PRESCRIPTION DRUG ABUSE

Patrick Foley PharmD, BCPP, BCPS

1

A little epidemiology

2

Overview

Prescription Drug AbuseSedative-hypnotics

Barbiturates Benzodiazepines

StimulantsAnalgesics

5

SEDATIVE-HYPNOTICDRUGS

History of mama’s little helper

In the middle of the 19th century, bromide and chloral hydrate replaced alcohol and opium for sedation

Barbiturates replaced these in the early 1900s

Finally the latest improvement were the benzodiazepines in the 1960s

Sedative-Hypnotics

Pharmacology

Affect neurons in a way that causes A state of calm, relaxation, drowsiness, and

eventually sleep Also called tranquilizers and anxiolytics

(anti-anxiety) Largely represented by the barbiturates

and the benzodiazepines

Sedative-Hypnotics

Pharmacology

All carry the risk of inducing physical and psychological dependence

Large degree of tolerance occurs from liver enzyme induction

Cross tolerance common between barbiturates

Sedative-Hypnotics

ETHYL ALCOHOL (CONSUMABLE

ALCOHOL)Fits the criteria (from previous 2 slides) for a sedative-hypnotic

drug

Barbiturates

“Barbs”

First introduced into medicine in 1912 Barbiturates were the drug of choice for

anxiety and insomnia from 1912 to about 1960

PHARMACOKINETICSBarbiturates are classified based

on their pharmacokinetic properties

Absorption

Absorbed from oral and rectal routes to varying degrees

Onset of action is 10-60 minutes following oral ingestion

Onset is almost immediate to 5 minutes following intravenous administration

Pharmacokinetics

Metabolism Broken down slowly in the liver

Pharmacokinetics

Excretion 20-30% unchanged in the urine Remainder is metabolized first and then

excreted in the urine

Duration of action 3-6 hours after IV injection 6-8 hours after oral ingestion

Pharmacokinetics

Half-life

Ranges from 3 hours to 6 days

Readily crosses the placenta

Pharmacokinetics

Pharmacological Effects

Have a low degree of selectivity and a small therapeutic index (dangerous)

DO NOT have analgesic properties Barbs are cognitive inhibitors causing

sedation and depressing memory function

Pharmacological Effects

Sleep patterns are markedly disturbed

Suppress dreaming Rebound REM sleep occurs with

withdrawal Behavioral and motor depression

are similar to that seen with alcohol

Adverse reactions

Drowsiness Impair motor, and intellectual

performance and judgment Additive to alcohol in their effects Sedative doses have minimal effects on

respiration Overdose amounts profoundly depress

respiration

Tolerance

Develops by two mechanisms

Induction of drug-metabolizing enzymes Adaptation of neurons in the brain to the

presence of the drug

Tolerance develops to the sedative effects much faster than to the respiratory depressant effects

Physical Dependence

Normal doses used in medicine can induce physical dependence

Withdrawal from high doses may result in hallucinations, restlessness, disorientation, and life-threatening convulsions

Psychological Dependence

These drugs are prone to abuse because they relieve anxiety and produce a state of euphoria

NON-BARBITURATE SEDATIVE-HYPNOTICS

Carry the same abuse potential as barbiturates Ethchlorvynol, Methylprylon, Methaqualone

(Quaalude®), Meprobamate , Chloral Hydrate Originally used as anxiolytics, daytime

sedatives, and hypnotics Interchangeable pharmacologically with

Barbiturates Rarely used today

Benzodiazepines and Second generation Anxiolytics

Benzodiazepines

Became available in early 1960’s 15 have been released in the US market Became the most widely used class of

drugs in the 60’s Their tendency to produce dependency

as time went on has limited their use Currently still marketed for use as

sedatives/hypnotics, anxiolytics, muscle relaxants, IV anesthetics, and anticonvulsants

Benzodiazepines

Still widely considered drugs of choice for short term treatment of acute anxiety

Behavioral therapies and antidepressants have replaced them for treating chronic anxiety

Absorption Well absorbed orally with peak blood

levels occurring in about 1-2 hours

Pharmacokinetics

Metabolism Many metabolized to active metabolites

prior to being metabolized to in-active compounds

Occurs mainly in the liver

Excretion Mostly eliminated in the urine after being

metabolized

Pharmacokinetics

Half-life Ranges from one hour to greater than 3

days

Pharmacodynamics Agonist of the GABA-benzodiazepine

chloride complex Work as anxiolytics by stimulating

GABA’s action in the Limbic system Anxiolysis occurs because the Amygdala

is depressed and this is the brain center largly associated with fear and anxiety

