Drug Abuse

Greg Connell, Ph.D.Office: 3-126 BSBE; Phone: 624-3132 Email:[email protected]

PRESCRIPTION DRUG ABUSE

Pharmacology: Drugs and Disease - Feb. 25, 2004

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

7. Protecting yourself from the professional patient

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

• decreased efficiency of the coupling of the receptor to thesignal transduction mechanism

• alteration of the drug’s metabolism

Physical Dependence

1: Definitions

B. Tolerance

Occurs when increasing amounts of the drug are requiredto achieve the same physiological or psychological effect.

Indicative of the development of a physical dependence.

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 tobe 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 isnecessary 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 drugfor non-medical purposes resulting in either a psychic and/or physical dependence.

G. Drug misuse

Results from either ill advised patterns of prescribing byphysicians 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

3. Emergence of a negative emotional state when access to the drug is prevented

2: Biological Basis of Drug Abuse

A. An Evolutionary Perspective

The neural mechanisms that regulate emotion and behaviorwere shaped by natural selection to maximize Darwinianfitness.

“Love joins hate, aggression, fear expansiveness, withdrawal and so on, in blends designed not to promotethe happiness of the individual, but to favor the maximumtransmission of the controlling genes “ (E.O. Wilson)

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.

2: Biological Basis of Drug Abuse

The occasional use of an abusable drug is distinct from repeated use and the emergence of chronic drug addiction.

The cellular and molecular mechanisms that mediatethe transition from occasional controlled drug use to addictionare only just beginning to be understood.

B. A Biochemical Perspective

Biochemistry of Drug Abuse

Drug use results in changes to specific neurotransmitter systemswithin a highly limited band of structures including specificparts of the amygdala and nucleus accumbens.


Changes occur in the signals mediated by several neurotransmitters including but not limited to dopamine, opioid peptides and cotropin-releasing factor.

Increases in neurotransmitter concentrations can result in several short-term and long-term changes.


receptor

Gs

GTP GDP

adenylcyclase

ATP

cAMP

cAMP dependentkinase

dopamine

CH2CH2NH2

OH

OH

cAMP response element-binding protein

alterations in gene expression

(dopamine)

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.

Facilitated Learning Hypothesis

Dopamine release highlights or draws attention to certainsignificant events and by underscoring such events thedopamine signal helps the animal to learn to recognize them and in some cases to repeat them.

3. Prescription Drugs with Abuse Potential

Drugs that produce a pleasurable effect such as an elevated mood, euphoria or calming.

Drugs that do not produce a mood altering effect are rarely intentionally abused.

• an exception is anabolic steroid use by athletes


A. Opioid agonists -heroin, morphine, meperidine, oxymorphone, hydrocodone, fentanyl, sufentanil

i. abuse potential: (+++) high

ii. acute intoxication: euphoria, rush sedation

iii. withdrawal symptoms: (+++) high but are rarely lifethreatening. Symptoms can include opioid craving, irritability, hyperalgesia, cramps, muscle aches, nausea/vomiting, mydriasis, sweating, tachycardia,hypertension, fever.

Opioid Agonists

iv. additional consequences: (+++) high; life-expectancydecreased by 50%; i.v. users risk HIV infection.

v. treatment switch from short-acting drug to long-acting drug likemethadone

clonidine:2 agonist reduces aspects of withdrawal

naltrexone


B. anxiolytic-sedative-hypnotics

B.1: Barbituates: secobarbitol, pentobarbitol, amobarbitol

i. abuse potential: (+++) high

ii. Acute intoxication: 1. Stimulant-like effects at low doses: euphoria, increased talkativeness

2. Depressant at high doses: ataxia, slurred speech

Anxiolytic-Sedative-HypnoticsB.1: Barbituates

iii. withdrawal symptoms: (+++) high; life threatening, tremor, nausea, sweating, hypertension, seizures

iv. additional consequences: (+++) high; death fromoverdose, 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

3. Prescription Drugs with Abuse PotentialC: Stimulants

C.1: amphetaminei. structure:

• 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

CH CH NH2 2CH3

Amphetamine

ii. function: • increases the synaptic dopamine concentration resultingin an increased state of wakefulness and attentiveness.

• acts primarily on two areas of brain: 1. reticular activating system (regulation of sensoryinput into the brain)

2. medial forebrain bundle (pleasure center)

Amphetamine

iii. clinical uses: • narcolepsy

• attention deficit hyperactivity disorder (ADHD)

• appetite suppression -discouraged now because there is significant abuse potential

iv. adverse effects:

• cardiovascular side effects

•irritability, nervousness, restlessness

•long-term intoxication can result in a schizophrenia-like reaction

Amphetamine

v. abuse potential: (++++++) very high

vii. withdrawal symptoms: (+) low; drug craving, fatigue,bradycardia

viii. additional consequences: (+++) high; depression, toxic-psychosis, cerebrovascular and cardiovascularaccidents

vi. acute intoxication: euphoria, increased alertness,increased motor activity

StimulantsC.2 Methylphenydate (Ritalin)

Structure, clinical uses, adverse effects and withdrawal symptoms similar to amphetamine.

Mild CNS stimulant that does not have significantperipheral actions.

Mechanism of action is not completely understood, but it may involve blockage of dopamine uptake.

3. Prescription Drugs with Abuse PotentialD. Marijuana ( -tetrahydrocannibinol)

i. therapeutic uses:

1. Approved (THC) for the prevention of nausea andstimulation of appetite in cancer patients receivingchemotherapy and in patients with AIDS.

2. Other uses that are not approved include: reduction ofthe intraocular pressure in glaucoma, analgesic, muscle relaxant.

ii. mechanism of action: agonist acting on the endogenouscannabinoid receptors

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

4. Reasons to be Aware of a Drug Abuse Potential

A professional responsibility to prescribe drugs appropriately

The physical and mental condition of the patient is oftenrelated directly or indirectly to drug abuse

A personal responsibility not to become an easy target for diversion

5. Individuals of Concern

The “professional patient”

Health care professionals - potential for self-medication

• Type I patient - obtains drugs of abuse through deceptionof health care providers.

• Type II patient - initially takes drugs for a legitimatemedical condition but later becomes addicted.

6. Physicians Who Prescribe Inappropriately

Common causes for Minnesota Medical Practice actions:

• prescribing for patients with known dependencies oraddiction histories

• prescribing controlled substances for chronic pain,anxiety or insomnia without proper reassessment.

• prescribing without performing physical examinations.

• prescribing in the face of known drug interactions.

6. Physicians Who Prescribe Inappropriately

“The Four “Ds” - Physicians as sources of drug diversion(AMA National Informal Steering Committee on PrescriptionDrug Abuse)

• dishonest

• disabled

• deceived

• dated

7. Protecting Yourself from the Type I Patient

Protection of prescription pads• store unused prescription pads in a safe place

• minimize the number of pads in use at one time

• have prescription blanks numbered consecutively so thatmissing sheets would be detected

• never sign prescription blanks in advance

• Write out the actual quantity in addition to using an Arabic or Roman numeral

• Do not use prescription blanks for writing notes or memos

7. Protecting Yourself from the Type I Patient

Patient behavior which may suggest drug abuse• request for specific medications

• request for higher or more frequent dosing

• claims of allergy or lack of efficacy of specific drugs

• evasive answers regarding medical history

• traveling through town -not a resident

• does not give name of primary or referring physician

• claims to have lost prescription

• requests appointment for late afternoon

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

Drug Abuse

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