CNS Stimulants Asst Prof - PowerPoint Presentation

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CNS Stimulants

Asst Prof Dr Inam S. Arifisamalhaj@yahoo.comPharm.dr.isamalhaj@uomustansiriyah.edu.iq

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Psychomotor stimulants and hallucinogens

Two groups of drugs act primarily to stimulate CNSPsychomotor stimulants cause excitement and euphoria, decrease feelings of fatigue, and increase motor activityHallucinogens produce profound changes in thought patterns and mood, with little effect on the brainstem and spinal cord

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Psychomotor Stimulants

MethylxanthinesTheophylline, found in tea; Theobromine,

found in cocoa; and Caffeine

Caffeine,

the most widely consumed stimulant in the world, is found in highest conc. in certain coffee products (e.g. espresso, tea, cola drinks, energy drinks, chocolate candy, and cocoa).

Mechanism of action:

Several/including:

translocation of EC calcium

increase in cAMP & cGMP caused by inhibition of PDEs

blockade of adenosine receptors

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CNS of

caffeine: 1-2 cups of coffee (100 to 200 mg) causes a decrease in fatigue and increased mental alertness as a result of stimulating the cortex and other areas of the brain12 to 15 cups of coffee/ 1.5 g of caffeine produces anxiety and tremors 2 to 5 g / spinal cord stimulation / only by very high doses

Tolerance can rapidly develop to the stimulating properties of

caffeine

Withdrawal consists of

feelings of fatigue and sedation

CVS:

A high dose of

caffeine

has +

ve

inotropic and chronotropic

Diuretic action:

Caffeine

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

Gastric mucosa:

Because methylxanthines stimulate secretion of gastric acid / peptic ulcers should avoid foods and beverages containing methylxanthines.

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Therapeutic uses:

Caffeine and its derivatives relax SMs of the bronchiolesRecently replaced by other drugs??? Used in combination with the analgesics acetaminophen

and aspirin

for the management of headaches in both prescription and OTC

Pharmacokinetics:

well absorbed orally, distributes throughout the body, including the brain, cross the placenta to the fetus and are secreted into the breast milk, metabolized by CYP1A2 pathway, and excreted in the urine.

Adverse effects:

Moderate doses of

caffeine

cause insomnia, anxiety, and agitation

A high dosage is required for toxicity, which is manifested by emesis and convulsions

The lethal dose is 10 g of

caffeine

(about 100 cups of coffee), which induces cardiac arrhythmias

Death from

caffeine

is, therefore, highly unlikely

Lethargy, irritability, and headache occur in users who routinely consume more than 600 mg of

caffeine

per day (roughly six cups of coffee per day) and then suddenly stop.

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Nicotine/tobacco

Uses:Mechanism of action:I- CNS: highly lipid solublity & readily crosses the BBB

Cigarette smoking or low doses produces euphoria and arousal, as well as relaxation

It improves attention, learning, problem solving, and reaction time

High doses result in central resp. paralysis & severe hypotension / medullary paralysis

Nicotine

is also an appetite suppressant.

II-

Peripheraleffects

:

Stimulation of

symp

. ganglia & adrenal medulla / BP & HR/ hypertensive patients???

Many patients with peripheral vascular disease / exacerbation of symptoms with smoking

Nicotine

- induced vasoconstriction decrease coronary BF / patient with angina ???

Stimulation of parasympathetic ganglia also increases motor activity of the bowel

At higher doses, BP falls & both GIT & bladder musculature???

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Pharmacokinetics: Highly lipid soluble, absorption readily occurs via the oral mucosa, lungs, GI mucosa, and skin, the placental membrane and is secreted in the breast milkBy inhaling tobacco smoke, smoker takes in 1 to 2 mg of nicotine /cigarette

The acute lethal dose is 60 mg

More than 90% of the

nicotine

inhaled in smoke is absorbed

Clearance of

nicotine

involves metabolism in the lung and the liver and urinary excretion

Tolerance to the toxic effects of

nicotine

develops rapidly, often within days.

Adverse effects:

The CNS effects

/

irritability and tremors

Intestinal cramps, diarrhea, and increased HR & BP

Cigarette smoking increases the rate of metabolism for a number of drugs.

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Withdrawal syndrome:

Nicotine is an addictive substance, and physical dependence develops rapidly and can be severe Withdrawal symptoms / irritability, anxiety, restlessness, difficulty concentrating, headaches, and insomnia Appetite is affected, and GI upset often occurs

The transdermal patch and chewing gum containing

nicotine

have been shown to reduce

nicotine

withdrawal symptoms and to help smokers stop smoking

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Other forms of

nicotine replacement used for smoking cessation include the inhaler, nasal spray, and lozenges Bupropion, an antidepressant, can reduce the craving for cigarettes.

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Varenicline

A partial agonist at neuronal N Ach Rs in CNSLess euphoric effects than nicotine (

nicotine

is a full agonist)

Useful as an adjunct in the management of smoking cessation in patients with

nicotine

withdrawal symptoms

Attenuate the rewarding effects of

nicotine

if a person relapses and uses tobacco

Patients taking

varenicline

should be monitored for suicidal thoughts, vivid nightmares, and mood changes

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Cocaine

Addictive drug/ because of its abuse potentialBlock reuptake of the monoamines (NE, 5-HT, & DA) into the presynaptic terminals/ potentiates and prolongs the CNS and peripheral actions of these monoamines /prolongation of DA effects in the brain’s pleasure system (limbic system) produces the intense euphoria Chronic intake of cocaine depletes DA/ triggers the vicious cycle of craving for cocaine that temporarily relieves severe depression

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Amphetamine

a sympathetic amine / similar cocaine Dextroamphetamine Methamphetamine

/ can be smoked and is preferred by many abusers

3,4-Methylenedioxymethamphetamine

(also known as MDMA, or Ecstasy) is a synthetic derivative of

methamphetamine

with both stimulant and hallucinogenic properties

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Mechanism of action

Indirect effects on the CNS and peripheral nervous system Elevation of the level of catecholamine Amphetamine enhances release of catecholamine storesInhibits monoamine oxidase (MAO) and is a weak reuptake transport inhibitorAs a result: the behavioral effects of amphetamine and its derivatives are similar to those of

cocaine.