GABA stimulation in the Cerebral Cortex accounts for side effects such as sedation, increased seizure threshold, and muscle relaxation

Pharmacologic Effects

Stimulation of GABA receptors in the Cerebral Cortex and Hippocampus leads to mental confusion and amnesia

Mild muscle relaxation occurs due to anxiolysis and GABAergic effects in the spinal cord, brain stem, and cerebellum

Stimulation of nerves in the Ventral Tegmentum and Nucleus Accumbens accounts for the behaviorally rewarding aspect

Indications (Uses) Acute anxiety Sedative/hypnotic Muscle relaxant Antegrade amnesia Panic attack Alcohol withdrawal Seizure disorders

Date Rape Drug

Rohypnol® is Flunitrazepam Not marketed in this country Exhibits “Mickey Finn” like action

Side effects and Toxicity

Side effects include Sedation, drowsiness, ataxia, lethargy, mental

confusion, motor and cognitive impairments, disorientation, slurred speech, amnesia, and worsening of dementia

When used for insomnia, some people have a paradoxical agitation effect

Appears to be a ceiling to the respiratory depressant effect and therefore is not as serious a concern as the Barbiturates

Tolerance and Dependence

Especially associated with extended use (>3 weeks)

Rebound increases in insomnia, restlessness, agitation, irritability, seizures, and hallucination

Most withdrawal symptoms subside within 1 to 4 weeks

Those prone to dependence show a pattern of multi-drug abuse

Effects in pregnancy

Freely crosses the placenta Increased number of fetal abnormalities

when taken during the first trimester Excreted in breast milk leading to

accumulation in the infant

PSYCHOSTIMULANT DRUGS

Psychostimulants

Increase behavioral activity Elevate mood Increase motor activity Increase alertness Decreases sleepiness Increase brain metabolic activity Increase neuronal activity

Pharmacology

Cocaine, Amphetamine, and other stimulants

Stimulate the monoamine neurotransmitters dopamine, norepinephrine, and serotonin

Stimulate the nucleus accumbens (the reward center)

NUCLEUS ACCUMBENS

Area of the brain associated with behavioral reinforcement,

compulsive abuse, and drug dependency

Amphetamines and other stimulants

Developed in the 1930’s Had 39 purported uses up until 1946 Currently used for:

Narcolepsy ADHD Weight loss

Pharmacokinetics Absorption - well absorbed orally Distribution - quickly to the brain where

levels reach 80% of serum levels Metabolism - extensively in the liver to

inactive metabolites, though not to the same extent as cocaine

Excretion - 17-73% unchanged in the urine with remainder at inactive metabolites, they are detectable for 48 hours

Half-life – 10.5 hours

Concentrated in breast milk 3-7 times that of maternal serum

Pharmacodynamics Sympathomimetic agents which mimic actions of

adrenaline Exert most CNS effects by stimulating release of

norepinephrine and dopamine from presynaptic nerve terminals

PNS effects are caused by increased norepinephrine levels

Pharmacodynamics Behavioral stimulation and increased psychomotor activity

is mediated by amphetamine’s effect on dopamine receptors in the meso-limbic system

Much of its pharmacological activity is like cocaine Potency =

methamphetamine>dextroamphetamine>amphetamine

Low dose effects (5-20mg)

Peripherally causes: Hypertension Tachycardia Bronchodilation In general, induces

fight or flight pattern

CNS causes: Potent psychomotor

stimulation Increased alertness Euphoria Excitement Wakefulness Reduced sense of

fatigue Loss of appetite Mood elevation

Performance is enhanced while dexterity is usually decreased

Moderate dose effects (20-50mg)

Additional to low dose effects include: Stimulate respiration Slight tremors Restlessness Insomnia Agitation

Chronic users: Stereotypical behaviors Sudden outbursts of aggression and violence Paranoid delusions Severe anorexia

High dose effects (>50mg)

Psychosis Weight loss Skin sores Progressive deterioration in social,

personal, and occupational affairs Amphetamine psychosis with paranoid

ideation (especially seen with methamphetamine abuse)

Toxic doses

Occur at doses as small as 20-30mg Some people tolerate doses >400mg Primary toxicity usually occurs due to

chronic use Acute toxicity outside of CNS due to

hypertension which leads to MI and stroke

Acute toxicity in the CNS includes psychosis and hyperthermia

Non-amphetamine stimulants

Do not have the amphetamine nucleus, but share the same action of potentiating sympathomimetic actions

