Toxicology of Drugs of Abuse

Robert Paul S. Lim, RPh

OVERVIEW
AMPHETAMINES COCAINE DXM GHB HALLUCINOGENS MARIJUANA NICOTINE OPOIDS & OPIATES PCP

AMPHETAMINE
Chemically similar to phenylethylamine Added side chains promote different levels of catecholamine & serotonin activity Dextroamphetamine Methylphenidate (Ritalin) Fenfluramine Dexfenfluramine Methamphetamine MDMA=Alexander Shulgin to Leo Zeff

Mechanism of Toxicity
activating the sympathetic nervous system via central nervous system (CNS) stimulation peripheral release of catecholamines, inhibition of neuronal reuptake of catecholamines, or inhibition of monoamine oxidase. Fenfluramine and dexfenfluramine cause serotonin release and block neuronal serotonin uptake.

Pharmacokinetics

Good oral BA Metabolized by the liver Vd = 333 L/kg Pemoline, with Vd = 0.20.6 L/kg rapidly eliminated in an acidic urine

Toxic Dose

low therapeutic index 1mg/kg of dextroamphetamine=FATAL high degree of tolerance can develop after repeated use

ACUTE INTOXICATION
SYMPATHOMIMETIC TOXIDROME:
Agitation Anxiety AMS Mydriasis HPN Tachycardia Diaphoresis Tremor Muscle Rigidity Hyperthermia Seizures

CHRONIC INTOXICATION

Anorexia Paranoia Cardiomyopathy Pulmonary HPN Vasculitis Aortic & Mitral Regurgitation

TREATMENT
No specific antidote Hypertension Phentolamine nitroprusside Tachyarrhythmia Propranolol/esmolol Arterial vasospasms Ergots Seizures Benzodiazephine

COCAINE
Erythroxylum coca Route of administration Intranasal Inhalation IV Ingestion Most rapid onset of action? Longest duration of action?

COCAINE

Crack Most addictive form of cocaine Easily volatilizes More heat stable Speed ball IV inj. Combo of cocaine & heroin

MECHANISM TOXICITY
Local anesthetic CNS stimulation, and inhibition of neuronal catecholamines. CV effects:

uptake

of

Blockade of Na channel Depression of conduction contractility

&

PHARMACOKINETICS

Metabolism: Plasma & liver Cocaethylene Longer half life Significantly sudden death Less euphoria

TOXIC DOSE

Rapid intravenous injection or smoking transient high brain and heart levels resulting in convulsions or cardiac arrhythmias

TOXIC DOSE

intranasal local anesthesia is 100 200 mg (12 mL of 10% solution). snorted contains 2030 mg or more Crack is usually sold in pellets or rocks containing 100150 mg 1 g=FATAL

ACUTE INTOXICATION

CNS (30-60 MINS) Cerebral ischemia/infarction Intracranial hemorrhage Agitation Delirium psychosis, tremulousness, muscle rigidity or hyperactivity, and seizures

ACUTE INTOXICATION

Cardiovascular effects Myocardial infarction Cardiac arrythmias Stroke HPN

ACUTE INTOXICATION

Other effects:
Shock Cocaine induced chest pain (5%) Hammonds Crunch Nasal septum perforation Coke burns

TREATMENT

Detection: Blood & urine samples Agitation Benzodiazepines Angina pectoris Nitrates

DEXTROMETORPHAN

OTC Antitussive D-isomer of 3-methoxy-Nmethylmorphinan Triple Cs Dex DXM

MECHANISM OF TOXICITY

Serotonin reuptake inhibition

Serotonin syndrome

NMDA receptor antagonism O-methylated DXM HBr=Bromide poisoning

PHARMACOKINETICS

Orally absorbed Crosses the BB High affinity to Debrisoquin hydroxylase enzyme (P450IIDC) RM: t1/2= 3-4 hours PM: t1/2= > 24 hours Onset of therapeutic action= 15-30 mins.

