Stimulants

Cocaine, Stimulants, and MDMA

ASAM’s 2008 Review Course

in Addiction Medicine ACCME required disclosure of

relevant commercial relationships:

Dr. Drexler has nothing to disclose.

Objectives

The participant will be able to understand: How chemical structure of stimulants

influences pharmacology Basic neurobiology of stimulant

dependence How to recognize and manage acute

stimulant intoxication and withdrawal

Overview

Background Stimulant- structure and pharmacology Neurobiology of stimulant addiction Management of acute intoxication and

withdrawal Relapse Prevention

Background

Stimulants have been used by humans for thousands of years to increase energy.

Plant-derived stimulants have been refined and new drugs developed to increase potency and duration.

As potency increases negative effects become apparent.

History of Stimulant Use 3000 B.C. – Ma-Huang 0 A.D. – Coca leaf chewing and

coca tea 1860 – Cocaine isolated 1887 – Amphetamine synthesized 1914 – Harrison Narcotic Act

MDMA 1919 – Methamphetamine 1930s – Benzedrine inhaler 1959 – Benzedrine banned 1980s – Crack

Epidemiology

Cocaine 2nd most widely used illicit drug in U.S. Most frequent illicit drug in ED visits In 2004 (NHSDA and DAWN)

11.2% lifetime use; 1.5% past year; 0.8% past month

2.7% lifetime prevalence of dependence 19% of drug-related ER visits 39% of drug-related deaths

Cocaine Abuse/Addiction Liability

Epidemiology

Synthetic Stimulants Non-prescription use peaked at 1.3% in 1985 In 2004 (NHSDA)

6.6% lifetime non-prescription use 1.7% lifetime prevalence of dependence Methamphetamine

Most commonly used synthetic stimulant In 2004, 59% of users had a use disorder

Up from 27.5 % in 2002.

Methamphetamine Lab Seizures

Trends in Illicit Drug Use

Trends in Methamphetamine Use

Trends in Drug Use Disorders

Club Drugs Epidemiology DAWN, July 2001

Overview


withdrawal

Structure and Pharmacology

All stimulant drugs share a common basic phenylalkylamine structure. Additions to the phenyl group tend to increase

hallucinogenic properties. Additions of a methyl group to the nitrogen

atom tend to increase the stimulant properties.

N

OHOH

Stimulant Drugs

Plant-derived Caffeine Cocaine Ephedra Khat

Synthetic Amphetamine Methamphetamine Methylphenidate Mazindol Phenylpropanolamine Ephedrine Pseudoephedrine Phenylephrine MDA / MDMA*

Clinical Uses of Stimulants

Drug Trade name Street name CSA Indications

Amphetamine Adderal

Dexedrine

Amp, Dex

Bennies

II ADHD, Wt control Narcolepsy

Cocaine Coke, Crack

Flake, Snow

II Local anesthetic

Mazindol Sanorex IV Wt control

Methamphetamine Adipex

Desoxyn

Ice, crystal

Meth, Speed

II ADHD

Wt control

Methylphenidate Ritalin Rits, Vit R II ADHD

Narcolepsy

Cocaine Chemical Properties

Cocaine HCl High melting point

(195°C) Pyrolysis destroys

most of the drug Soluble in water

(EtOH:H2O = 1:8) Easily dissolved for

injection or absorption across mucous membranes

Crack or Freebase Low melting point

(98°C) Easy to smoke Insoluble in water

(EtOH:H2O = 100:1) Difficult to dissolve for

injection

Stimulant Chemical Properties

Most variations on phenylethylamine Phenylisopropylamine stimulants have

stereoisomers D-isomers - 3 – 5 times more CNS activity

D-methamphetamine – potent stimulant L-methamphetamine- OTC decongestant

N

OHOH

MDMA Properties

3,4- Methylenedioxymethamphetamine

Stimulant, hallucinogenic, empathogenic Taken orally as a pill

50 mg to 250 mg “Stacking” with other drugs (LSD, DM, ephedra)

Non-linear kinetics Saturation of high-affinity enzymes Large increase in response to small dose increase

Clinical Uses of Stimulants

Prescription cocaine Local anesthetic

Prescription stimulants ADHD Narcolepsy Weight loss Bronchdilation Depression, pain*

Parenteral phenylephrine Spinal anesthesia Antihypotensive Terminate SVT

OTC stimulants Decongestion Bronchodilation

None for MDMA

Methamphetamine

Brand name: Desoxyn ADHD: 20 – 25 mg / day Obesity: 15 mg / day Binge: 125 mg – 1000

mg/dose Toxic doses*:

