Pharma-Drugs of Abuse

8/3/2019 Pharma-Drugs of Abuse

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DRUGS OF ABUSE

J. ONA CRUZ, MD, MHPED, FPOGS


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DEPENDENCE VS. ADDICTION

BASIC NEUROBIOLOGY


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DEPENDENCE

Physical dependence

Addictive: euphoria, rewards, adaptive changes

(tolerance effects)

Withdrawal manifestations upon drug

discontinuation

Not very common (1 in 6)


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Addiction

Psychological dependence

Compulsive, relapsing drug use even with bad

consequences

Triggers: cravings

Common in addicts after successful withdrawal


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Addiction and Dopamine Levels


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Addiction and Dopamine Levels

All addictive drugs activate the mesolimbicdopamine system


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Specific Molecular Targets: Three

Classes of drugs-


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TOLERANCE AND WITHDRAWAL

Dependence:


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TOLERANCE

RESULTS AS THE BRAIN ADAPTS TO REPEATED

EXPOSURE TO AN ADDICTIVE AGENT SUCH THAT

THE DOSE HAS TO BE INCREASED PROGRESSIVELY

IN ORDER TO ACHIEVE A PARTICULAR EFFECT


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Tolerance to Opioids

Reduction of concentration of a drug

Shorter duration of action in the target tissue

Changes in receptor function e.g. internalization Yet undefined mechanisms (morphine)


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Withdrawal

Drug withdrawal occurs because the body is

physically dependent on the effects of a drug.

When the drug is stopped, the body must adjust to

the absence of the drug. Nerves throughout thebody become excessively stimulated without the

drug, which causes the symptoms of drug

withdrawal.


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Withdrawal: Symptoms

MILD- anxiousness, abdominal pain, diarrhea,

insomnia, headache, nausea, vomiting, tremors

SERIOUS- rapid pulse, fever, palpitations, excessive

sweating, difficulty in walking, rapid breathing,

hallucinations, confusion, seizures


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DEPENDENCE: MECHANISM

(e.g. opioids)


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ADDICTION- maladaptive learning

High motivation to use a drug despite the negative

consequences

Recalcitrant, relapsing, chronic disease

HIGH RISK of relapse after successful withdrawal

Triggered by:

stress

drug re-exposure

condition/context that recalls prior drug use


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Mechanism of Relapse

Drug + neutral stimulus (contextual cues) switch

triggers addiction-related behavior

Involves learning and memory system

DOA continue to raise dopamine even when reward

is already expected (in contrast to natural rewards):

overriding of the prediction error signal


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Vulnerability to Addiction

LARGE INDIVIDUAL DIFFERENCES

Environment + genetics

Potential for addiction to certain drugs maybestrongly inherited (e.g. cocaine)

The RR for addiction correlates with its

hereditability


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NONADDICTIVE Drugs of Abuse

Alter perception without sensation of reward and

euphoria (hallucinogens, dissociative anesthesia)

Target: cortical and thalamic areas*

LSD, Phencyclidine

May have long-term effects**


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BASIC PHARMACOLOGY:

DRUGS OF ABUSE


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Basis of Classification of DOAs

Molecular targets and underlying mechanisms

1st- action on Gio protein-coupled receptors

2

nd

- interact with ionotropicreceptors and ionchannels

3rd-bind to monoamine transporters

*nonaddictivedrugs are also classified the same

way


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Pharmacology and clinical aspectsTreatment

Drugs that activate Gio-coupled

receptors


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OPIOIDS

Agonists at

When activated, these receptors have distinct and

sometimes opposing effects*

Commonly abused opioids are morphine, heroin,

codeine, oxycodone

Meperidine- among health professionals

Strong tolerance and dependence


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Opioid Withdrawal

Dysphoria

Nausea and vomiting

Muscle aches

Lacrimation

Rhinorrhea

Mydriasis

Piloerection

Sweating

Diarrhea

Yawning

Fever


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Treatment

Naloxone- life saving, may precipitate acute

withdrawal

Methadone- treatment of opioid addiction


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CANNABINOIDS

E.g. marijuana: THC (strong psychoactive drug)

Disinhibition of dopamine neurons by presynaptic

inhibition of GABA neurons in the VTA

Half-life- 4 hours

Onset-minutes

Maximum effect-2 hours


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Cannabinoid THC effects

Euphoria, relaxation, visual hallucinations,

depersonalization, psychotic episodes, increased

appetite, attenuation of nausea, decreased IOP,

relief of chronic pain Chronic use-dependence and withdrawal symptoms

RR=2


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Cannabinoid Withdrawal

Usually mild and short

Restlessness, irritability, mild agitation, insomnia,

nausea, cramping


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THC ANALOGS

DRONABINOL

NABILONE


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GHB

Synthetic GHB first used as GA*

Euphoria, enhanced sensory perception, feelings of

social closeness, amnesia, sedation, coma

club drug, liquid ecstasy

Used in date rapes (odorless, readily soluble)

Rapid absorption

Max plasma levels-20 to 30 minutes

Elimination half-life-30 minutes


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GHB: target

GABA neurons more sensitive to GHB than

dopamine neurons so at recreational uses only

GABA neurons are inhibited basis for addiction

Higher doses eventually hyperpolarizes dopamineneurons to inhibit dopamine release (anti-craving

effect)


