Transcript Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

 PRESCRIPTION DRUG ABUSE
Pharmacology: Drugs and Disease - Feb. 25, 2004
Greg Connell, Ph.D.
Office: 3-126 BSBE; Phone: 624-3132
Email:[email protected]
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 t
signal transduction mechanism
• alteration of the drug’s metabolism
Physical Dependence
1: Definitions
B. Tolerance
 Occurs when increasing amounts of the drug are requi
to achieve the same physiological or psychological effect.
 Indicative of the development of a physical dependence
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
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 behavior
were shaped by natural selection to maximize Darwinian
fitness.
 “Love joins hate, aggression, fear expansiveness,
withdrawal and so on, in blends designed not to promote
the happiness of the individual, but to favor the maximum
transmission 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
B. A Biochemical Perspective
 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 mediate
the transition from occasional controlled drug use to addiction
are only just beginning to be understood.
Biochemistry of Drug Abuse
 Drug use results in changes to specific neurotransmitter systems
within a highly limited band of structures including specific
parts of the amygdala and nucleus accumbens.
Biochemistry of Drug Abuse
 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.
Biochemistry of Drug Abuse
OH
OH
(dopamine)
CH2CH2NH2
g
dopamine
receptor
GTP
adenyl
cyclase
B
Gs
ATP
GDP
cAMP
cAMP dependent
kinase
alterations in
gene expression
cAMP response elementbinding protein
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 certain
significant events and by underscoring such events the
dopamine 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
3. Prescription Drugs with Abuse Potential
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 life
threatening. Symptoms can include opioid craving,
irritability, hyperalgesia, cramps, muscle aches,
nausea/vomiting, mydriasis, sweating, tachycardia,
hypertension, fever.
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
 clonidine: a2 agonist reduces aspects of withdrawal
 naltrexone
3. Prescription Drugs with Abuse Potential
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-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
3. Prescription Drugs with Abuse Potential
C: Stimulants
C.1: amphetamine
i. structure:
CH2
CH
NH2
CH3
• 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
• 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 schizophrenialike reaction
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.
3. Prescription Drugs with Abuse Potential
D. Marijuana (D  -tetrahydrocannibinol)
i. therapeutic uses:
1. Approved (THC) for the prevention of nausea and
stimulation of appetite in cancer patients receiving
chemotherapy and in patients with AIDS.
2. Other uses that are not approved include: reduction of
the intraocular pressure in glaucoma, analgesic, muscle
relaxant.
ii. mechanism of action: agonist acting on the endogenous
cannabinoid 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 often
related directly or indirectly to drug abuse
 A personal responsibility not to become an easy target for
diversion
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
6. Physicians Who Prescribe Inappropriately
 Common causes for Minnesota Medical Practice actions:
• prescribing for patients with known dependencies or
addiction 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 Prescription
Drug 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 that
missing 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