Pharm 100 - Lesson B.7
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The amphetamines are a class of central nervous system (CNS) stimulant drugs that enhance theactivity of the brain. The amphetamines include dextroamphetamine, methamphetamine, and a host ofdesigner drugs such as methylenedioxyamphetamine (MDA). There are other drugs that are CNSstimulants and function in a analogous manner to the amphetamines, e.g. methylphenidate (Ritalin).
History of Amphetamines
- The following list of dates demonstrates that amphetamine was once considered a panacea for anumber of disorders (34 at one time), but is now a drug of widespread abuse.
- 1887 First synthesis of amphetamine.
- 1933 Discovery of CNS stimulant action of amphetamine.
- 1939-1945 Use of amphetamines during World War II as anti-fatigue agents.
- 1945 First marketing of amphetamine as an appetite suppressant in U.S.A. This led to a largenumber of patients dependent on the drugs.
- 1945-1958 Epidemic of abuse of amphetamines in Japan that was eventually eliminated.
- 1960’s Outbreaks of abuse of amphetamines in Sweden, U.S.A. and Canada. Amphetaminebecame a drug of “choice”
- 1973 Classification of amphetamines as controlled drugs in Canada and restriction of legal use tocertain medical problems (epilepsy, narcolepsy – sudden, uncontrollable attacks of sleep,parkinsonism, mental retardation, hyperkinetic disorders and hypotension during anesthesia). The reader will note that suppression of appetite is not allowed.
Chemistry of amphetamines
The amphetamines are synthetic organic compounds that are structurally similar to norepinephrine,epinephrine and dopamine found in the body. Three common amphetamine compounds areamphetamine, dextroamphetamine, and methamphetamine.The amphetamines can be synthesized readily, and this has resulted in the illicit manufacturing ofthese substances, especially methamphetamine, in underground laboratories. However, the purity ofillicit methamphetamine (Meth, Crystal, Speed) is variable, and may contain side-products of thechemical reaction, unreacted chemicals and “cutting” agents (e.g. starch, baking soda).
The amphetamines stimulate both the CNS and the sympathetic nervous system (e.g. increasedblood pressure, dilation of pupils). Methamphetamine seems to produce more central stimulation andless sympathetic stimulation compared to amphetamine. In the CNS, the amphetamines act primarilyby releasing the neurotransmitters, norepinephrine and dopamine, from nerve terminals. Theneurotransmitters then act on postsynaptic receptors giving a response. The effects produced byamphetamines depend on the drug dose and the route of administration
CVS (Cardiovascular System) effects of amphetamine
- CVS (Cardiovascular System) effects of amphetamine are due to drug-induced displacement ofnorepinephrine from adrenergic nerve terminals, which then acts on postsynaptic " (vasculature) and $1(heart) receptors.
- The effects include: 1. Fight-flight response.2. Increased blood pressure.3. Increased heart rate.
CNS effects of amphetamine
- CNS effects of amphetamine are mediated by the actions of catecholamines in the CNS, wherebyamphetamine primarily increases release (by displacement) and also inhibits active reuptake of dopamineand norepinephrine in several brain regions. Dopamine appears to be involved primarily in many of theCNS effects. The CNS stimulation is dose-dependent, with low doses primarily affecting the cerebralcortex and high doses affecting the entire cerebrospinal axis, and can manifest as
- 1. Behavioural and psychomotor stimulation (alertness, hyperactivity, insomnia).
- 2. Anorexia (reduction in appetite).
- 3. Hyperthermia (increase in body temperature).
- 4. Respiratory centre stimulation.
- 5. neurotransmission in spinal cord.
- 6. Convulsions, with high doses.
The amphetamines act on the following brain areas:
- 1. Reticular activating system (RAS). The amphetamines decrease the threshold for transmittingsensory (peripheral) input to the cerebral cortex.
- 2. The medial forebrain bundle (MFB) is stimulated. This area is involved in mediating reward.
