis, vomiting and G.I spasm).
2. Diagnosis of opium addiction (precipitate withdrawal symptoms).
3. Decreases the neonatal respiratory depression secondary to administration
of morphine, because it can traverse the placental barrier. It is given to the
mother before delivery or to the infant through the umblical vein after
delivery.
Parkinsonism is due to an imbalance between the levels of acetylcholine and dopamine in the
basal ganglia (substantia nigra, corpus striatum that are responsible for motor control).
In parkinsonism, the dopamine content is low so that the cholinergic system is dominant.
Treatment of parkinsonism
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Tolerance occurs after prolonged use, increasing the dose will increase
the side effects.
Examples:
-
Benztropine (Cogentin).
Trihexphenidyl (Artane).
It acts by:
-
Bromocryptine (Parlodel):
It is an ergot derivative.
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Selegiline
Selectively inhibits monoamine oxidase B (MAOB) which metabolizes
dopamine, but doesn't inhibit MAOA (which metabolizes norepinephrine
and serotonin). Thus, by decreasing the metabolism of dopamine,
selegiline has been found to increase dopamine levels in the brain.
Therefore, it enhances the actions of L-Dopa and when these drugs are
administered together, selegiline substantially reduces the required dose
of L-Dopa.
L-Dopa:
It is the precursor of dopamine.
L-Dopa
Dopamine
ganglia.
95% of given L-Dopa is transformed to dopamine in the peripheral tissues
To:
1. Decrease the dose of L-Dopa.
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e.g.
chlorpromazine
(block
dopamine
receptors),
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Learning objectives:
By the end of this topic, the student will be able to:
1. Classify sedative-hypnotic drugs.
2. Describe their mechanism of action.
3. List their therapeutic uses, side effects, contraindications, toxicity and
addictive potentiality.
4. Recognize the basic pharmacology of some antipsychotic drugs
(chlorpromazine and newer antipsychotic drugs).
5. State the therapeutic advantages of new antipsychotics.
6. Classify antidepressant drugs.
7. Outline their mechanism of action.
8. Enumerate the therapeutic uses of antidepressants, their side effects, contraindications, important drug interactions and toxicity.
9. Identify drugs acting as CNS stimulants (Niketamide, Doxapram, Caffeine,
amphetamine, cocaine,etc).
10. Mention their possible therapeutic uses, undesired effects and abuse
potentiality.
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I. BENZODIAZEPINES
Benzodiazepines (BZs) are the most widely used anxiolytic drugs. They
have largely replaced barbiturates in the treatment of anxiety, since BZs are
more effective and safer. BZs induce sleep when given in high doses at night,
provide sedation, and reduce anxiety when given in low, divided doses during
the day.
Mechanism of Action:
Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter
in the CNS. BZs potentiate GABA-ergic inhibition at all levels of the CNS.
BZs bind to specific, high affinity BZ receptors present in various parts of
the CNS. These receptors are separate but adjacent to the receptor for GABA.
The binding of BZ enhances the affinity of the GABA receptors for GABA
neurotransmitter, resulting in a more frequent opening of adjacent chloride
channels. The increased influx of Cl- into the neuron results in enhanced
hyperpolarization and inhibition of neuronal firing.
Pharmacological Actions:
BZs have neither antipsychotic activity nor any analgesic action and do not
affect the autonomic nervous system. BZs exhibit the following actions:
4. Anticonvulsant effect.
Pharmacokinetic Aspects:
BZs are lipophillic and are rapidly and completely absorbed after oral administration. BZs as well
as most other sedative-hypnotics bind extensively to plasma proteins.
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BZs are metabolized by the hepatic microsomal metabolizing system and are excreted in urine as
glucuronides or oxidized metabolites.
Classification of Benzodiazepines
BZs can be roughly divided into short, intermediate and long-acting groups.
The longer acting agents form active metabolites with long half-lives.
Short-acting; triazolam (3-8 hours).
Intermediate-acting; alprazolam (10-20 hours).
Long-acting; diazepam (1-3 days).
Therapeutic Uses:
1. Anxiety state: BZs should only be used for short periods of time because
of addiction potentials e.g. alprazolam.
2. Insomnia: The most commonly prescribed BZs for sleep disorders are
long-acting flurazepam, intermediate-acting temazepam, and short-acting
triazolam.
3. As anticonvulsants:
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3. limited capacity to produce profound and fatal CNS depression (i.e. BZs are
relatively safe in overdose in contrast to many sedative hypnotics e.g.
barbiturates).
psychological
and
physical
dependence
may
develop.
