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Pharmacology: Drugs and Disease - Feb. 25, 2004 Greg Connell, Ph.D. Office: 3-126 BSBE; Phone: 624-3132 Email:gconnell@lenti.med.umn.edu
Drug Abuse
Overview
1. Definitions 2. Biological basis of drug abuse 3. Prescription drugs with abuse potential 4. Reasons to be aware of a potential for drug abuse 5. Individuals to be concerned about 6. Physicians who prescribe inappropriately
1: Definitions
A. Physical dependence A normal physiological adaptation to repeated use of some categories of drugs Examples may include: down-regulation of receptor number
Physical Dependence
1: Definitions
B. Tolerance
Occurs when increasing amounts of the drug are requi to achieve the same physiological or psychological effect.
Tolerance
Tolerance
1: Definitions
C. Cross-tolerance The development of tolerance to one drug also increases tolerance to related drug categories
1: Definitions
D. Withdrawal syndrome Occurs when drug administration to a physically dependent person is abruptly terminated
Symptoms are characteristic of the class of drug and tend to be opposite the original effects of the drug before tolerance developed
Withdrawal Syndrome
1: Definitions
E. Psychic or psychological dependence The individual believes that the presence of the drug is necessary to maintain a state of well being. All major drugs of abuse produce a negative emotional state in dependent humans during acute abstinence. Regaining a sense of well-being provides a positive reinforcement or craving for continued abuse
1: Definitions
F. Drug abuse A behavioral definition: the self-administration of a drug for non-medical purposes resulting in either a psychic and/or physical dependence.
G. Drug misuse Results from either ill advised patterns of prescribing by physicians or improper use by patients within the context of medical treatment.
1: Definitions
H. Addiction
A behavioral definition: recurrent drug use becomes the primary goal and disrupts the ability to function in family social or career settings rather than being an incidental part of life. Characterized by three major elements: 1. Compulsion to seek and take the drug 2. Loss of control in limiting intake
An Evolutionary Perspective
Drugs of abuse are inherently pathogenic because they create a signal in the brain that indicates, falsely, the arrival of a huge fitness benefit and thereby hijack the incentive mechanisms of liking and wanting.
The cellular and molecular mechanisms that mediate the transition from occasional controlled drug use to addiction are only just beginning to be understood.
(dopamine)
CH2CH2NH2
B Gs
GDP
cAMP
cAMP dependent kinase
Significance of Dopamine
Sex, chocolate, alcohol, marijuana, amphetamine, cocaine, nicotine and heroin all directly or indirectly increase the synaptic dopamine concentration within a highly localized region of the brain.
Dopamine system plays a fundamental role in encouraging behaviors, such as feeding, needed for life in organisms ranging from slugs to primates.
Drugs that do not produce a mood altering effect are rarely intentionally abused.
an exception is anabolic steroid use by athletes
Opioid Agonists
iv. additional consequences: (+++) high; life-expectancy decreased by 50%; i.v. users risk HIV infection. v. treatment switch from short-acting drug to long-acting drug like methadone
i.
ii. Acute intoxication: 1. Stimulant-like effects at low doses: euphoria, increased talkativeness 2. Depressant at high doses: ataxia, slurred speech
Anxiolytic-Sedative-Hypnotics
B.1: Barbituates
iii. withdrawal symptoms: (+++) high; life threatening, tremor, nausea, sweating, hypertension, seizures iv. additional consequences: (+++) high; death from overdose, suicide B.2: Benzodiazepines: diazepam, flurazepam i. abuse potential: (+) low
ii. acute intoxication: similar to barbiturates iii. withdrawal symptoms: (++) intermediate; cramps, agitation, anxiety, rarely seizures
CH2
CH CH3
NH2
amphetamine is a mixture of two stereoisomers: 1. d-isomer (dextroamphetamine) - stimulates the CNS more effectively than the l-isomer 2. l-isomer (levoamphetamine) - stimulates the cardiovasculature system more than the d-isomer
Amphetamine
ii. function: increases the synaptic dopamine concentration resulting in an increased state of wakefulness and attentiveness.
acts primarily on two areas of brain: 1. reticular activating system (regulation of sensory input into the brain) 2. medial forebrain bundle (pleasure center)
Amphetamine
iii. clinical uses: narcolepsy
Amphetamine
v. abuse potential: (++++++) very high vi. acute intoxication: euphoria, increased alertness, increased motor activity vii. withdrawal symptoms: (+) low; drug craving, fatigue, bradycardia viii. additional consequences: (+++) high; depression, toxic-psychosis, cerebrovascular and cardiovascular accidents
Stimulants
C.2 Methylphenydate (Ritalin)
Structure, clinical uses, adverse effects and withdrawal symptoms similar to amphetamine. Mild CNS stimulant that does not have significant peripheral actions. Mechanism of action is not completely understood, but it may involve blockage of dopamine uptake.
Marijuana
iii. abuse potential: (+) low
iv. acute intoxication: euphoria, heightened sensory perception, hallucinations and motor impairment at high doses v. withdrawal symptoms: (+) low; restlessness, irritability, agitation, sleep disturbances, nausea
The physical and mental condition of the patient is often related directly or indirectly to drug abuse
5. Individuals of Concern
The professional patient
Type I patient - obtains drugs of abuse through deception of health care providers.
Type II patient - initially takes drugs for a legitimate medical condition but later becomes addicted. Health care professionals - potential for self-medication
LECTURE OBJECTIVES
1. Understand the following definitions: physical dependence tolerance cross-tolerance withdrawal psychic or psychological dependence drug abuse drug misuse addiction 2. Be aware of the biological basis of addiction and the major classes of abused drugs: opioids, anxiolytic-sedative-hypnotics, stimulants, marijuana