Psychopharmacology: CNS Stimulants and Drugs of abuse

CNS STIMULANTS & DRUGS OF ABUSE

CNS stimulants

are classified according to their action into:

a.Psychomotor stimulants

b.Hallucinogen (psychotomimetic or psychedelics) drugs

1. Psychomotor stimulants

cause: Excitement, Euphoria, Decrease feeling of fatigue & Increase motor activity

Ex.: Methylxanthines (caffeine, theobromine, theophylline), nicotine, cocaine, amphetamine, atomoxetine, modafinil, methylphenidate.

2. Hallucinogens (psychotomimetic):

Affect thought, perception, and mood, therefore produce profound changes in thought patterns & mood, little effect on the brain stem & spinal cord

           Ex.: Lysergic acid diethylamide (LSD), Phencyclidine (PCP), Tetrahydrocannabinol (THC),          

Rimonabant.

Therapeutic Indications and Contraindications for CNS Stimulants

·         Obesity (anorectic agents).

·         Attention Deficit Hyperactivity Disorder (ADHD

·         Narcolepsy: It is a relatively rare sleep disorder, that is characterized by Uncontrollable bouts of sleepiness during the day. It is sometimes accompanied by catalepsy, a loss in muscle control, or even paralysis brought on by strong emotion, such as laughter.

Contraindications:

patients with anorexia, insomnia, asthenia, psychopathic personality, a history of homicidal or suicidal tendencies.

PSYCHOMOTOR STIMULANTS

A. METHYLXANTHINES

·         Theophylline (found in tea) : long-acting, prescribed for night-time asthma

·         Theobromine: found in cocoa.

·         Caffeine: (short-acting) the most widely consumed found in

o   coffee (200 mg/cup), 

o   carbonated soft drinks (60 mg/can),

o   cocoa and chocolate

Mechanism of action: include

Mechanism of action of Methylxanthine: A2 receptors antagonist responsible for CNS stimulation & smooth muscles relaxation

Pharmacokinetics

·         The methylxanthines are well absorbed orally.

·         Caffeine distributes throughout the body, including the brain. The drugs cross the  placenta to the fetus and is secreted into the mother's milk.

·         All are metabolized in the liver, the metabolites are then excreted in the urine.

Adverse effects

·         Moderate doses: insomnia, anxiety, agitation

·         High doses: emesis, convulsion

·         Lethal dose (10 gm of caffeine): cardiac arrhythmia

·         Suddenly stop: lethargy, irritability, headache

B. NICOTINE:

·         Nicotine is the active ingredient in tobacco.

·         Used in smoking cessation therapy,  Nicotine remains important, because:

·         it is 2nd only to caffeine as the most widely used CNS stimulant

·         and 2nd only to alcohol as the most abused drug.

Actions of Nicotine:

·         Low dose: ganglionic depolarization  

·         High dose: ganglionic blockade

Actions of Nicotine

1. CNS:

·         Low dose: euphoria, arousal, relaxation, improves attention, learning, problem solving and reaction time.

·         High dose: CNS paralysis, severe hypotension (medullary paralysis)

Peripheral effects:

·         Stimulation of sympathetic ganglia and adrenal medulla→↑BP and HR (harmful in HTN patients)

·         Stimulation of parasympathetic ganglia→↑ motor activity of the bowel 

·         At higher doses, BP falls & activating ceases in both GIT and bladder

Pharmacokinetics:

·         Highly lipid soluble absorbed everywhere (oral mucosa, lung, GIT, skin).

·         Crosses the placental membrane, secreted with milk.           

·         Most cigarettes contain 6-8 mg of nicotine, by inhaling tobacco smoke, the average smoker takes in 1 to 2 mg of nicotine per cigarette.  

·         the acute lethal dose is 60 mg,

·         90% of nicotine inhaled in smoke is absorbed.

·         Tolerance to toxic effects of nicotine develops rapidly.

Adverse effects:

·         CNS; irritability and tremors

·         Intestinal cramps, diarrhea  

·         ↑HR & BP

C. VAREMCLINE

           It produces less euphoric effects than those produced by nicotine itself (nicotine is full agonist at these receptors).