- 3. Hypothalamus. The temperature-regulating and feeding centres are modified.
- 4. Limbic system. This system is involved in emotion. Amphetamine may lead to aggressivebehaviour and mood swings.
- The common amphetamines vary in their CNS potency.
- Dextroamphetamine > amphetamine
- .Methamphetamine > dextroamphetamin
Therapeutic uses of amphetamine-like drugs:
- 1. Narcolepsy. Both amphetamine and methylphenidate are effective; however, methylphenidate isthe drug of choice because of the reported lower incidence of cardiovascular effects. No tolerancedevelops to the therapeutic effect during chronic use.
- 2. Attention-deficit hyperactivity disorder (hyperactive child syndrome). This disorder, usually firstevident in childhood, consists of disruptive behaviour, decreased attention/concentration spans andpoor scholastic achievement. Both D-amphetamine and methylphenidate have been used to treatthis disorder. However, methylphenidate is the drug of choice because of the lower incidence ofcardiovascular and anorectic effects. Drug therapy increases classroom attention/concentration andcan improve scholastic performance. During chronic therapy, no tolerance develops to thetherapeutic effect. It must be emphasized, however, that the treatment approach should consist ofbehavioural therapy, special educational curriculum and family counseling in combinationwith drug therapy.
- 3. Parkinson’s disease. Some Parkinsonian patients benefit from amphetamines. This may be relatedto the enhanced dopamine levels in the brain
The amphetamines produce euphoria and are effective CNS stimulants; for these reasons, they arewidely abused. The source of street amphetamines is usually illicit laboratories. Street names foramphetamines are: Bennies, black beauties, copilots, eye-openers, uppers, etc. Dextroamphetamine iscalled dexies and methamphetamine is referred to as speed, crystal meth or crack. A smokable form ofmethamphetamine is called, ice, Hawaiian salt or rock candy. Most common amphetamines are takenorally, injected or smoked. Occasionally it is sniffed or snorted.
Effects of Short-Term Use – Low Dose
- CNS: overstimulation, restlessness, dizziness, insomnia, euphoria, dysphoria (fearful reactions),mild confusion, tremor, and in rare instances, panic and psychosis; reduced appetite, increasedtalkativeness, alertness and energy, reduction of fatigue and drowsiness, general increase in activity, anda feeling of well-being, enhanced performance.
- Cardiovascular: irregular heartbeat, headache, increased blood pressure.
- Respiratory: increased respiratory rate.
- Other: increase or decrease in libido, possible temporary impotence.
Effects of Short-Term Use – Higher Doses
- Increase in the exhilaration and euphoria. Ideas flow rapidly, feeling of increased strength. Theindividual becomes talkative and may demonstrate excitation, agitation and irritability. Stimulantpsychosis may occur, which consists of paranoid thinking, confusion, and distortion of events withhallucinations. The amphetamine rush might be accompanied with violent behaviour. The user maysuffer a seizure, high fever and stroke.
- Cardiovascular: The user may suffer a heart attack, angina pain, dysrhythmias (irregular heartrhythm), changes in blood pressure and fainting. Finally cardiovascular collapse can occur.
Effects of Long-Term Use
- Long-term use leads to chronic sleeping problem (insomnia, awakening at night, and poor qualitysleep). The subject is anxious and tense. They have a poor appetite. The blood pressure may beelevated and the cardiac rhythm abnormal. They are suspicious and paranoid and exhibit repetitivebehaviour.
- In addition, a number of health risks are associated with contaminated needles, poor nutrition andthe lifestyle of the addict (AIDS, hepatitis, collapsed vessels, etc.).
The Amphetamine Run
In an attempt to maintain the initial effects of exhilaration and enhanced awareness and selfconfidence induced by the drugs, abusers will repeatedly administer the drug to maintain the rush orhigh. This may continue for several days. The terms “speeders” or “speed freaks” have been used torefer to these abusers. The run stops when the drug supply or the abuser is exhausted.
