11/11/04SUBSTANCE ABUSE: Stimulants(Cocaine/Amphetamines/PCP/Caffeine)John Gualtieri, PharmDClinical Assistant ProfessorDept. of Experimental and Clinical PharmacologyCollege of Pharmacy, University of MinnesotaOBJECTIVES1. Describe the pharmacology and pathophysiology of cocaine, amphetamines, PCP and caffeine2. Be able to recognize the clinical manifestations of cocaine, amphetamines, PCP and caffeine3. Be familiar with the some of the street drug names associated with the stimulants.4. Identify potential pharmacotherapeutic and non-pharmacotherapeutic interventions used for the treatment ofcocaine, amphetamines, PCP and caffeine intoxication.5. Identify potential pharmacotherapeutic interventions used for the treatment of the withdrawal from cocaine,amphetamines, and caffeine.COCAINEI. AVAILABLE FORMS• Cocaine is an alkaloid derived from the leaves of the species Erythroxylon coca, an indiginous plant ofCentral and South AmericaCocaine hydrochloride: nasal insufflation, IV, SQ, or IM injection; vaginally, rectally, sublingually.Cocaine base or “Crack Cocaine”: alkaloid form which is used for smoking. “ Crack” doesn’t actuallyburn, but vaporizes resulting in the release of the fat soluble alkaloid which readily crosses the blood-lung andblood-brain barriers resulting in a rapid intense “high” comparable to intravenous cocaine administration. Theterm “Crack” was applied to this form of cocaine because of the characteristic cracking and popping sounds itmakes when burned and smoked.II. SOCIAL IMPACTIn the 1970s, cocaine gained and has, thus far, retained the dubious distinction of being the most commonly abusedstimulant. A dramatic 15-fold increase in cocaine-toxicity related emergency room visits were reported between 1976and 1986. In 1985, it was estimated that 30 million people in the USA have used cocaine. Today, approximately 2million people use cocaine regularly. Beginning in the mid-1980s, “Crack” cocaine has become an increasinglypopular drug of abuse owing to its ease of production and rapid and intense drug effect when smoked.John Belushi, Chris Farley, Len Bias, and River Phoenix are examples of celebrities whose deaths were linked to heavydrug and/or alcohol abuse with cocaine being one of their primary agents of abuse.III. STREET DRUG IDENTIFICATION AND ANALYSISTerms• Nose Candy, Coke• Blow• Chaz• Charlie• Snow White• Speedball (cocaine mixed with heroin taken IV)• Peruvian Lady• Crack Cocaine (Candy, Rock, Freebase, Scud, Pebbles, Wash)21/11/04Adulterants• Lactose• Sodium bicarbonate (“baking soda”)• Lidocaine• Procaine• PCP (Phencyclidine)• Amphetamines• Caffeine• TalcCocaine Doses and Quantities• Line 1/8” x 2” 50 mg• Eight Ball 1/8 oz• Cokespoon 5-10 mg• Cadillac 1 oz• Stimulatory Dose 50-100 mg• G or G-rock 1 gramIV. PHARMACOLOGY1. Inhibition of neuronal catecholamine uptake resulting in generalized sympathetic nervous systemstimulation.2. Central nervous system stimulation with release of dopamine.3. Serotonin release and/or blockade of serotonin reuptake.4. Inhibition of the fast Na-K channels on neural and cardiac tissues which disrupts phase zero depolarizationof the normal action potential resulting in a local anesthetic effect (i.e membrane stabilizing effect). Thisaction lowers the threshold for ventricular arrhythmias. I. PHARMACOKINETICS• Absorption is rapid and complete through all mucosal membranes.ONSETPEAKDURATIONSnorted10-15 min15-60 min60-90 minIV or Smoked15-60 sec5-10 min30-60 minDistribution: Cocaine concentrations in the brain may be 20 times higher than in the plasma.Plasma half-life: 60-90 minutes but may be prolonged after insufflation due to continued absorptionthrough the nasal membranes.Metabolism: It is rapidly hydrolyzed by plasma and liver cholinesterase to ecgonine methyl ester,and it undergoes non-enzymatic hydrolysis to benzoylecgonine. These are the twomajor metabolites and are eliminated primarily in the urine and are the targetcompounds for most urine drug screens.fi Cocaine metabolites may be detected in the urine 5-10 days after last use.VI. RANGE OF TOXICITYThe toxic dose is highly variable and depends on individual tolerance and the route of administration. Rapidintravenous injection or smoking may produce transient high brain and heart levels, whereas the same dose swallowedor snorted may produce only euphoria.• The average dose of cocaine orally which may produce serious intoxication is 500 mg.• The classic fatal dose is 1 gm., but death has been reported with doses as small as 20 mg intranasally.31/11/04VII. MOOD ALTERING EFFECTS• Euphoria• Excitement• Heightened energy• Increased self esteem• Enormous self confidence• Lower anxiety and social inhibitions• Perceived increase in sexual desire and performanceVIII. TOXICOLOGICAL EFFECTSMost of the manifestation of cocaine intoxication can be explained by excessive central and systematic neuralstimulation. Because of this excessive stimulation, cocaine may cause life-threatening problems in multiple organsystems. Cardiovascular and central nervous system toxicity deserve special attention.A. Cardiovascular:COMPLICATIONS FROM ACUTE USE1. Severe hypertension: may cause hemorrhagic stroke or aortic dissection.2. Arrhythmia: may result in fatal ventricular tachycardia or fibrillation.A. Early Onset Arrhythmias: Likely due to the direct cardiotoxic effect of cocaine on the heart caused by theinhibition of the fast Na-K channels of the myocardial conduction system. This “membrane-stabilizing”effect may result in the sudden onset of potentially fatal arrhythmias. These arrhythmias typically occurearly on in the patient’s presentation (1-2 hours post-exposure) and require the inclusion of intravenoussodium bicarbonate as one of the first-line pharmacologic agents in the ACLS treatment guidelines.B. Late Onset Arrhythmias: May occur in those patient’s who present with a suspected cocaine-induced myocardial infarction. These late-onset arrhythmias likely occur secondary to post-MIischemic injury and are not likely due to the direct effect of cocaine on the myocardial conductionsystem. These arrhythmias typically occur late in the patient’s presentation (4-8 hours post-exposureor post-MI). Pharmacotherapeutic management of late-onset arrhythmias in the post-MI patienttypically involves the use of intravenous lidocaine.3. Myocardial ischemia