Abrupt
Contraindications:
1. Pregnant and lactating women: due to
a) The ability of BZs to cross fetal placental barrier. If these drugs are
given in the pre-delivery period, they may contribute to the
depression of neonatal vital functions.
b) Sedative-hypnotics are detectable in breast milk during lactation and
may exert depressant effects on CNS function in the nursing infant.
2. In patients with myasthenia gravis: due to the muscle relaxing effect of
BZs.
3. In acute depression or psychosis: due to their additive CNS depression.
Drug Interactions:
BZs have additive or synergistic effects with other CNS depressants such
as alcohol, barbiturates and antihistaminics. Although BZs are safer than other
sedative-hypnotic drugs even in acute overdosage, they are used cautiously in
treating patients with liver disease.
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BZ antagonist Flumazenil
Mechanism of action
Flumazenil carries similar structure to BZs, and competitively antagonize
the binding of BZs to their receptors. It blocks many of the actions of BZs but
does not antagonize the CNS effects of other sedative-hypnotics, ethanol,
opioids or general anesthetics.
Therapeutic uses
1. To reverse the sedative effect of BZs used during anaesthesia
2. In the treatment of acute BZs overdose.
3. Hepatic coma
II. BUSPIRONE
Buspirone is a non-sedating alternative to BZs but it may take up to four weeks
to act. (Useful in chronic anxiety states)
Also, it
Advantages of buspirone:
1.
2.
3.
4.
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III. ZOLPIDEM
Mechanism of action:
Zolpidem is a hypnotic that binds selectively to a subset of the BZs receptor
family and facilitates GABA-mediated neuronal inhibition.
Zolpidem has a rapid onset and a short duration of action (about 4 hours), its
actions are antagonized by flumazenil. It has minimal muscle relaxing and
anticonvulsant effects. Respiratory depression may occur if large doses of
zolpidem are ingested together with other central depressants.
IV. BARBITURATES
Non-selective CNS depressants, which produce effects ranging from sedation
and reduction of anxiety to hypnosis and unconsciousness. Barbiturates were
in the past the mainstay of treatment used to sedate or to induce and maintain
sleep.
Today, they have been largely replaced by BZs, because barbiturates induce
drug-metabolizing enzymes, produce tolerance and physical dependence and
severe withdrawal symptoms.
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Classification:
Ultra-short acting: Thiopental Na is highly lipid soluble; it is an IV
anaesthetic that acts within seconds with duration of action of 20
minutes. (refer to pharmacokinetics of anaesthesia).
Short-acting: Pentobarbital and secobarbital act for 3-8 hours.
Long-acting: Phenobarbital (more than 24 hours).
Mechanism of Action:
Barbiturates facilitate the actions of GABA at multiple sites in the CNS but
they do not bind to the same site of BZs on the GABA-receptor/chloride
channel. They cause activation of GABAA receptors. This increases the
duration of opening of the Cl- channel associated with the receptor, and the
neuronal membrane is therefore hyperpolarized and less likely to fire.
Actions :
At low doses, barbiturates produce sedation, at higher doses, they cause
hypnosis followed by anaesthesia. Overdosage may cause respiratory
depression and death.
Pharmacokinetics:
Lipid solubility and ionization influence the onset and duration of action. The ultra-short acting
drug; thiopental is very lipid soluble, and a high rate of entry into the CNS contributes to the rapid
onset of its central effects. Also the drug is rapidly redistributed from the brain, first to highly perfused
tissues such as skeletal muscle and subsequently to poorly perfused adipose tissue. These processes
contribute to the termination of its major central nervous system effects.
Long-acting agents (less lipid soluble) have slower onset and longer duration of action. They are
slowly metabolized by the liver microsomal enzymes. Barbiturates cross the placental barrier and their
concentrations in the fetal blood approach that in maternal blood.
Barbiturates and their metabolites are excreted by the kidney and their rate of excretion is
increased by alkalinization of urine.
Therapeutic Uses:
1. Anaesthesia: Thiopental Na is used intravenously to induce anaesthesia.
2. As sedative-hypnotic agents: Barbiturates have been replaced by BZs.
However, pentobarbital may still be used as sleeping pills.
3. Anticonvulsants:
in status
epilepticus by thiopental as the last approach. Phenobarbital is used in longterm management of tonic-clonic seizures and eclampsia.
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Side effects
1. CNS effects: drowsiness that can interfere with motor and mental
performance; hangover. In large doses, barbiturates cause marked
depression of CNS and are likely to be fatal.