Include such OTC’s as ephedrine, found in Ma-huang, and pseudoephedrine, found in sudafed

Methylphenidate (C-II)Ritalin, Concerta

Regular release tablets have half-life of 2-4 hours

Several sustained-release tablets available Pharmacodynamically it increases the synaptic

concentration of dopamine by blocking the presynaptic dopamine transporter and also by slightly increasing dopamine release presynaptically

If injected IV, an individual would experience a Cocaine-like high, but the slow uptake into the brain when given orally would limit its degree of positive reinforcement

Sibutramine (C-IV)Meridia

Inhibits reuptake of serotonin, norepinephrine, and (to some extent) dopamine

Used as an anti-obesity drug with modest results

Rapidly metabolized in the liver to active metabolites that are responsible for its pharmacologic action (prodrug)

Metabolites reach a peak at 3-4 hours in plasma

Half-life of 14-16 hours Drug does not appear to have significant

abuse potential

Modafinil (C-IV)Provigil

Nonamphetamine psychostimulant with unknown MOA

May potentiate excitatory glutamate neurotransmission and inhibit GABA activity

Used for narcolepsy Recently FDA approved for use by truck

drivers as a stimulant

Atomoxetine (Rx)Strattera

Nonamphetamine behavioral stimulant Inhibits presynaptic norepinephrine

transporter Developed as an antidepressant Used to treat ADHD

ANALGESIA

Pain relief

Three types of analgesics

Opioids Non-opioids Adjuvant agents

Opiates Most important drug in medicine for the

relief of severe pain Work by mimicking the actions of

endogenous endorphins to suppress pain Derived from opium in early 1800’s Used extensively during Civil War

subsequent to the invention of the hypodermic needle

Access was restricted by the Fed’s with the Harrison Narcotic Act of 1914

Opioid receptors

Mu Kappa Delta

Classification of Opioid analgesics

Pure agonists Pure antagonists Mixed agonist-

antagonists Partial agonists

Pure opiate agonist

Results in both analgesia and euphoria Prone to cause dependency Examples: morphine, methadone, heroin,

fentanyl

Mixed opiate agonist-antagonist

Produce agonist effect at one receptor and an antagonist effect at another

Clinically useful drugs are Kappa agonists and weak mu antagonist

Have a ceiling to their analgesic effects Can precipitate withdrawal in opiate

addicts Example: pentazocine (Talwin)

Partial opiate agonist

Binds to an opioid receptor but has low intrinsic activity

Exert analgesic activity but have a ceiling to their effect

Example: buprenorphine (Suboxone)

PURE AGONIST OPIOID (MORPHINE C-II)

No other drug has shown to be more effective for treating severe

pain

Absorption GI absorption is slow and erratic From rectum is adequate IV can produce profound respiratory

depression

Pharmacokinetics

Distribution Morphine crosses BBB slowly Only about 20% reaches brain Fentanyl and Heroin cross BBB much

faster The flash or rush that heroin produces is

due to the rapidity with which it reaches the brain

Pharmacokinetics

Metabolism Morphine - in the liver to an active

metabolite called morphine-6-glucuronide Metabolite of morphine is 10-20 times

more potent than parent compound Heroin - in liver to morphine

Pharmacokinetics

Excretion Via the urine Morphine can be detected in the urine for

2-4 days post Heroin dose

Pharmacokinetics

Half-life Morphine - 2 to 4 hours Ranges from 10 minutes to 30 hours for

all pure opioid agonists

Pharmacodynamics

Analgesia Euphoria Sedation and anxiolysis Respiratory depression Cough suppression Pupillary constriction Nausea and Vomiting GI symptoms Other effects

Analgesia

Morphine produces intense analgesia and indifference to pain

Occurs without loss of consciousness

Euphoria Includes feeling of contentment, well

being, and lack of concern (important part of efficacy and reinforcing properties)

Euphoric effects are less intense with repeated use

Body produces endorphin which is its own “Morphine” and responsible for the “runner’s high”

Activate mu receptors in the meso-limbic reward system which causes reinforcing effects of opioids

Sedation and Anxiolysis

Produces anxiolysis, sedation, and drowsiness

Sedation is not as deep as that of CNS depressants

Prominent mental clouding with apathy, complacency, lethargy, and sense of tranquility

Respiratory Depression

Morphine causes profound respiratory depression

Single most important acute side effect of morphine and usually the one implicated as the cause of death in overdoses

Pupillary constriction

Morphine as well as other mu and kappa agonists cause pupillary constriction

Nausea and Vomiting (N/V)