TOXIC DOSE

>10mg/kg Usual dose adult= 60-120 mg/d Children= 30mg/d

CLINICAL PRESENTATION

Serotonin Syndrome
SSRIs Hyperthermia Muscle rigidity Hypertension

Anticholinergic Toxidrome
DXM+anticholinergic

CLINICAL PRESENTATION
Dizziness Ataxia Hallucinations Dystonias Miosis Nystagmus Coma, stupor Respiratory depression

TREATMENT

ANTIDOTE: Naloxone 0.06-0.4mg

GAMMA HYROXYBUTYRATE

Structural analog of GABA Original indication: Anesthesia Delirium Myoclonus Bradycardia Xyrem(Oxybate) Club Drug, Rape drug

GAMMA HYROXYBUTYRATE
Cherry Meth, Easy Lay, G caps, Gamma Hydrate, Georgia Home Boy, Grievous Bodily Harm, Liquid E, Liquid Ecstasy, Natural Sleep-500, Oxy-sleep, Scoop, Soap, Somatomax PM, Vita G

OTHER CHEMICALS RELATED TO GHB

GBL Gamma-butyrolactone Hydrolysis 1,4 BD 1,4butanediolHydroxybutyraldeha yde-> GHB

MECHANISM OF TOXICITY

GHB CNS depressant effect Acts on GABA General anesthesia Respiratory depression Death

PHARMACOKINETICS
Onset of CNS depressant effects begins within 1015 minutes after oral ingestion of GHB and 28 minutes after intravenous injection. Peak effects occur within 2545 minutes, depending on the dose. The duration of effect is 12.5 hours after anesthetic doses of 5060 mg/kg

TOXIC DOSE

GHB: 30 mg/kg Abrupt onset of sleep Enuresis Hallucinations 50mg/kg unconciousness 60mg/kg: deep coma

TOXIC DOSE
GBL: 1.5 g produced sleep lasting 1 hour. 1,4-BD is equipotent to GHB, although in the presence of ethanol, competition for the metabolic enzyme alcohol dehydrogenase may delay or decrease the peak effect.

CLINICAL PRESENTATION
Soporific & euphoria: within 15 mins PO Delirium and tonic-clonic seizures are possible. Bradypnea Cheyne-Stokes respiration Vomiting is seen in 3050% of cases, Incontinence may occur. tachycardia and mild hypertension

HALLUCINOGENS

Entactogens LSD MDMA AMT DMT Mescaline Psilocybin

NATURAL HALLUCINOGENS
SALVINORIN A BUFOTENINE Salvia divinorum Bufo alvaris

MESCALINE PSILOCIN

Lophophora williamsii Psilocybe sp.

LYSERGIC ACID Ipomea violacea HYDROYETHYLAMIDE

Myristicin

Nutmeg

MECHANISM OF TOXICITY

stimuLates 5-HT2receptors alter the activity of serotonin and dopamine in the brain Central and peripheral sympathetic stimulation : anxiety, psychosis, dilated pupils, and hyperthermia Neurotoxic (MDMA)

CLINICAL PRESENTATION
Bad trippin tachycardia, Mydriasis diaphoresis, bruxism, short attention span tremor, hyperreflexia, hypertension, and fever.

PSYCHOTROPIC EFFECTS

Visual & auditory hallucinations Time distortion Synesthesia Intense color perception Feelings ecstasy or terror

TREATMENT

Supportive care IV fluid for rhadomyolysis Benzodiazephine Quiet, dark, nonstimulating environment

MARIJUANA

Cannabis sativa THC MJ pot piff magic clover

COMMON FORMS OF CANNABIS

Marijuana Hashish Kief Bhang Budder

TERMS

Bong Pipe used to smoke MJ Reefers/Joint Cigarette made by rolling MJ

WAYS HOW TO INGEST MJ

Baked goods Bhang Green Dragon

MECHANISM OF ACTION
binds to anandamide receptors in the brain, may have stimulant, sedative, or hallucinogenic actions depending on the dose and time after consumption. Catecholamine release (resulting in tachycardia) and Inhibition of sympathetic reflexes (resulting in orthostatic hypotension)

PHARMACOKINETICS
1020% of ingested dronabinol is absorbed, with onset of effects within 3060 minutes and peak absorption at 24 hours. Metabolized by hydroxylation to active and inactive metabolites. Elimination half-life is 2030 hours, but may be longer in chronic users.

TOXIC DOSE
Typical marijuana cigarettes contain 13% THC, More potent: contain up to 15% THC. Hashish contains 36% and hashish oil 3050% THC. Dronabinol is available in 2.5-, 5-, and 10-mg capsules

ACUTE MJ USE

Tachycardia Orthostatic hypotension Conjunctival erythema IOP Slurred speech Ataxia

CHRONIC MJ USE

Amotivational syndrome Obesity pulmonary disease

Subjective Effects
euphoria, palpitations, heightened sensory awareness, and altered time perception followed after about 30 minutes by sedation. More severe intoxication: impaired short-term memory, depersonalization, visual hallucinations, and acute paranoid psychosis.