2. GIT disturbance.
3. Folate deficiency.
4. Induction of P450 thus the rate at which they are metabolized increases
over the first few days of administration. Also, it leads to increased
metabolism of other drugs e.g. warfarin and oestrogen (reducing the
effectiveness of oral contraception and oral anticoagulants).
5. Tolerance.
6. Physical dependence with prolonged use.
7. Teratogenicity.
Contraindications:
Liver and kidney diseases.
During labour.
Old age.
Shock.
In patients with acute intermittent porphyria.
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N.B. Hepatic porphyria is an inherited disorder in which the enzymes required for haem
synthesis are lacking; this will lead to acute attacks of GIT, neurological, and behavioral
disturbances due to accumulation of porphyrincontaining haem precursors. Barbiturates
induce amino laevulinic acid (ALA) synthetase, which stimulates the hepatic formation of
porphyrins from these precursors.
Drug Interactions:
As barbiturates are potent inducers of hepatic metabolizing enzymes, they
are liable to cause drug interactions. They increase the rate of metabolic
degradation of many other drugs i.e. dicumarol, phenytoin, digitalis, and
griseofulvin.
Additive effects to other CNS depressants.
Chloral hydrate is an effective sedative and hypnotic that induces sleep in about 30 minutes and
lasts about 6 hours. It causes GIT irritation and epigastric distress and an unpleasant taste sensation.
Chloral hydrate is metabolized into two major metabolites; trichloroethanol (active and relatively nontoxic) and the other is trichloroacetic acid, which is toxic and tends to accumulate in the body.
Paraldehyde produces hypnosis in about 15 minutes and its effect lasts for 4-8 hours. It has a
strong odour, bad taste and may irritate the GIT. Paraldehyde was used in patients with hepatic or
renal failure as it is mainly eliminated through the lung.
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Alcohol-Drug Interactions:
I.
II.
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Mechanism of Action:
All of psychotropic drugs block dopamine receptors in the brain and in the
periphery specifically D2 receptors. Some of the newer psychotropic drugs
(clozapine and risperidone) exert part of their action through inhibition of
serotonin receptors.
Pharmacokinetic Aspects:
Most antipsychotic drugs are readily but incompletely absorbed; many
undergo significant first pass metabolism. These drugs have a large volume of
distribution and are highly protein bound. They are highly lipid soluble, cross
easily into the CNS and accumulate in fatty tissues. These drugs are almost
completely metabolized and then excreted by the kidney and through bile.
Pharmacological Actions:
1. Antipsychotic effects: These are now though to be produced -at least in
part- by their ability to block dopamine D2 receptors in the mesolimbic system.
Antipsychotic drugs relieve hallucination, improve thoughts and calm the
hyperactive psychotic patients.
The therapeutic effects of antipsychotic drugs take several weeks to occur.
3. Antiemetic effect:
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Therapeutic Uses:
1- Treatment of schizophrenia: The traditional antipsychotic drugs are most
effective
in
treating
positive
symptoms
of
schizophrenia
(delusion,
Adverse Effects:
Most of the unwanted effects of antipsychotics are extension of their known
pharmacologic actions, but a few are allergic and some are idiosyncratic.
1. Extrapyramidal effects.
2. Autonomic effects: Orthostatic hypotension, impaired ejaculation and
anticholinergic adverse effects.
3. Endocrine effects: Weight gain, hyperprolactinemia in the form of
galactorrhea, amenorrhea in women and gynecomastia, changes in libido and
impotence in men.
4. Tardive dyskinesia: It is the most important adverse effect of long-treatment
with antipsychotic drugs and is characterized by involuntary movements,
including lateral jaw movements and fly-catching motions of the tongue.
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Contraindications:
1- During withdrawal from alcohol or other drugs, antipsychotic drugs may
aggravate acute agitation.
2- Chlorpromazine is contraindicated in patients with seizure disorders, since
it can lower seizure threshold.
Drug Interactions:
1- Antipsychotic drugs through the -adrenoceptor blockade produce
vasodilatation and lower systemic pressure. The concomitant use of
antihypertensive agents must be noticed.
2- Phenothiazines in particular produce a quinidine-like depression of the
myocardium. Their use with antiarrhythmic drugs such as quinidine, or digitalis
glycosides could produce marked depression of the myocardium.
3- Epinephrine stimulates both adrenergic 1 and 2 receptors, providing a
balance of vasoconstrictor and vasodilator actions. With antipsychotic drug,
the 1 receptors are blocked. Thus, the effects of epinephrine on the
vasodilatory 2 receptors would predominate, resulting in hypotension.