4- 6 mg/kg q2h (>3 gm/day) 37% loss of dopamine

*Segal et al: 2003; Neuropsychopharmacology

Pharmacokinetics

Smoking and IV Reaches brain in 6 – 8

seconds Onset of action and

peak occur in minutes Rapid decline in effect Rapid onset of

withdrawal symptoms and craving

Intranasal and oral Slower absorption and

peak effect (30 – 45 minutes)

Longer peak effect and gradual decline

Peak intensity less than smoking or IV

Alkalinization enhances absorption

Pharmacokinetics

Smoked

Oral

Metabolism and Elimination

Cocaine Hydrolysis of ester

bonds Ecgonine methylester Benzoylecgonine

Cytochrome P450 Eliminated in urine

Benzoylecgonine detectable for ~3 days

Acidifying s excretion

Amphetamines To metabolites

Deamination- inactive Oxidation- active Parahydroxylation-

active

Eliminated in urine- Increased by lower pH

Drug Interactions

Other stimulants- sympathetic activity Cardiac arrhythmia Hypertension Seizure Death

MAOIs- inhibit metabolism of stimulants Tricyclics- may block presynaptic uptake Cocaine + EtOH = cocaethylene

cardiac toxicity due to longer half-life

Stimulant Effects

Range of effects vary depending on Structure Dose Route of administration Duration and intensity of use

Typical initial doses for desired effects: 5 to 20 mg of oral amphetamine, methylphenidate 100 to 200 mg of oral cocaine 15 to 20 mg of smoked cocaine 50 to 250 mg of MDMA

Acute Stimulant Effects

CNS Euphoria (low dose)

energy, alertness sociability appetite

Dysphoria (high dose) Anxiety, panic attacks Irritability, agitation Suspciousness Psychosis Movement disorders Seizures

Cardiovascular HR, BP, vascular

resistance, temperature Acute myocardial infarction

(AMI), ischemia, arrhythmia

Stroke

Pulmonary Shortness of breath Bronchospasm Pulmonary edema

Acute Stimulant Effects (cont)

Musculoskeletal Rhabdomyolysis

Renal Acute renal failure

secondary to myoglobinuria

Endocrine Ketoacidosis in

diabetics Activation of HPA

Sexual function Increased arousal Prolonged erections

Head and neck Chronic rhinitis, nasal

septal perforation Xerostomia Bruxism

Fetal effects Most Category C

Mechanisms of Action

All stimulants enhance monoamine activity Inhibition of presynaptic monoamine

transporters Dopamine – reward, psychosis Norephinephrine – physiological arousal Sertonin – mood elevation, psychosis

OTC stimulants bind to and activate norepinephrine receptors

Mesocorticolimbic Pathway

Ventral tegmental area

Nucleus accumbens

Anterior cingulate

Prefrontal cortex

Dopamine (DA)

Stimulants acutely enhance dopamine activity Cocaine, methylphenidate- transporter blockers Amphetamines- false substrates

Stimulants chronically deplete dopamine DA activity key in mediating addictive potential

Fluctuations in mesolimbic DA parallel cocaine self-administration

Stimulant potency correlates with potency for binding at DA transporter

CocaineMicrodialysis in Awake Squirrel Monkeys

Norepinephrine (NE)

Stimulants acutely block NE transporter plasma NE and epinephine NE release correlates with subjective and

physiological stimulant effects Ephedrine related compounds stimulate

alpha-adrenergic NE receptors

Serotonin (5-HT)

All stimulants acutely enhance 5-HT activity by blocking serotonin transporter MDMA s 5-HT by blocking transporters Cocaine acutely s firing in mesolimbic

serotonergic neurons, but s firing in dorsal raphe nucleus

Serotonin appears to play a permissive, but not obligatory role in reward

Other Neurotransmitters

Endogenous opioid activity No direct stimulant effect Cocaine indirectly s

Mesolimbic glutamate Cocaine s Amphetamine s

Acetylcholine Cocaine s

Sodium channel blockade (cocaine only)