Tolerance develops to some, but not all of the effects of the amphetamines. Tolerance developsrapidly to the euphoria and mood elevating effects. Tolerance also occurs to the anorectic effects of thedrug, but not the drug-induced psychosis. Tolerance also develops to the lethal effects of the drugs. Tolerance has also been reported to the cardiovascular and respiratory stimulatory effects of theamphetamines.
Cessation of administration of the amphetamines results in mood depression that may be profound,prolonged sleep, huge appetite, lassitude and fatigue. The mood depression may be long-lasting andcould be the main symptom of the withdrawal syndrome and hence, physical dependence on theamphetamines.
Psychological (Psychic) Dependence
- Amphetamines usually are self-administered to produce pleasurable effects, including euphoria andan abrupt awakening sensation (“rush”). These effects act as rewards and users will crave the drug’seffects so intensely that if it is not available they will experience panic.
- Other drugs may be sought concurrently with the amphetamines (e.g. benzodiazepines, barbiturates,opioids)in an attempt to antagonize various toxic effects of the amphetamines.
Potential for Abuse
- The abuse liability of the amphetamines is considered to be extremely high. Both amphetamine andmethamphetamine produce powerful euphoria. These drugs are water soluble in their salt forms andlarge doses can be readily injected.
- Inherent harmfulness of the amphetamine reside in the long-term toxicities (cardiovascular effectsand drug-induced psychoses). In addition, there is a substantial health risk with the user life style, i.e.contaminated needles and poor nutrition. The inherent harmfulness of the drug does not appear to be adeterrent to abusers.
Cocaine is a naturally-occurring alkaloid found in the leaves of the cocoa bush that is indigenous toBolivia, Columbia and Peru. The local people in these areas have chewed cocoa leaves for centuries. Cocaine is classified pharmacologically as a local anesthetic and as a CNS stimulant. In terms of law,cocaine is classified as a narcotic according to the Narcotic Control Act of Canada.
- 1884 Sigmund Freud studied the CNS effects of cocaine and used it clinically to withdraw acolleague from morphine, which then led to dependence on cocaine. Freud then spoke outagainst cocaine, calling it the “third scourge” of humanity.
- 1884 Karl Koller introduced cocaine into medicine as a local anesthetic.
- 1970’s to 1990’s: Dramatic increase in non-medical use of cocaine in North America. Cocaine replaced amphetamines as a major stimulant drug, subject to abuse. Currently cocaine is one of the most popular recreational drugs, next to alcohol, nicotine,caffeine and marijuana.
- CNS effects are due to generalized CNS stimulation produced by cocaine and are dose-dependent. In general, the behavioural effects of cocaine are very similar to those produced by the amphetamines. However, the duration of these effects is relatively brief, usually less than an hour, compared with theduration of amphetamine-induced effects.
- Cocaine inhibits the active re-uptake of released dopamine and norepinephrine into the presynapticnerve terminal. This increases the concentration of these transmitters in the synaptic cleft and in turn anincrease in the activation of the postsynaptic receptors. In the CNS, the stimulatory effect appears to bemediated mainly via dopamine and in the periphery, changes in blood pressure which is mediated bynorepinephrine.
- The local anesthetic effect of cocaine is due to its blockade of nerve impulse in sensory nervefibres. Note that cocaine can interfere with the function of all organs in which conduction ortransmission of impulses occurs (e.g. heart). The probability of such action is proportional to the cocaineconcentration in the systemic circulation.
Cocaine is almost indistinguishable from amphetamine in its acute effects and its pattern of toxicity. The main differences are:
- Shorter duration of action for cocaine.
- Lower incidence of complications associated with intravenous use as cocaine is usually sniffed orsmoked.
- Tolerance does not develop as readily to the hallucinatory and behavioural effects of cocaine ascompared to the amphetamines.
