PRESCRIPTION DRUG ABUSE Patrick Foley PharmD, BCPP, BCPS 1
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)