           Thus, it is useful as an adjunct in the management of smoking cessation in patients with nicotine withdrawal symptom.

D. COCAINE (HIGHLY ADDICTIVE DRUG)

l. Mechanism of action:

·         blockade of reuptake of the monoamines (NE, serotonin and dopamine)

·         Thus, potentiates and prolongs the CNS and peripheral actions of these monoamines. 

·         Initially produces the intense euphoria by prolongation of dopaminergic effects in the brain's pleasure system (limbic system).

·         Chronic intake of cocaine depletes dopamine. This depletion triggers the vicious cycle of craving for cocaine that temporarily relieves severe depression.

2. Actions:

a.CNS-behavioral effects result from powerful stimulation of cortex and brain stem.

·         Cocaine acutely increase mental awareness and produces a feeling of wellbeing and euphoria  similar to that produced by amphetamine.

·         Like amphetamine, cocaine can produce hallucinations and delusions of paranoia or grandiosity.

·         Cocaine increases motor activity, and at high doses, it causes tremors and convulsions, followed by respiratory and vasomotor depression.

b. Sympathetic NS: peripherally potentiate the action of NE→ fight or flight

 c. Hyperthermia:

·         Impair sweating & cutaneous vasodilation   

·         ↓perception of thermal discomfort

d. local anesthetic action:

·         Cocaine is the only LA that causes vasoconstriction, chronic inhalation of cocaine powder → necrosis and perforation of the nasal septum

·         Cocaine is often self-administered by chewing, intranasal snorting, smoking, or intravenous (IV) injection.

Adverse effects:

Anxiety reaction that includes hypertension, tachycardia, sweating, and paranoia. Because of the irritability, many users take cocaine with alcohol. A product of cocaine metabolites and ethanol is coca ethylene, which is also psychoactive and cause cardiotoxicity.

Depression: Like all stimulant drugs, cocaine stimulation of the CNS is followed by a period of mental depression.

Addicts withdrawing from cocaine exhibit physical and emotional depression as well as agitation. The latter symptom can be treated with benzodiazepines or phenothiazines.

Toxic effects:

·         Seizures RX I.V diazepam 

·         fatal cardiac arrhythmias. propranolol

E. AMPHETAMINE

Is a non catecholamine, (shows neurologic and clinical effects quite similar to those of

Dextroamphetamine is the major member of this class compounds.

Methamphetamine (speed) is a derivative of amphetamine that can be smoked and it is preferred by many abusers.

Methylenedioxymethamphetamine (also known as MDMA, or Ecstasy) is a synthetic  derivative of methamphetamine with both stimulant and hallucinogenic properties.

1.Mechanism of action:

Amphetamine, act by

·         releasing intracellular stores of catecholamines.

·         also inhibits MAO, high level CAOs are readily released into synaptic spaces.

2.Actions:

a.CNS: the major behavioral effects of amphetamine result from a combination of its dopamine and NE release enhancing properties. Amphetamine stimulates the entire cerebrospinal axis, brainstem, and medulla.

This lead to increase alertness, decrease fatigue,  depressed appetite, and insomnia.

b.Sympathetic Nervous System: indirectly stimulating the receptors through NE release.

Narcolepsy:

Amphetamine, methylphenidate.

Recently, a new drug, modafinil and its R-enantiomer derivative, armodafinil, have become available to treat narcolepsy.

Modafinil produces fewer psychoactive and euphoric effects as well as, alterations in mood, and feelings typical of other CNS stimulants.

4. Adverse effects:

The amphetamines may cause addiction, dependence, tolerance, and drug seeking behavior.

a. CNS: insomnia, irritability, weakness, dizziness, tremor, hyperactive reflex, confusion, delirium, panic states, and suicidal tendencies, especially in mentally ill patients.

-Chronic amphetamine use produce a state of "amphetamine psychosis" that resembles the psychotic episodes associated with schizophrenia.

  ATOMOXETINE

·         approved for ADHD in children and adults.

·         It is a NE reuptake inhibitor (should not be taken by individual on MAOI).  

·         It is not habit forming and is not a controlled substance.

