cocaine, stimulants, and mdma. asam’s 2008 review course in addiction medicine accme required...
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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
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.
Overview
Background Stimulant- structure and pharmacology Neurobiology of stimulant addiction Management of acute intoxication and
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
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
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
Background Stimulant- structure and pharmacology Neurobiology of stimulant addiction Management of acute intoxication and
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
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
Background Stimulant- structure and pharmacology Neurobiology of stimulant addiction Management of acute intoxication and
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)
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.
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