Overview


withdrawal

DSM-IV Substance Dependence

>/= 3 of the following over a 12-month period: Tolerance Characteristic withdrawal Larger amounts than intended Persistent efforts to cut down or control use A great deal of time spent getting the substance,

taking it, or recovering Important activities given up or reduced Continued use despite psychological or physical

problem caused by or exacerbated by use

Neurobiology of Dependence

Sensitization of incentive salience Drug Conditioned cues

Impairment of inhibition of urges to use Chronic effects of drug

Signal transduction Gene transcription

Mesocorticolimbic Pathway

Ventral tegmental area

Nucleus accumbens

Anterior cingulate

Prefrontal cortex

Amygdala – Limbic Connections

Nucleus accumbens

Amygdala

Prefrontal - Limbic Inhibition

Nucleus accumbens

Orbitofrontal cortex

Left Right

-34 mm

-19 mm

-9 mm

+34 mm

+19 mm

+9 mm

insula

anteriorcingulate

amygdala

subcallosalcortex nucleus

accumbensarea

drug use - neutral

Cocaine craving-related neural activations: Men

Overview


withdrawal

Initial Evaluation of Stimulant Intoxication

Drug history Physical examination Laboratory examination Manage basic life support functions

T> 102°F – Cooling blanket T> 106°F – Cool saline hydration, ice water lavage

Remove drug from GI tract Activated charcoal or gastric lavage If within one hour of ingestion

Management of Severe Agitation

Benzodiazepines- first line Protect against CNS and cardiovascular toxicity Lorazepam 2 – 4 mg PO or IV q 15 min until

sedate Repeat every 1 – 3 hours

Antipsychotics- second line May prevent heat dissipation, lower seizure

threshold, prolong QTc, increase dyskinesias Haloperidol 2 to 10 mg PO, IM or IV q 6 – 24 hours

Avoid physical restraints

Cardiovascular Effects of Stimulants

Myocardial ischemia is common. Vasoconstriction Increased myocardial workload Increased platelet aggregation

Differential - AMI, aortic dissection, pneumothorax, endocarditis, or pneumonia

Arrhythmias Due to ischemia, catecholamines, or sodium

channel blockade

Management of Chest Pain

Observe for 12 – 24 hours ECG-

Low sensitivity (36%) Low predictive value (18%)

Cardiac enzymes: Serial CPK- MB or troponin

~ 15% of patients with stimulant-induced chest pain will have AMI.

Management of Arrhythmias

Treat underlying conditions AMI Electrolyte and acid-base abnormalities Hypoxia

Many will resolve without treatment Avoid Class I antiarrhythic drugs Follow ACLS guidelines

Management of Seizures

Benzodiazepines Lorazepam 2 to 10 mg IV over 2 minutes Diazepam 5 to 10 mg IV over 2 minutes Repeat as needed Monitor respirations, intubation available

Management of Rhabdomyolysis

Diagnosis requires high suspicion Muscle swelling and myalgia often absent Plasma CK > 5 times normal Urinalysis positive for heme without RBCs

IV hydration – urine output 2 ml/kg/hour Urine pH > 5.6 – sodium bicarbonate

Management of Hypertension

Benzodiazepines first line Lower myocardial oxygen demand Lower seizure risk*

If severe hypertension persists Alpha-adrenergic blocker

Phentolamine 2 to 20 mg IV over 10 min No beta-adrenergic blockers

Unopposed alpha stimulation s vasoconstriction

DSM-IV Cocaine Withdrawal

A. Cessation of (or reduction in) cocaine use that has been heavy and prolonged.

B. Dysphoric mood and two (or more) : Fatigue Vivid, unpleasant dreams Insomnia or hypersomnia Increased appetite Psychomotor retardation or agitation

Management of Withdrawal

Most symptoms resolve within 2 weeks without treatment

Hospitalization for suicidality or psychosis Pharmacologic treatment not necessary

Relapse Prevention

Psychosocial treatment Cognitive behavioral

therapy (CBT) Contingency management

(MIEDAR) 12-step facilitation- ? Motivation Enhancement

Therapy- ? MATRIX model

Treat comorbidities

Pharmacotherapy No FDA approved

medications Antidepressants Dopaminergic agents Disulfiram Anticonvulsants (GVG,

topiramate)

Disulfiram Patients Have Less Cocaine Use

Carroll et al, 2004

Modafinil Decreases Cocaine Use

Dackis 2005

Summary

Stimulants are common causes of drug-related morbidity and mortality.

Chemical structure of stimulants relates to the pharmacologic properties.

Neurobiology of stimulant addiction is related to blockade of monoamine transporters.

Management of acute intoxication and withdrawal is symptom driven.

Relapse prevention is based on comprehensive biopsychosocial treatment.

Documents

Stimulants