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Actions

CNS: The major behavioral effects of amphetamine result from a combination of its DA & NE release-enhancing propertiesStimulates the entire cerebrospinal axis, cortex, brainstem, & medulla

leads to increased alertness, decreased fatigue, depressed appetite, and insomnia

Used in hyperactivity in children, for narcolepsy, and for appetite control

At high doses, psychosis and convulsions can ensue.

Sympathetic NS:

indirectly stimulating the receptors through NE release.

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Therapeutic uses

chronic use/development of tolerance to the euphoric and anorectic effects.I-Attention deficit hyperactivity disorder (ADHD): Some young children are hyperkinetic and lack the ability to be involved in any one activity for longer than a few minutes Dextroamphetamine, methamphetamine

, the

mixed amphetamine salts,

&

methylphenidate

help improve attention & alleviate behavioral problems

Lisdexamfetamine

a prodrug converted to the active component

dextroamphetamine

after GI absorption and metabolism

Atomoxetine

is a nonstimulant drug approved for ADHD in children and adults.

This drug should not be taken by individuals on MAO inhibitors and by patients with angle-closure glaucoma.]

Atomoxetine

is more selective for inhibition of NE reuptake

Therefore, it is not considered habit forming and is not a controlled substance.

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II-Narcolepsy:

rare sleep disorder characterized by uncontrollable bouts of sleepiness during the day, sometimes accompanied by catalepsy, a loss in muscle control, and even paralysis brought on by strong emotions such as laughterThe sleepiness can be treated with drugs, such as the mixed amphetamine salts or methylphenidate

Modafinil and its R-enantiomer derivative,

Armodafinil

, are considered

first-line agents for the

treatment of narcolepsy (mechanism!!!)

promotes wakefulness, fewer psychoactive and euphoric effects and fewer alterations in mood, perception, thinking, and feelings typical of other CNS stimulants.

effective orally, extensive hepatic metabolism, excreted in urine

SE: Headaches, nausea, and nervousness

Modafinil

and

armodafinil

may have some potential for abuse and physical dependence, and both are classified as controlled substances.

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III-

Appetite suppression: Phentermine and Diethylpropion are sympathomimetic amines that are related structurally to amphetamine

Used as

epitite

-suppressants in obesity

Pharmacokinetics:

completely absorbed from the GI, metabolized by liver

Alkalization of urine???

Euphoria caused by

amphetamine

lasts 4 to 6 hours, or four- to eightfold longer than the effects of

cocaine.

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Adverse effects:

may cause addiction, leading to dependence, tolerancea. CNS effects: insomnia, irritability, weakness, dizziness, tremor, and hyperactive reflexescan also cause confusion, delirium, panic states, and suicidal tendencies / BZDs ( lorazepsam, are often used in the management of agitation and CNS stimulation secondary to amphetamine overdose)

Chronic

amphetamine

/“

Amphetamine Psychosis

” resembles psychotic episodes, psychic and physical dependence, tolerance within a few weeks

The anorectic effect of

amphetamine

is due to its action in the lateral hypothalamic feeding center.

b. CVS:

palpitations, cardiac arrhythmias, hypertension, anginal pain, etc.

c. GIT:

anorexia, nausea, vomiting, abdominal cramps, and diarrhea.

d. CI:

Patients with hypertension, cardiovascular disease, hyperthyroidism, glaucoma, or a history of drug abuse or those taking MAOIs

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Methylphenidate

CNS-stimulant properties similar to amphetamine and may also lead to abuse, although its addictive potential is controversialIs now one of the most prescribed medications in childrenThe pharmacologically active isomer, dexmethylphenidate, is also a used for the treatment of ADHD.

Mechanism of action:

increasing both DA & NE in the synaptic space

less potential for abuse than

cocaine,

because it enters the brain much more slowly than

cocaine

and, thus, does not increase DA levels

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Therapeutic uses:

ADHD, narcolepsy. Unlike methylphenidate, dexmethylphenidate is not indicated in the treatment of narcolepsy.Pharmacokinetics: Both methylphenidate

and

dexmethylphenidate

are readily absorbed after oral administration

Methylphenidate

is available in extended-release oral formulations and as a transdermal patch for once-daily application

The

deesterified

product,

ritalinic

acid, is excreted in urine.

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Adverse Effects

GI: include abdominal pain and nauseaAnorexia, insomnia, nervousness, and fever In seizure patients, methylphenidate may increase seizure frequency, especially if the patient is taking antidepressants. It is contraindicated in patients with glaucomaMethylphenidate can inhibit the metabolism of warfarin, phenytoin, phenobarbital, primidone,

and the tricyclic antidepressants.

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Hallucinogens

A few drugs have, as their primary action, the ability to induce altered perceptual states reminiscent of dreams Many of these altered states are accompanied by visions of bright, colorful changes in the environment and by a plasticity of constantly changing shapes and color The individual under the influence of these drugs is incapable of nor- mal decision making because the drug interferes with rational thought These cpds are known as hallucinogens,

and

lysergic acid diethylamide (LSD)

and

tetrahydrocannabinol

(from marijuana) are examples of agents in this class.