4- Additive effects may occur when antipsychotic drugs are combined with
others that have sedative, -adrenoceptor blocking or anticholinergic effects.
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TRICYCLIC ANTIDEPRESSANTS
TCAs- so called because of the characteristic three-ring nucleus have been used clinically for almost
four decades.
Mechanism of Action:
TCAs inhibit the neuronal reuptake of norepinephrine and serotonin into
presynaptic nerve terminals leading to an increased concentration of
monoamines in the synaptic cleft. Like phenothiazines, TCAs block adrenergic,
histamine and muscarinic receptors.
As the antidepressant action of TCAs develops after several weeks of
continued treatment, it has been suggested that monoamine receptors in the
brain may change over a 2 to 4 week period with drug use and may be
important in the onset of activity.
Pharmacokinetic Aspects:
TCAs are well absorbed upon oral administration, and because of their
lipophillic nature, are widely distributed and penetrate into the CNS. The initial
treatment period is typically 4 to 8 weeks. These drugs are metabolized by the
hepatic microsomal system and conjugated with glucuronic acid and excreted
as inactive metabolites via the kidney.
Pharmacological Actions:
TCAs elevate the mood, improve mental alertness and increase physical
activity. In non-depressed patients, TCAs cause sedation, confusion and motor
incoordination. These effects occur in the first few weeks of treatment and
disappear by the onset of the antidepressant effect. TCAs can be used for long
periods without loss of effectiveness.
Therapeutic Uses:
TCAs are effective in treating severe major depression and some panic
disorders.
1- Unipolar depression.
2- Bipolar depression with lithium.
3- Together with antipsychotic drugs in the treatment of depressed psychotic
patients.
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Adverse Effects:
One of the major drawbacks of most TCAs has been their many irrelevant
pharmacologic actions- a trait inherited from the phenothiazine antipsychotic
agents.
1. Anticholinergic effects: blurred vision, dry mouth, urinary retention,
constipation and aggravation of glaucoma and epilepsy.
2. Blockade of -adrenoceptors leading to orthostatic hypotension. In
clinical practice, orthostatic hypotension, reflex tachycardia and arrhythmias
are the most serious problem in the elderly.
3. Sedation, confusion and motor incoordination may be prominent
particularly in the first few weeks of treatment.
4. TCAs may cause weight gain and sexual dysfunction.
5. TCAs have narrow therapeutic index. Depressed patients tend to be
suicidal and should be given only limited quantities of these drugs and
should be monitored closely.
6. Toxic manifestations include severe anticholinergic effects, arrhythmia
(due to cardiac overstimulation by the increased catecholamine activity),
seizures, hyperpyrexia, and respiratory depression.
Contraindications:
TCAs are contraindicated in:
1- Patients with prostate hypertrophy.
2- Patients with hyperthyroidism.
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Drug Interactions:
1. Additive sedative effects with other CNS depressants especially alcohol.
Small amount of alcohol in patients taking TCAs may cause severe
respiratory depression and death.
2. Additive
anticholinergic
effects
with
anti-parkinsons
drugs
and
antipsychotic drugs.
3. TCAs are strongly bound to plasma proteins, their effects are enhanced by
competing drugs e.g. aspirin.
NB.
Antidepressants dont cause addiction.
They have delayed effect.
Fluoxetine is relatively safe in pregnancy.
Pharmacological Actions:
Fluoxetine is the prototype of SSRIs. It is as effective in the treatment of major
depression as TCAs. However, it inhibits various drug-metabolizing enzymes,
which has led to a number of significant drug interactions.
Other antidepressants that primarily inhibit serotonin reuptake include
sertraline and fluvoxamine but they differ from fluoxetine in their relative effects
on the reuptake of serotonin and norepinephrine.
Therapeutic Uses:
1- Treatment of depression and panic disorders.
2- Obsessive-compulsive disorders.
3- Some eating disorders especially bulimia.
4- Pain associated with diabetic neuropathy.
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5- Anorexia nervosa.
6- Premature ejaculation.
Advantages of SSRIS:
SSRIs lack many of the adverse effects of tricyclic antidepressants
(anticholinergic, cardiovascular effects, weight gain) and MAO inhibitors (food
and drug interactions). SSRIs are much safer in overdose.
Adverse Effects:
SSRIs may cause nausea, headache, insomnia, fatigue, and sexual
dysfunction (delayed ejaculation).
