Drugs of Abuse

what is a craving

intense desire to re-experience the effects of a psychoactive substance

the cause of relapse after long periods of abstinence

craving

what is priming

new exposure to a formerly abused substance

this exposure can precipitate rapid resumption of abuse at previous levels or at higher levels

what is relapse

what can trigger relapse

resumption of drug-seeking or drug taking behavior after a period of abstinence

priming, environmental cues, and stress can trigger intense craving and cause a relapse

what is reward

what is an example

stimulus that the brain interprets as intrinsically positive or as something to be attained

dopamine

what is sensitization

increase in the expected effect of a drug after repeated administration

also refers to patient hypersensitivity to the effect of a drug in a person w/ a history of exposure to that drug

one of the neurobiology mechanisms involved in craving and relapse

sensitization

substance abuse is characterized by

recurrent and clinically significant adverse consequences related to the repeated use of substances, such as failing to fulfill major role obligations, use of drugs in situations in which it is physically hazardous, occurrence of substance-related legal problems and continued drug use despite the presence of persistent or recurrent social or interpersonal problems

for substance dependence to be diagnosed, at least three of the following must be present:

symptoms of tolerance, symptoms of withdrawal, use of a substance in larger amounts or for longer periods than intended; persistent desire or unsuccessful attempts to reduce or control use; the spending of considerable time in efforts to obtain the substance; a reduction in important social, occupational, or recreational activities because of drug use; and continued use of a substance despite attendant health, social, or economic problems

alcohol has what effect:

alcohol withdrawal therefore has what effect:

depressant

excitation- tachycardia, HTN, seizures, etc.

(excitatory glutamate is produced to counteract the depressant of alcohol. when alcohol taken away will still see the high glutamate in alcoholics)

many drugs of abuse act on these two receptors:

ionotropic (fast)- ion gated ligand channels

metabotropic (slow)- G-protein. activation creates/activates a second messenger (drug of abuse is first messenger)

alcohol withdrawal treatment

benzodiazepines: act on the same Cl- receptor as alcohol

examples of ionotropic drugs:

nicotine

benzodiazepines

nicotine- binds to nicotine cholinergic receptors- contain a sodium channel

benzodiazepines, barbituates, ethanol- bind to GABA receptors facilitating entry of chloride

three types of VMATs

serotonergic

dopaminergic

noradrenergic

opioids: ionotropic or metabotropic

mechanism

classic hallucinogens

metabotropic: bind to opioid receptors which reduce cAMP levels

cannabinoids bind to cannabinoid receptors

classic hallucinogens are partial agonists of serotonin receptors

amphetamines and cocaine have an indirect action on receptors:

increasing the synaptic levels of dopamine, NE, and serotonin- facilitating release and inhibiting reuptake respectively

vicodin=

hydrocodone + acetaminophen

stimulants: sympathomimetic drugs (4)

cocaine

amphetamines

bath salts

cathinones

which drug is most addictive:

cocaine

MJ

LSD

none of these are addictive

cocaine

routes of cocaine administration

occasionally combined with?

snorted

smoked

injected

occasionally combined w/ heroin and injected (speedball)

speedball

heroin and cocaine

injected

cocaine: used in religious ceremonies of the 13-16th centuries. andes workers chewed " " in fields to increase productivity

leaves

(bulging cheeks)

why can males handle more alcohol than females

males have more alcohol dehydrogenase in intestinal tract and don't absorb as much compared to females

cocaine trade preparations were used for

solutions for mucosal anesthesia

Cocaine is a schedule ___ drug

II

since 1970

source of cocaine

coca bush leaves- leaves of the erythroxylon coca

benzoylmethylecgonine

cocaine

important because we don't test for cocaine itself in urine because half life is very short

two main uses of cocaine

mechanism of cocaine in the CNS

local anesthetic and CNS stimulation

inhibition of neuronal uptake of catecholamines- generalized sympathetic stimulation simulating amphetamine intoxication

cocaine increases CNS synaptic concentrations of:

primarily those originating in what area of the brain

dopamine

primarily those originating in the ventral tegmental area of the brain (tiny structure at tip of brainstem)

also nucleus accumbens, ventral palladium, and frontal cortex

increases dopamine in limbic system

ANES- cocaine

cocaine: blocks initiation of or conduction of nerve impulse following local application

cocaine: manifests as a feeling of well-being and euphoria: sometimes:

increased doses- (movements)

dysphoria

increased doses- tremors, and eventually clonic-tonic convulsions

cocaine CNS manifestations of toxicity:

may occur soon after these routes of administration

delayed after these routes of administration:

what are some of the s/sx

soon- IV or smoking

delayed after snorting, mucosal application, or oral ingestion

anxiety, agitation, delirium, psychosis, tremulousness, muscle rigidity or hyperactivity, and seizures may follow initial euphoria

cocaine: seizures- usually short or status epilepticus?

seizures are usually brief and self-limited

status epilepticus suggests continued drug supply- cocaine filled packets or condoms in the GI tract or hyperthermia

this may suggest that someone has continued cocaine drug supply

status epilepticus

usually seizures are brief and self-limited

(when someone has any s/sx like chest pain, HTN, or seizures for a long time expect scenario like mule because shouldn't last that long)

cocaine- what might small doses do to HR?

moderate doses and greater?

BP?