PHYSICAL FINDINGS
Tachycardia, orthostatic hypotension, conjunctival injection, incoordination, slurred speech, and ataxia. Stupor with pallor,

NICOTINE
Ingestion of chewing tobbaco Ingestion of cigarettes Ingestion of or dermal exposure to nicotine containing pesticide Ingestion of or dermal exposure to nicotine replacement product

MECHANISM OF TOXICITY
binds to nicotinic cholinergic receptors, resulting initially, via actions on ganglia, in predominantly sympathetic nervous stimulation. With higher doses, parasympathetic stimulation and then ganglionic and neuromuscular blockage may occur. Direct effects on the brain may also result in vomiting and seizures.

TOXIC DOSE
25 mg can cause nausea and vomiting 4060 mg in an adult is said to be lethal Cigarette tobacco=1.5% nicotine, or 1015 mg of nicotine per cigarette. Moist snuff =1.5% nicotine; most containers hold 30 g of tobacco. Chewing tobacco=2.58% nicotine

TOXIC DOSE
Nicotine gum= 2 or 4 mg per piece Transdermal nicotine patchesdeliver an average of 522 mg of nicotine over the 1624 hours of intended application, depending on the brand and size. Nicotine nasal spraydelivers about 1 mg

CLINICAL PRESENTATION
N&V Diarrhea Abdominal pain Salivation Diaphoresis Pallor Agitation then lethargy

CLINICAL PRESENTATION
increase in: HR BP RR Severe CNS depression Muscle fasciculations then paralysis seizure

TREATMENT

Atropine Bronchorrhea Cardiac depression Benzodiazephine

Seizures

Mecamylamine

OPIATES & OPOIDS

Opoids: Morphine Codeine Heroin Opiates: Fentanyl Butorphanol meperidine

MECHANISM OF TOXICITY
opioids share the ability to stimulate a number of specific opiate receptors in the CNS,sedation and respiratory depression. Death results from respiratory failure: apnea or pulmonary aspiration of gastric contents.

PHARMACOKINETICS
Peak effects occur within 23 hours, but absorption may be slowed by their pharmacologic effects on gastrointestinal motility. Most drugs have large volumes of distribution (35 L/kg). The rate of elimination is highly variable, from 12 hours fentanyl derivatives versus 1530 hours for methadone

TRIAD OF SYMPTOMS
Miosis Tramadol, propoxyphene, meperidine CNS depression Respiratory depression Cause of most opoid related deaths Mu & delta receptors=brainstem respiratory centers Bronchospasms, pulmonary edema Fentanyl: chest wall rigidity

Other symptoms
CV effects
Hypotension Bradycardia

Dermatological
Pruritus Flushing

 Propoxyphene & norpropoxyphene

QRS prolongation

Meperidine
Serotonin syndrome

Antidote: Naloxone
0.4-2mg (+) t1/2=renal failure

PHENCYCLIDINE (PCP)
Dissociative anesthetic agent with properties similar to those of ketamine peace pill, angel dust, hog, goon, animal tranquilizer, and krystal.

MECHANISM OF TOXICITY

NMDA antagonism Reuptake of cathecholamines Modulation of sigma opoid receptors

PHARMACOKINETICS
PCP is rapidly absorbed by inhalation or ingestion. (Vd) is about 6 L/kg. The duration of clinical effects after an overdose is highly variable and ranges from 1114 hours in one report to 14 days in another. PCP is eliminated mainly by hepatic metabolism, although renal and gastric excretion account for a small fraction and are pH dependent.

TOXIC DOSE
16 mg, which results in hallucinations, euphoria, and disinhibition. Ingestion of 610 mg causes toxic psychosis and signs of sympathomimetic stimulation 150200 mg has resulted in death

MILD INTOXICATION
Lethargy Euphoria hallucinations Quiet catatonia and loud or agitated behavior. Vertical and horizontal nystagmus are prominent

SEVERE INTOXICATION
adrenergic hyperactivity, including hypertension, rigidity, localized dystonic reactions, hyperthermia, tachycardia, diaphoresis, convulsions, and coma. The pupils are sometimes paradoxically small. Death may occur as a result of self-destructive behavior or as a complication of hyperthermia (eg, rhabdomyolysis, renal failure, coagulopathy, or brain damage).

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