Drug Interactions:
A dangerous pharmacodynamic interaction may occur when fluoxetine is used
in the presence of MAO inhibitors. The combination of increased stores of the
monoamine plus inhibition of reuptake after release- is thought to result in
marked increase of serotonin in the synapses leading to the serotonin
syndrome which is potentially lethal and must be avoided. This syndrome is
characterized by hyperthermia, muscle rigidity, agitation, hypotension and
coma.
Therapeutic Uses:
MAOIs are helpful in patients with atypical depression. Depressed patients
with considerable anxiety and phobic features are the ones who respond best
to these drugs. The therapeutic effects of MAOIs may take up to 4 weeks to be
manifested.
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Adverse effects:
MAOIs may cause sleep disturbances, orthostatic hypotension, sexual
dysfunction, weight gain as well as dangerous and even fatal interactions with
other drugs or certain food.
Drug Interactions:
1- Tyramine-induced hypertension: Many kinds of food and beverages (e.g.
wine, beer, chicken liver, aged cheese) contain tyramine, which is
normally degraded in the gut by MAO-A. Since the enzyme is inhibited by
MAOIs, tyramine from ingested food is absorbed, and then taken up into
adrenergic neurons, where it is converted into octopamine -a false
transmitter. This results in a massive release of NE and may result in
hypertensive crisis.
2- The use of MAO inhibitors with TCAs causes elevated levels of NE and
hypertensive crisis.
3- Concurrent use of a MAOI and fluoxetine may lead to the serotonin
syndrome.
4- With local anaesthetics (often contain a sympathomimetic drug) or cold
medications (which contain pseudoephedrine or ephedrine). These drugs
would
have
synergistic
effects
with
the
increased
levels
of
LITHIUM
Mechanism of action
The mode of action is unknown but it is proposed that lithium acts by altering
the cellular concentration of the second messenger inositol triphosphate (IP3).
Therapeutic uses
Lithium salts (e.g. carbonate or citrate) are used in:
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1. Manic-depressive patients.
2. Manic episodes of bipolar disorders
3. Mania and hypomania
4. Preventing relapse of depression.
Lithium at therapeutic concentrations is devoid of autonomic blocking effects
and of activating or sedating effects.
NB. Lithium has a narrow therapeutic margin so plasma level monitoring is
important.
Adverse Effects:
1. Neurological:
tremors,
motor
hyperactivity,
ataxia,
confusion,
and
convulsions.
2. Renal: polydipsia and polyuria (nephrogenic diabetes insipidus).
3. Cardiac: the bradycardia-tachycardia syndrome.
4. Edema due to sodium retention.
5. Enlargement of thyroid gland with decreased function.
Drugs which cause CNS stimulation fall into three broad categories:
1. Convulsants and respiratory stimulants.
2. Psychomotor stimulants.
3. Psychotomimetic drugs (hallucinogens).
N.B. Anatomically, CNS stimulants were divided into; spinal cord, brain stem, and cerebral cortex
stimulants.
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these drugs is narrow and unpredictable. In high doses, most of the analeptics
are capable of producing generalized convulsions.
Mechanism of Action:
The mechanism of action of most of CNS stimulant drugs is unclear.
Generally, there is a balance between excitatory and inhibitory influences,
which normally maintain the CNS functions. Drugs can increase excitability
either by blocking the inhibition (inhibitory transmitter) or by enhancing
excitation.
Examples of analeptics:
1- Nikethamide (Couramine): It is available in aqueous solution for oral use
or parenteral administration to stimulate the VMC and RC. Nikethamide is
of short-term duration and large doses may cause convulsions.
Strychnine blocks the receptors for glycine which is the main inhibitory
transmitter acting on motor neurons this will lead to increased reflex excitability
of the spinal cord.
Any sensory stimulus, will initiate asymmetrical, uncoordinated tonic
convulsions of all limbs that affect the most powerful muscles acting at a given
joint. The back is arched, the neck is thrown backwards and the face shows a
bitter smile.
1. Transfer the patient to quiet dark room under the supervision of well-trained
staff. Any external stimulus must be avoided.
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2- PSYCHOMOTOR STIMULANTS
These drugs have marked effect on the mental function and behavior; they
produce excitement, euphoria, reduced fatigue, and increased motor activity.
Some are drugs of abuse.
Examples: methylxanthines, amphetamines, and cocaine.
A. Methylxanthines
These include theophylline found in tea, theobromine found in cocoa, and
caffeine. Caffeine, the most widely consumed stimulant in the world, is found
in highest concentrations in coffee but is also present in tea, cola drinks,
chocolate candy and cocoa.