Morphine stimulates mu receptors in the CRTZ of the medulla causing vomiting

Other effects Cause histamine release -

local itching Adversely affects white

blood cells

Tolerance and Dependence

Development of tolerance with repeat use is a feature of all opioids

Tolerance is mediated by activation of glutamate NMDA receptors which counteract opioids actions at mu receptors

Clinically, morphine doses may be increased from a starting dose of 50-60mg per day to 500mg per day in as little as 10 days

Tolerance to one opioid leads to cross-tolerance of all opioids

Withdrawal

Leads to profound reduction in the release of dopamine in the nucleus accumbens and a threefold increase in norepinephrine

Symptoms of withdrawal are the opposite of the pharmacologic effects

Magnitude of the withdrawal symptoms is directly related to the dose and frequency of the opiate taken

Withdrawal is not considered to be life threatening

Partial Opioid Agonists

Buprenorphine (Suboxone, Subutex) Works much like methadone does in

treating opiate withdrawal Does not have the reinforcing properties

that methadone does

Long acting opioid agonists

Methadone LAAM Simply replace the shorter acting opiate

and are decrease the dose over time

Other pure Agonist opioids

Codeine Heroin Hydrocodone (Vicodin, Lortab) Hydromorphone (Dilaudid) Oxycodone (Percocet, Oxycontin) Oxymorphone Meperidine (Demerol) Methadone LAAM Propoxyphene (Darvon) Fentanyl Sufentanil Alfentanil Remifentanil

Codeine (C-II, C-III, C-V)

Occurs naturally in opium Usually used in combo with

Acetaminophen or aspirin for mild to moderate pain relief

Metabolized to morphine Ceiling to its effectiveness as an

analgesia that morphine does not have

Hydromorphone and Oxymorphone (C-II)

Both structurally related to morphine 6-10 times more potent than morphine Causes somewhat less sedation Causes equal amounts of respiratory

depression

Meperidine (C-II) Structurally different than morphine Synthetic opioid 1/10th as potent as morphine Produces similar type of euphoria Equally as likely to produce dependence

when compared to morphine Produces more excitatory side effects

than morphine such as tremors, delirium, hyper-reflexia, and convulsions

Withdrawal reactions occur more rapidly due to its shorter half-life

Methadone (C-II) Synthetic mu agonist with a pharmacological

profile similar to morphine Very effective PO Extended duration of action in suppressing

withdrawal symptoms Methadone maintenance programs that

prescribe an average daily dose >50mg/day have higher retention rates and lower illicit drug use rate

Even when doses are adequate, 1/3rd of patients will still experience withdrawal

Has half-life of about 24 hrs

Propoxyphene (C-IV)(Darvon)

Structurally similar to methadone Less potent than codeine but more

potent than aspirin Large doses demonstrate opioid-like

effects

Fentanyl/Sufentanil/Alfentanil/Remifentanil (C-II)

Short acting IV opioid agonists related to meperidine

Fentanyl is available as patches, injectable solution, and oral lozenges

80 to 500 times as potent as morphine Profoundly depresses respiration

Partial Agonist Opioids

Buprenorphine (Suboxone/Subutex)

Tramadol (Ultram)

Buprenorphine (C-V (inj),

C-III) Semi synthetic which has limited stimulation of

mu receptors As a partial agonist there is a limit to its

analgesic effects Has limited ability to produce euphoria and

respiratory depression Administration routes include PO, or IV Subutex® (C-III) is indicated for opioid

withdrawal Suboxone® (C-III) contains buprenorphine and

the antagonist naloxone and is used for maintenance treatment for opioid dependence

Tramadol (Rx)

Partial agonist at mu receptors Blocks presynaptic uptake of

norepinephrine and serotonin As a partial agonist it exhibits a ceiling to

its analgesic effects Limited potential for abuse ad respiratory

depression Many side effects which limit its

usefulness including drowsiness, vertigo, nausea, vomiting, constipation, and HA

Mixed agonist-antagonist opioids

Week mu agonists Most analgesic effect comes from affinity for

kappa receptors Quite limited in its analgesia producing abilities Good for moderate pain relief Ceiling to analgesia effectiveness Produce acute withdrawal in opioid dependent

individuals High incidence of psychomimetic side effects

such as dysphoria, anxiety reactions, and hallucinations

Mixed agonist-antagonist opioids

Pentazocine (C-IV) (Talwin) Butorphanol (C-IV) (Stadol) Nalbuphine (Rx) (Nubain)