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LSD, MESCALINE, PSILOCYBIN

Hallucinogens, Psychotomimetics

Somatic symptoms, Flashbacks

Not usually addictive but repetitive exposure may

lead to tolerance (tachyphylaxis)

Non-rewarding: does not stimulate dopamine

release, increase cortical glutamate release


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LSD,mescaline, psilocybin: Target

5-HT2A receptors which couple to G proteins

increase release of intracellular calcium


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Drugs that mediate their effects via

ionotropicreceptors


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Nicotine

Exceeds all other forms of addiction

Smoking, chewing, snuff

Selective agonist of the nicotine acetylcholine

receptor (nAChR)* which is normally activated by

acetylcholine

Rewarding effect: increase in dopamine release in

VTA (nAChR are present on dopamine neurons)


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Nicotine Withdrawal

Milder than in opioids

Irritability, sleeplessness

Relapse is very common

RR=4


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Treatment

Substitute smoking with nicotine gum, inhalational

nicotine, or nicotine patches

Bupropion

Behavior therapy


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BENZODIAZEPINES

Commonly used as anxiolytic and sleep agent

Moderate risk of addiction (euphoric effects)

Usually abused with other drugs


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Benzodiazepines: mechanism

Positive modulators of GABAA receptors

(pentamereswith subunits)

Disinhibitionof mesolimbic dopamine system:

rewarding effect

Receptors with 5-mediates tolerance to Bzs


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Benzodiazepines: Withdrawal

Occurs within days of discontinuation

Varies as a function of the elimination half-life

Irritability, insomnia, phono- and photophobia,

depression, muscle cramps, seizures

Gradually subside in 1-2 weeks


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Ketamine and Phencyclidine (PCP)

Were used as general anesthetics

club drug, angel dust etc.

Use-dependent noncompetitive antagonism of the

NMDA channel effect

White crystalline powder (pure), liquids, capsules,

pills

Snorted, ingested, injected, smoked


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K and PCP: Effects

unpleasant dreams and hallucinations uponrecovery from surgery

Psychedelic effects lasts for 1 hour

Increased BP, impaired memory, visual alterations Higher doses: unpleasant out-of-body experience,

near-death experiences

RR=1

Long-lasting psychosis (esp.PCP) with chronicexposure


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Inhalants

Abuse: recreational exposure to chemical

vapors*which are present in many common

household and industrial products

sniffing, huffing, bagging

Inhalant abuse common in children and young adults


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Inhalants: Mechanism

Largely unknown

Altered function of ionotropic receptors and ion

channels demonstrated in some

e.g. nitrous oxide NMDA receptors

fuel additives GABAAreceptors

Most produce euphoria e.g. toluene increases VTA

excitability addiction risk Management of overdose: supportive


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Drugs that bind to transporters of

biogenic amines


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COCAINE

Alkaloid from Erythroxylon coca

Initially used as local anesthetic and mydriatic

Highly addictive at RR=5

Water soluble, can be absorbed through mucosal

surfaces (nasal snorting) or injected

heated in alkaline solution smoked (crack cocaine

) swift distribution to brain rush


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Cocaine: Mechanism

Inhibits DATInhibits DAT Decreasedsynapticclearance

Decreasedsynapticclearance

Increasedextracellularlevels ofDopamine

Increasedextracellularlevels ofDopamine


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Cocaine: Effects

Activation of sympathetics (blocks NET) increase in

BP, tachycardia, ventricular arrhythmias

Loss of appetite and sleep, hyperactivity

Increased risk of intracranial hemorrhage, ischemic

stroke, MI, seizures

Hyperthermia, coma, death


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Cocaine addiction and dependence

Develops after only a few exposures in susceptible

individuals

Withdrawal is not as strong as in opioids

Tolerance, reverse tolerance*

Very strong cravings

No specific antagonists

Supportive management of intoxication


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AMPHETAMINES

Synthetic, indirect-acting sympathomimetics

Substrates of DAT and competes with dopamine


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Competesfor DATCompetesfor DAT

Withincell:

interfereswithVMAT

Withincell:

interfereswithVMAT

DepletesNTS

content invesicles

DepletesNTS

content invesicles


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Amphetamine Use

IV use and hard core addiction is more common

than with ecstasy, club drugs

Pills, smokes, injectables


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Amphetamine Effects

Elevates catecholamine levels increases arousal

and reduces sleep

Elevates dopamine euphoria, abnormal

movements, psychotic episodes

Effects on serotonin hallucinations, anorexia,hyperthermia?

NEUROTOXIC*


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Amphetamine: Effects

Increased alertness, euphoria, agitation, confusion

Tooth grinding, skin flushing

Tachycardia, dysrhythmias

Hypertensive crisis, vasoconstriction, strokes

HIV and hepatitis infection (needle sharing)

Tolerance with chronic use


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Amphetamine withdrawal

Dysphoria

Drowsiness

Insomnia

Irritability


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ECSTASY (MDMA)

Derivatives of methylmedioxymethamphetamine

(MDMA)

Same mechanism as amphetamines

Designer drug

Oral


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Ecstasy: Effects

Fosters feelings of intimacy and empathy

Has preferential affinity for SERT (serotonin

transporter ) increases extracellular serotonin*

NEUROTOXIC

Serotonin syndrome**


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Ecstasy: Effects

Severe acute toxic effects (hyperthermia,

dehydration)

Seizures


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Ecstasy Withdrawal

Depression for several weeks

Increased aggression

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