Mechanism of Action:
Methylxanthines act by several mechanisms including:
1. Translocation of extracellular calcium.
2. Inhibition of phosphodiesterase leading to increases in cyclic adenosine
monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP).
Pharmacological Effects:
1. Central nervous system:One or two cups of coffee (100-200 mg) cause;
diminished fatigue, insomnia, improved concentration and a clear flow of
thoughts. Higher doses cause anxiety and tremors.
2. Cardiovascular system:Therapeutic doses of caffeine have no effect on
the heart but a high dose has inotropic and chronotropic effects.
3. Gastrointestinal tract: All methylxanthines stimulate secretion of HCl from
the gastric mucosa.
4. Smooth muscles: Relaxation of smooth muscles especially the bronchial
muscle (theophylline).
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Pharmacokinetics:
Methylxanthines are well absorbed orally; caffeine distributes throughout the
body, including the brain, crosses the placenta to the fetus and is secreted into
the mothers milk. All methylxanthines are metabolized in the liver and the
metabolites are excreted in the urine.
Therapeutic Uses:
1- Caffeine: In combination with salicylates to relief simple headache and in
combination with ergotamine to relief migraine. To stimulate the depressed
CNS in case of alcohol ingestion.
2- Theophylline: In cases of bronchial asthma, biliary colics, congestive heart
failure and cardiac edema.
Adverse Effects:
Moderate doses of caffeine cause insomnia and agitation. Xanthines cause
tolerance and habituation. Irritability and headache occur in users who have
routinely consumed more than 600 mg of caffeine per day and then suddenly
stop it.
B. Amphetamine
It is a sympathomimetic acting by releasing intracellular stores of
catecholamines (mainly NE and dopamine) into synaptic spaces. (refer to
pharmacology of autonomic nervous system)
C. Cocaine
Cocaine is an inexpensive, widely available and highly addictive drug. Cocaine
acts by blocking NE, 5-HT and dopamine reuptake by nerve terminals. This
block potentiates and prolongs the CNS and peripheral actions of these
catecholamines.
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3- PSYCHOTOMIMETIC DRUGS:
Psychotomimetic drugs or hallucinogens produce profound changes in thought
patterns and mood, with little effect on the brain stem and spinal cord. They
cause sensory changes, hallucination, and dissociation from the surrounding.
Examples of hallucinogens; lysergic acid diethylamide (LSD), cannabis, and
phencyclidine. LSD may precipitate schizophrenia in susceptible people.
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Characteristics of Seizure
Generalized
Grand mal
Absence
Myoclonic
Clonic
Tonic
Atonic
Partial
[1] Simple (awareness is
retained)
Motor symptoms
Sensory symptoms
Autonomic symptoms
Psychologic symptoms
[2] Complex (impairment of
awareness)
[3] Partial seizure that
becomes generalized
seizure
neurotransmission,
principally
glutamate,
and
inhibitory
Carbamazepine
Carbamazepine is structurally related to the tricyclic anti-depressants.
Mechanism of action
1. Use-dependent
blockade
cell
Pharmacokinetics
Absorption of carbamazepine is slow and incomplete after oral administration.
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Therapeutic uses:
1. Carbamazepine is useful in most types of epilepsy, except myoclonic
epilepsy or absence seizures. These types of epileptic fit can be
exacerbated by carbamazepine. It is particularly effective for treatment
of partial and secondarily generalized tonic-clonic seizures (Drug of
choice).
2. Neuropathic pain (e.g. trigeminal neuralgia.)
3. Mood stabilizer in manic-depressive patients.
Side effects
GIT upset.
Skin rashes.
Teratogenicity is common.
Phenytoin (diphenylhydantoin)
Mechanism of action
Use-dependent
blockade
cell
Therapeutic uses:
1. Phenytoin is effective against all forms of epilepsy, except
absences.
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Pharmacokinetics
1. Phenytoin is well, but slowly, absorbed from the gut. Slow intravenous
injection can be used if a rapid onset of action is needed. Intramuscular
injection of phenytoin should be avoided since absorption by this route is
poor and muscle damage can occur.
2. Phenytoin is highly protein bound (about 90%). The concentration of
phenytoin in saliva reflects the free drug concentration in plasma and can
be useful to adjust the clinical effect.
3. Phenytoin
is
eliminated
by
hepatic
Side effects
Most unwanted effects of these drugs are dose-related:
1. Nausea or vomiting.
2. Impaired brainstem and cerebellar function, producing confusion,
nystagmus, blurred vision, ataxia, and dysarthria (signs of overdosage).