Therapeutic Uses of Cocaine
The only legitimate use of cocaine is as a local anesthetic for the mouth and throat. It is rarely used.
Cocaine is metabolized to an inactive metabolite benoylecgonine which is excreted in the urine. This metabolite can be detected up to 48 hours after a single dose and up to two weeks in a chronic user
Cocaine is a very powerful CNS stimulant that increases alertness, reduces the need for sleep, andproduces an intense feeling of euphoria. The drug is widely abused. Street names for cocainehydrochloride (salt) are: C., coke, flake, snow and stardust. The names for the freebase of cocaine are: crack, rock and freebase. Cocaine is also used in combination with other drugs, e.g. heroin. Cocainehydrochloride is usually “snorted” into the nose. It can also be injected. The freebase of cocaine is notwater-soluble, but is volatile when heated and is usually smoked or inhaled.
Effects of Short-Term – Low Doses
- CNS: dilation of the pupils; exaggerated reflexes; euphoria and a sense of well-being;postponement of physical and mental fatigue; reduced appetite and need for sleep; increasedtalkativeness or quiet contemplation; increased self-confidence and feelings of superiority; increasedspeed of performance on fairly simple physical and intellectual tasks. The euphoric phase may befollowed by a period of dysphoria characterized by agitation and anxiety.
- Cardiovascular: vasoconstriction, increase in heart rate after initial slowing, and increased bloodpressure.
- Respiratory: increased respiratory rate.
Effects of Short-Term – Higher Doses
- Intensification of cocaine’s low-dose effects may occur at higher doses, in addition to the following.
- Behavioural: intense euphoria followed by a state of severe agitation. Users may experienceanxiety, rapid flight of ideas, feelings of grandiosity, paranoid thinking, and often bouts of repeated,seemingly meaningless behaviour (stereotypy). With repeated use, the cocaine user may suffer from aparanoid psychosis.
- Neurological: tremor and muscle twitches, seizures, headache, hemorrhagic stroke and cerebralinfarction.
- Cardiovascular: high blood pressure, headache, pallor, rapid weak pulse and heart attack.Gastrointestinal: nausea and vomiting
- .Respiratory: Hazardous dose levels may cause rapid, irregular and shallow breathing; pulmonaryedema (fluid accumulation in the lungs) and other lung damage including hemorrhage (coughing upblood), lung tissue diseases and hypersensitivity lung reactions. Lung trauma may also result from thehigh pressures sometimes used to force cocaine into the lungs rapidly or from the cocaine-anesthetizedairways allowing inhalation of foreign objects and very hot vapours.
- Renal: acute renal failure, secondary to the deterioration of muscle tissue.
- Other: elevated body temperature and cold sweat.
Effects of Long-Term Use
The heavy user is nervous, agitated and excitable with mood swings. Users often experience a toxicpsychosis including paranoia. They often experience hallucinations or sensations of insects crawlingunder the skin. Sleep disorders are common as are eating disorders. Sexual function is impaired. Theremay be permanent damage to the brain and impairment of neuronal function. They may exhibit highblood pressure and an irregular heart rhythm. As the drug is “snorted” changes occur to the nasalmucosa. The cocaine user also experiences social problems. They are obsessed with obtaining the drugand abandon their friends and family. The drug-induced irritability also contributes to the socialproblems.
The Cocaine Binge
Heavy cocaine users may take the drug repeatedly over several hours to days. The attempt is tomaintain the euphoric experience. The binge is followed by a crash, manifested as depression, lethargyand hunger.
- Tolerance develops to some, but not all, of the effects of cocaine. Tolerance to the mood-elevatingeffect of cocaine occurs, but tolerance does not develop to the drug-induced psychotic effect.
- Physical dependence on cocaine has been demonstrated by the appearance of a withdrawalsyndrome following the cessation of drug use. The withdrawal symptoms are very similar to thoseassociated with physical dependence on the amphetamines.
