CNS STIMULANTS.�DRUG DEPENDENCE AND SUBSTANCE ABUSE.

Definition.

• These are drugs that act to stimulate the central nervous system (CNS).
• Psychomotor stimulants.
• Hallucinogens or Psychotomimetic drugs.

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Psychomotor Stimulants

• These drugs cause excitement and euphoria, decrease feelings of fatigue and increase motor activity.

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• Amphetamine. Dextroamphetamine. Lisdexamphetamine. Theophylline. Theobromine. Caffeine. Cocaine. Nicotine. Armodafinil. Atomoxetine. Methylphenidate. Modafinil. Varenicline.

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Hallucinogens or Psychotomimetics.

• These drugs produce profound changes in thought patterns and mood, with little effect on the brain stem and spinal cord.

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• Lysergic acid diethylamide(LSD). Phencyclidine(PCP). Tetrahydrocannabinol(THC).

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Psychomotor stimulants.

Methylxanthines.

• Theophylline. Theobromine. Caffeine.

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Mechanism of action.

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• Translocation of extracellular calcium.

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• Increase in cyclic adenosine monophosphate and cyclic guanosine monophosphate caused by inhibition of phosphodiesterase and blockade of adenosine receptors.

Pharmacologic actions.

CNS.

• Caffeine causes a decrease in fatigue and increased mental alertness as a result of stimulating the cortex and other areas of the brain.

Cardiovascular system.

• Caffeine has positive inotropic and chronotropic effects on the heart.

Diuretic action.

• Caffeine has a mild diuretic action that increases urinary output of sodium, chloride and potassium.

Gastric mucosa.

• All methylxanthines stimulate secretions of hydrochloric acid from the gastric mucosa.

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Therapeutic uses.

• Caffeine and it derivatives relax the smooth muscles of the bronchioles.

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Pharmacokinetics.

• The methylxanthines are well absorbed orally.
• Caffeine distributes throughout the body, including the brain.
• The drugs cross the placenta to the fetus and its secreted into the mother’s milk.
• All methylxanthines are metabolized in the liver by the CYP 1A2 pathway.
• Metabolites are excreted in the urine.

Adverse effects.

• Caffeine causes insomnia, anxiety and agitation(moderate doses).
• Emesis and convulsion(high doses).
• Lethargy, irritability and headache.

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Nicotine.

• Contained in tobacco.
• CNS stimulant (second to caffeine)
• Drug of abuse (second to alcohol)
• Carcinogenic.

Mechanism of action.

Low dose.

• Nicotine causes ganglionic stimulation by depolarization.

High dose.

• Nicotine causes ganglionic blockade.
• Nicotine receptors exist at a number of sites in the CNS.

Pharmacological action.

CNS

• Nicotine is highly lipid soluble and readily crosses the blood-brain barrier.
• It improves attention, learning, problem solving and reaction time.
• Nicotine is an appetite suppressant.
• High doses can result in central respiratory paralysis
• Can result to severe hypotension caused by medullary paralysis.

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Peripheral effects.

• Stimulation of sympathetic ganglia and the adrenal medulla increases BP and heart rate.

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• Nicotine-induced vasoconstriction decreases coronary blood flow affecting a patient with angina.

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• Stimulation of parasympathetic ganglia increases motor activity of the bowel.

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• At higher doses, BP falls and activity ceases in both the gastrointestinal tract and bladder musculature as a result of a nicotine-induced block of parasympathetic ganglia.

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Pharmacokinetics

• Nicotine readily absorbed via the oral mucosa, lungs, gastrointestinal tract and skin(lipid soluble).
• Crosses the placental membrane and is secreted in the milk of lactating women.
• Clearance of nicotine involves metabolism in the lung and liver and urinary excretion.

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Adverse effects

• CNS effects include irritability and tremors.
• Intestinal cramps, diarrhea, increased heart rate and BP.
• Increases rate of metabolism for a number of drugs.

Withdrawal syndrome.

• Withdrawal is characterized by irritability, anxiety, restlessness, difficulty concentrating, headaches and insomnia.
• Appetite is affected and gastrointestinal pain occurs.
• Bupropion, an antidepressant can reduce the craving for cigarettes.

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Varenicline.

• This is a partial agonist at neuronal nicotinic Ach receptors in the CNS.
• Varenicline tends to attenuate the rewarding effects of nicotine.
• Patients should be monitored for suicidal thoughts, vivid nightmares and mood changes.

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Cocaine.

Mechanism of action.

• The central and peripheral effects of cocaine is blockade of reuptake of the monoamines(norepinephrine, serotonin, dopamine) into the presynaptic terminals from which these neurotransmitters are released.

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• The blockade is caused by cocaine binding to the monoaminergic reuptake transporters thus potentiates and prolongs the CNS and peripheral actions of these monoamines.

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• The prolongation of the dopaminergic effects in the brain’s pleasure system(Limbic system).

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Pharmacologic actions.

CNS.