3. Chronic connective tissue effects: gum hyperplasia, coarsening of
facial features, hirsutism and acne (for this reason, it is usual to avoid
phenytoin in young women or adolescents)
4. Skin rashes.
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Lamotrigine
Mechanism of action
1. Use-dependent inhibition of neuronal Na+ channels (like carbamazepine
and phenytoin)
2. It interferes with synthesis of glutamate and aspartate.
3. Reduces glutamate release, possibly through inhibition of voltagesensitive Ca+2 channels.
Pharmacokinetics
Lamotrigine is well absorbed orally and half-life is long
Therapeutic Use
It is effective for partial and generalized seizures. In patients with newly
diagnosed partial or generalized seizures, lamotrigine alone was as effective
as carbamazepine or phenytoin, and better tolerated.
However,
it
can
make
myoclonic
epilepsy
worse
(similar
to
Side effects
1. Influenza-like symptoms.
2. Skin rashes particularly with rapid dose escalation. It is recommended
to stop the drug.
3. Gastrointestinal disturbances, including vomiting.
4. CNS effects: drowsiness, headache and ataxia can be troublesome at
high dosages.
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Sodium valproate
Mechanism of action
1. Use-dependent blockade of Na+ channels.
2. Potentiation of GABA by enhanced synthesis and release as well as
reduced degradation.
3. Attenuation of the excitatory action of glutamate.
4. Inhibition of T-type Ca2+ channels
Pharmacokinetics
Sodium valproate is well absorbed from the gut. To reduce gastric upset,
tablets should be taken with food. The half-life is long. Also, there is an
intravenous preparation for rapid seizure control.
Therapeutic Uses
[I] Epilepsy:
It is effective for all forms of epilepsy e.g.
1. Primary and secondary generalized tonic-clonic seizures.
2. Absence seizures
3. Complex partial seizures
4. Myoclonic
5. Atonic
6. It is highly effective in treating photosensitive epilepsy (photosensitive
epilepsy precipitated by viewing a television from too close a distance)
[II] Other uses:
1. Bipolar disorder and mania
2. Prophylaxis of migraine
3. Neuropathic pain
NB: The
Side effects:
1. Pancreatitis: serum amylase should be measured if symptoms such as
abdominal pain or nausea and vomiting arise.
2. Weight gain caused by appetite stimulation.
3. Transient hair loss, with re-growth of curly hair.
4. CNS
disturbances:
ataxia,
tremors
and
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confusion.
Rarely,
Ethosuximide
Mechanism of action
In absence seizures, T-type Ca2+ channels are believed to generate excessive
activity in thalamo-cortical relay neurons. Ethosuximide inhibits these channels
and prevents neuronal firing.
Therapeutic Uses
Ethosuximide is a drug of choice in absence seizures. It is ineffective in other
types of epilepsy.
Side effects
1. Anorexia, nausea and vomiting (less frequent if the drug is taken with
food and if the dose is gradually increased)
2. CNS disturbances
3. Skin rashes
4. Agranulocytosis and aplastic anaemia are rare complications
5. Teratogenicity.
Benzodiazepines
Clonazepam and diazepam
These drugs enhance the inhibitory action of GABA. Clonazepam is used
orally for prophylaxis, usually with other drugs. Diazepam or clonazepam can
be used intravenously to treat fits.
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Side effects
1. Partial
or
complete
tolerance
to
the
antiepileptic
action
of
Partial seizures:
Carbamazepine or phenytoin or valproate or lamotrigine.
Generalised seizures:
Tonic-clonic (grand mal)
Valproate or carbamazepine
or phenytoin or lamotrigine
Myoclonic
Valproate
Absence
Ethosuximide or valproate
Atonic
Valproate
Once started, treatment should usually be continued for at least 2-3 years after
the last seizure. If there is a continuing predisposing condition or the person
wishes to drive, treatment should probably be life-long. If withdrawal is
undertaken, then it should be gradual, in order to minimise the risk of rebound
seizures; when several drugs are used, one should be withdrawn at a time.
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Women taking antiepileptic drugs who wish to become pregnant should be informed about the
risk and offered antenatal screening during pregnancy, with -fetoprotein measurement (to detect
neural tube defects) and second-trimester ultrasound scanning.
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51
Pre-anaesthetic medications.
These are drugs used to facilitate smooth induction of anaesthesia and help to
lower the dose and side effects of anesthetic drugs. According to
circumstances, pre-medication may involve any combination of the following
drugs (i.e. balanced general anaesthesia):
1. Benzodiazepines or barbiturates to induce sedation and to relieve
anxiety.