- Psychological dependence on cocaine can occur. The pharmacodynamic characteristics ofsmoking “crack” (rapid onset and short duration of behavioural effects) are almost “ideal” for thedevelopment of compulsive drug use. The behavioural effects of cocaine usually are perceived aspleasurable and rewarding, and reinforce repeated drug use. Other types of psychoactive drugs often areused concurrently with cocaine (e.g. opioids, ethanol, sedative-hypnotic drugs).
Potential for Abuse
The abuse liability of cocaine is one of the highest among all drugs of abuse. This is due to thepowerful euphoria, which can be reached rapidly by injecting the drug or smoking the freebase.The inherent harmfulness of the drug is also among the highest among drugs of abuse. Users willexperience physical and psychological deficits. These include respiratory arrest, psychosis and seizures. In addition, cardiovascular damage can result. These events do not appear to deter the abuser
Caffeine is the most widely and regularly used drug in the world. It is found in significantconcentrations in tea, coffee, chocolate and cola drinks. Caffeine affects the CNS and the cardiovascularsystem.
- The CNS effects of caffeine involve several areas of the brain. In the cerebral cortex, caffeineincreases mental performance and decreases drowsiness and fatigue. It also enhances motor activity. These effects are observed with 100 to 250 mg of caffeine (one to two cups of strong coffee). In themedulla, the respiratory and vasomotor centres are stimulated, leading to increased respiration and heartrate.
- In the cardiovascular system (CVS), low doses may lead to an increase in heart rate and bloodpressure. High doses may lead to a disturbance in the normal rhythm of the heart
- The actions of caffeine are exerted by competitively blocking adenosine receptors in the brain.Adenosine exerts an inhibitory effect on a number of neurons and transmitter systems. When caffeineblocks these adenosine receptors, the neurons are released from the adenosine inhibition and the neuronalactivity is increased (stimulation).
Effects of Short-Term Use – Low Dose
- CNS: Caffeine can produce mild mood elevation and reduce fatigue. There probably is a smallincrease in performance, but this has not been conclusively demonstrated. Flow of thought may beclearer and more rapid. When taken by abstainers, caffeine, produces nervousness and the jitters. It canalso interfere with sleep.
- Cardiovascular: Caffeine produces constriction of cerebral blood vessels (useful in a headache),peripheral blood flow is increased and cardiac muscle is stimulated.
- Respiration: There is mild stimulation of the respiratory rate and a relaxation of bronchial smoothmuscle.
Effects of Short-Term Use – High Dose
- CNS: irritability, restlessness, nervousness, insomnia, rambling flow of thoughts and speech, andpsychomotor agitation (agitated movement of voluntary muscles).
- Cardiovascular: rapid and irregular heartbeat.
- Other: increased capacity for muscular work
Effect of Long-Term Use
Excess use of caffeine over a long period will lead to restlessness, nervousness, insomnia, increasedurinary output, gastric upset, and rambling speech and thought. There is no definite link betweencaffeine consumption and disease states, although not all experts agree on this view.
Tolerance and Dependence
- There is some evidence that tolerance does develop to caffeine, at least in some individuals. Thesame “pick me up” can occur with a cup of decaffeinated coffee as regular coffee suggesting that the actof drinking coffee is very important.
- Dependence on caffeine does develop. Abrupt cessation of caffeine intake will result in headache,fatigue and drowsiness. These symptoms can be alleviated with caffeine, the headache is amenable totreatment with analgesic, e.g. acetaminophen. Psychological dependence does occur.
Potential for Abuse
- The abuse liability of caffeine is low. Caffeine does act as a reinforcer, but the activity is low. The“high” experienced is mild in intensity and thus the abuse liability is low.
- The inherent harmfulness of caffeine is very low. Low to moderate intake of caffeine (three cups ofcoffee) each day does not appear to be associated with adverse events. Larger doses will result inirritability, nervousness, insomnia, and irregular rhythm of the heart.
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