METHYLPHENIDATE

·         It has CNS stimulant properties similar to those of amphetamine and may also lead to abuse, although its addictive potential is controversial.

·         Methylphenidate is a more potent dopamine transport inhibitor than cocaine, thus making  more dopamine available.

·         It has less potential for abuse than cocaine, because it enters the brain much more slowly than   cocaine and, does not increase dopamine levels as rapidly.

2.Therapeutic uses:

Methylphenidate has been used for several decades in the treatment of ADHD in children aged 6 to 16.

It is also effective in the treatment of narcolepsy.

Unlike methylphenidate, dexmethylphenidate is not indicated in the treatment of narcolepsy.

3.Adverse reactions:

GIT effects are the most common; abdominal pain and nausea.

Other reactions include anorexia, insomnia, nervousness, and fever.

In seizure patients, methylphenidate seems to increase the seizure frequency, especially if the patient is taking antidepressants.

Methylphenidate is contraindicated in patients with glaucoma.

HALLUCINOGENS (PSYCHOTOMIMETIC)

A few drugs have the ability to induce altered perceptual states reminiscent of dreams, arc accompanied by bright, colourful changes in the environment and by a plasticity of constantly changing shapes and colour.

The individual under the influence of these drugs is incapable of normal decision making, because the drug interferes with rational thought.

A. LYSERGIC ACID DIETHYLAMIDE

Multiple sites in the CNS are affected by lysergic acid diethylamide (LSD).

Activation of the sympathetic nervous system occurs, which causes pupillary dilation, increased BP, piloerection, and increased body temperature.

A. Adverse effects:

include hyperreflexia, nausea, and muscular weakness.

  High doses may produce long-lasting psychotic changes in susceptible individuals.   Haloperidol and other neuroleptics can block the hallucinatory action of LSD and quickly abort the syndrome.

B. Tetrahydrocannabinol (THC)

·         The main psychoactive alkaloid contained in marijuana is tetrahydrocannabinol (THC), which is available as dronabinol.

·         THC can produce euphoria, followed by drowsiness and relaxation.  

·         Affect short-term memory and mental activity,   decreases muscle strength and impairs highly skilled motor activity, such as that required to drive a car.

·         Its wide range of effects includes:

·         appetite stimulation, xerostomia, visual hallucinations, delusions, and enhancement of sensory activity

Mechanism of action:

These compounds, which bind to the CBI receptors, are membrane-derived and are synthesized on demand, and they may act as local neuromodulators.

Pharmacokinetics:

The effects of THC appear immediately after the drug is smoked, but maximum effects take about 20 minutes. By 3 hours, the effects largely disappear.

Dronabinol is administered orally and has a peak effect in 2 to 4 hours. Its psychoactive effects can last up to 6 hours, but its appetite-stimulant effects may persist for 24 hours.

It is highly lipid soluble and has a large volume of distribution.

Elimination: is largely through the biliary route.

Therapeutic uses of Dronabinol

l . as an appetite stimulant for patients with acquired immunodeficiency syndrome who are losing weight.

2. It is also sometimes given for the severe emesis caused by some cancer chemotherapeutic agents.

Adverse effects: include increased heart rate, decreased blood pressure, and reddening of the conjunctiva.

At high doses, a toxic psychosis develops. Tolerance and mild physical dependence occur with continued, frequent use of the drug.

RIMONABANT:

The CB I -receptor antagonist,

l . Obesity (decrease appetite and body weight in humans).

2. induce psychiatric disturbances, such as anxiety and depression, during clinical trials.

PHENCYCLIDINE:

           Phencyclidine (also known as PCP, or "angel dust")              inhibits the reuptake of dopamine, 5-HT, and norepinephrine.

           The major action of phencyclidine is to block the ion channel regulated by the NMDA subtype of glutamate receptor.

  Phencyclidine also has anticholinergic activity but, surprisingly, produces hyper salivation.

           Phencyclidine, an analog of ketamine, causes dissociative anesthesia (insensitivity to pain, without loss of consciousness) and analgesia.

           At increased dosages, anesthesia, stupor, or coma result, but strangely, the eyes may remain open. Increased sensitivity to external stimuli exists, and the CNS actions may persist for a week.