2. H1 blockers (anti-allergic) and H2 blockers (to reduce gastric acidity).
3. Anti-emetic e.g. metoclopramide.
4. Opioid analgesics e.g. morphine or pethidine
5. An anticholinergic e.g. scopolamine for prevention of bradycardia and to
decrease airway secretions.
Intravenous anaesthetics
Examples:
1. Thiopental
2. Ketamine
3. Propofol
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Properties of IV anaesthetics
Thiopental
Ketamine
Propofol
Pharmacological properties
1. IV barbiturate.
2. Short duration of
anaesthesia (about
Rapid
produces
anaesthesia
2-5 min).
3.
induction
appears
1. Rapid induction.
2. Rapid
&
more
pleasant
dissociative
(i.e.
patient
awake
but
3. Postoperative
nausea
and
unconscious
doesn't
(sedation up to 24
hrs)
anti-emetic action.
4. Potent
anesthetic
but no analgesic
and
immobility.
3. Good analgesia.
4. Associated
with
for
total
intravenous
anaesthesia or for up to 3
to sympathetic outflow.
requiring
controlled
Disadvantages
1. No analgesia
1. sympathetic outflow
3. BP & bradycardia
BP. (contraindicated in
No analgesic
injection
action &
into
large
stroke)
lidocaine.
post-operative
Dose-related
hallucinations &
depression,
nightmares.
and
occur.
respiratory
bradycardia,
hypotension
may
53
Inhalational anesthetics
Inhaled anesthetics are given with oxygen to avoid hypoxia during
anaesthesia.
Following
induction
with
an
intravenous
anesthetic,
an
Isoflurane
Volatile hydrocarbons
Nitrous oxide
Gaseous
anesthetic
Potency
Induction
High
High
weak
& Slow
rapid
Very rapid
recovery
BP & COP
CVS
Arrhythmia
1. risk
Minimal
No risk
No risk
No risk
No risk
2. sensitivity to
catecholamines
Hepatotoxicity risk
(but not in children)
Therapeutic
1- Of choice in
1. good muscle
advantages
children (pleasant
relaxation.
recovery.
odour)
2. Rapid recovery
2. Good
3. No sensitization to
analgesia.
(bronchodilataion)
catecholamines.
N.B.
Halothane (Fluothane): an old but still used inhalational agent for mask
induction in children, because it is the least irritant volatile agent.
Enflurane: old and not recommended because of its powerful cardiac and
respiratory depressant actions.
Isoflurane has largely replaced halothane and enflurane because it offers the
most rapid induction and recovery and has little post-anesthetic organ toxicity
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Nitrous oxide is not sufficiently potent to be used alone, but it has the
advantage of producing analgesia and is often used in combination with other
anesthetics, thus reducing the required dose of the other agent.
Liver. Most agents decrease liver blood flow. Mild hepatic dysfunction
because of specific hepatic toxicity is common after treatment with
halothane. However, about 1 in 30000 people will develop severe hepatic
necrosis following the use of halothane, especially after repeated exposure
within 3-months. This is because of interaction of reactive metabolites with
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Kidney. Both renal blood flow and renal vascular resistance decrease,
resulting in a reduced glomerular filtration rate.
Uterus. There is relaxation of the uterus, which may increase the risk of
haemorrhage if anaesthesia is used in labour. Nitrous oxide has less effect
on uterine muscle compared with the other agents.
Chemoreceptor
trigger
zone.
Inhalational
anaesthetics
trigger
Local anesthetics
Definition:
A local anesthetic is an agent that interrupts pain impulses in a specific region
of the body without loss of patient consciousness.
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Mechanism of action
Local anesthetics block nerve conduction:
1. By interacting directly with specific receptors on neuronal Na+ channels,
inhibiting Na+ ion influx.
2. By impairing propagation of the action potential in the axons.
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Amides
Examples
ointment.
duration,
not
active topically
Bupivacaine:
dissociate
risk
of
cardiotoxicity.
NB. Amides have two (i)s in their
names.
t1/2
Few minutes
Few hours
acid
is
High
(cross
allergy
between Rare
reactions
Side effects
[1] Local:
Irritation and inflammation at the site of administration.
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6. Intravenous regional anaesthesia (Bier block): Local anaesthetic injected into a vein of a limb
after application of a tourniquet. The resultant anaesthesia is produced by direct diffusion of the
local anesthetic from the vessels into the nearby nerves. It is used for manipulation of fractures or
surgery on wrist, hand and fingers.
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