• Cocaine acutely increases mental awareness and produces a feeling of wellbeing and euphoria.
• Hallucinations and delusions of paranoia or grandiosity.
• It increases motor activity.
• At high doses, can cause tremors and convulsions, followed by respiratory and vasomotor depression.

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Sympathetic nervous system.

• Cocaine potentiates the action of norepinephrine and it produces the fight or flight syndrome characteristic of adrenergic stimulation.
• This is associated with tachycardia, hypertension, pupillary dilation, peripheral vasoconstriction.

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Hyperthermia.

• Cocaine causes hyperthermia.

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Therapeutic uses.

.Local anesthetic agent.

Pharmacokinetics.

• Cocaine is rapidly de-esterified and demethylated to benzoylecgonine excreted in the urine.

Adverse effects.

• Anxiety
• Depression
• Toxic effects.

Amphetamine.

• This is a noncatecholaminergic sympathetic amine.
• It shows neurological and clinical effects similar to cocaine.

E.g.

• Dextroamphetamine.
• Methamphetamine(Speed).

Mechanism of Action.

• It elevates the level of catecholamine neurotransmitters in the synaptic spaces.
• Because amphetamine also inhibits MAO, high levels of catecholamines are readily released into synaptic spaces.
• Behavioral effects similar to that of cocaine.

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Pharmacologic actions.

CNS.

• Amphetamine stimulates the entire cerebrospinal axis, cortex, brainstem and medulla.
• This leads to increased alertness, decreased fatigue, depressed appetite, and insomnia.
• In high doses, psychosis and convulsions can ensue.

Sympathetic nervous system.

• Amphetamine acts on the adrenergic system, indirectly stimulating the receptors through norepinephrine.

Therapeutic uses.

• Attention deficit hyperactivity disorder (ADHD).
• Dextroamphetamine.
• Methylphenidate.
• Lisdexamphetamine
• Atomoxetine.
• Narcolepsy.
• Amphetamine
• Methylphenidate
• Modafinil
• Armodafinil

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Pharmacokinetics.

• Good oral bioavailability.
• Metabolized by the Liver and excreted in the urine.

Adverse effects.

Central effects.

• Insomnia. Irritability. .Weakness. .Dizziness. .Tremor. .Confusion.
• Delirium. .Panic states. .Suicidal tendencies.

Cardiovascular effects.

• Palpitations. .Cardiac arrhythmias. .Hypertension. .Anginal pain.
• Circulatory collapse. .Headache. .Chills. Excessive sweating.

Gastrointestinal system effects.

• Anorexia. .Nausea. .Vomiting .Abdominal cramps. .Diarrhea.

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Contraindications.

• Hypertension. Hyperthyroidism. Cardiovascular disease. Glaucoma.

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Methylphenidate.

Mechanism of action

• Methylphenidate is a potent dopamine transport inhibitor thus making more dopamine available.

Therapeutic uses.

• ADHD
• Narcolepsy

Pharmacokinetics.

• Good oral bioavailability.
• Concentrations in the brain exceed that of the plasma.
• Ritalinic acid is excreted in the urine.

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Adverse reactions.

• GIT effects e.g. nausea, abdominal pain.
• Anorexia, insomnia, nervousness and fever.

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HALLUCINOGENS

Lysergic acid diethylamide (LSD).

• The drug shows serotonin(5-HT) agonist activity.
• Activation of the sympathetic nervous system occurs which causes :
• Pupillary dilation
• Increased blood pressure
• Piloerection
• Increased body temperature.

Adverse effects.

• Hyperreflexia. Nausea. Muscular weakness.

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• Haloperidol and other neuroleptics can block the hallucinatory action of LSD and quickly abort the syndrome.

Tetrahydrocannabinol.

• The main psychoactive alkaloid in marijuana (THC).
• It affects short-term memory and mental activity.
• It decreases muscle strength and impairs highly skilled motor activity.
• Effects of THC include appetite stimulation,xerostomia,visual hallucinations, delusions and enhancement of sensory activity.

Receptor type

• CB1 receptors.
• Found on inhibitory presynaptic nerve terminals that interact synaptically with pyramidal neurons.
• Endocannabinoids have been identified in the CNS and may act as local neuromodulators.

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Pharmacokinetics.

• It is highly lipid soluble and has a large volume of distribution.
• Elimination is largely through the biliary route.

Adverse effects.

• Increased heart rate.
• Decreased blood pressure.
• Reddening of the conjunctiva
• Toxic psychosis.

Therapeutic use.

• Dronabinol is indicated as an appetite stimulant for patients with AIDS.
• Emesis
• Rimonabant (CB1 receptor antagonist) is used in obesity.

Phencyclidine.

• Also known as PCP or angel dust.
• It inhibits the reuptake of dopamine, 5-HT and norepinephrine.
• Phencyclidine blocks the ion channel regulated by glutamate receptor.
• This action prevents the passage of critical ions – Ca²⁺ through the channel.
• Phencyclidine has anticholinergic activity but produces hypersalivation.
• As an analog of ketamine, it causes dissociative anesthesia and analgesia.
• Produces numbness of extremities, staggered gait, slurred speech and muscular rigidity.

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