CV death?

slow HR because of vagal stimulation

HR increased

BP- prominent rise due to sympathetically mediated tachycardia and vasoconstriction

large doses- arrhythmias- (>QT), MI, cardiac failure due to direct depression of heart muscle, stroke, CNS bleed

effect of atherosclerosis w/ cocaine use

can worsen

increased plasminogen-activator inhibitor

increased platelet activation and agregateability

increased endothelial permeability

accelerated atherosclerosis and thrombosis

cocaine CV effects

fatal v tach or fibrillation (long QTc)

hemorrhagic stroke/aortic dissection

coronary artery spasm or thrombosis may-> MI, even in pts w/ no prior coronary dz

diffuse myocardial necrosis (similar to catecholamine myocarditis) and chronic cardiomyopathy

pneumothorax and pneumomediastinum causing pleuritic chest pain

myocardial, intestinal, or brain infarction

tachyarrhythmias may cause shock

intravascular hypovolemia produced by extravascular fluid sequestration due to vasoconstriction

most dangerous withdrawal consequence?

cocaine

heroin

ethanol

LSD

ethanol

cardiac dysrhythmias and conduction disturbances reported w/ cocaine use:

QT prolongation

cocaine effect on body temperature

why?

marked hyperthermia in some

increased muscle activity- arguments heat production w/ vasoconstriction decreasing heat loss- rhabdomyolysis

cocaine fever- direct action on the temperature regulating centers of the brain

cocaine: local anesthetic actions

where is it commonly used

block nerve conduction

now used primarily in the upper respiratory passages

cocaine: psychotoxicity

anxiety w/in hours after euphoria declines

suspiciousness and paranoia w/in hours of high-dose

full developed paranoia w/ visual hallucinations reported

perceptual changes or pseudo-hallucinations: heavy users- tactile cocaine bugs or visual snow lights

cocaine- well or poorly absorbed?

what effect has this had?

skin?

well absorbed

systemic toxicity has been described after mucosal application as a local anesthetic

*

absorbed from mucosal sites of application- not intact skin

cocaine- absorption w/ inflammation?

enhanced w/ inflammation (increased blood flow)

which route of cocaine produces maximum effects fastest

IV or smoking- 1-2 minutes

oral or mucosal absorption- may take 20-30 minutes

cocaine- once absorbed-

cocaine is degraded by

metabolism by hydrolysis w/ a half-life of about 60 minutes

plasma esterase

(half-life after oral or nasal administration- approximately 1 hour)

cocaine absorption faster with: smoking or IV

smoking

lungs have incredible blood flow and surface area

cocaine: excretion: largely charged or uncharged?

small amounts uncharged drug excreted in the urine unchanged + metabolites

How long can cocaine stay in the blood/urine?: short term vs. long term

after long term high dose use, cocaine metabolites (benzoylecgonine) may be detected in urine up to 8 days after intake has stopped

short term- 2-3 days

(cocaine itself half life only 1 hour)

this route of cocaine administration produces a "rush" that users describe as an intense sensation that lasts a few minutes

IV or smoked

this route of cocaine administration (or amphetamine) produces euphoria w/o the rush

intranasal

(IV and smoked produced rush)

crack cocaine 50 mg smoked -> peak concentrations similar in 40 minutes to:

106 mg nasally of HCl salt

(smoked way more potent)

cocaine powder: only snorted?

can be snorted or injected (H2O soluble)

Why is free base "rock" better than salt?

volatilizes at a lower temperature

is not as easily destroyed by heat as the crystalline hydrochloride salt

vaporizes before being destroyed by heat

how is crack cocaine made

made by dissolving cocaine HCl salt in an aqueous alkaline solution. it precipitates as "free base" (HCl removed)

free base then extracted w/ a solvent such as ether (flammable)

free base melting point- 98 deg C

HCl salt melts at 195 deg C

cocaine: s/sx of abuse

euphoria

accelerated pulse

increased BP

increased RR

acute psychosis

overly self-confident under the influence

depressed, irritable, low self-esteem while not under the influence (withdrawal)

impossible to tell coke from:

only difference:

coke vs. meth

meth lasts longer

cocaine: which form of dependence is greater

physical- moderate

psychological- very high

tolerance to cocaine

some CNS effects such as euphoric rush following IV administration and elevation in mood

not seen re cardiac effects ?

cocaine toxic dose is highly variable and depends on:

individual tolerance/usage volume

route of administration

presence of other drugs (sedative vs. stimulants)

rapid IV injection or smoking: may produce transient high brain and heart levels resulting in convulsions or cardiac arrhythmias- same dose swallowed or snorted may produce only euphoria

diagnosis of cocaine body "packers or stuffers":

based on hx, circumstances, or typical features of sympathomimetic intoxication (may be persistent)

when you see long duration of cocaine effect- suspect packing

cocaine: causes of death

renal failure?

sudden fatal arrhythmia &/or QT prolongation

intracranial hemorrhage

hyperthermia- seizures, muscular hyperactivity, or rigidity and is typically associated w/ rhabdomyolysis, myoglobinuric renal failure, coagulopathy and multiple organ failure

renal failure may result from shock, renal arterial spasm, or rhabdomyolysis w/ myoglobinuria

cocaine: chronic use toxicity

insomnia

undesired weight loss

paranoid psychosis

nasal septal perforation may occur after chronic snorting

accidental SubQ injection of cocaine may cause localized necrotic ulcers (coke burns)

why do nasal/oral perforations occur w/ chronic cocaine use

alpha agonist- decrease circulation. tissue necrosis

cocaine and pregnancy

uterine contractions

fetal tachycardia

excessive fetal activity

increased spontaneous abortions

low birthweight

first trimester- placental abruption or infarction

fetal death later in pregnancy w/ increased precipitous labor and hemorrhage

may be increased risk for sudden infant death among babies born to cocaine-dependent mothers

systemic use CI in pregnancy or breastfeeding

cocaine treatment serious intoxication:

what can angina pectoris or MI be treated w/:

ABC

treat coma, agitation, seizures, hyperthermia, and arrhythmias if they occur

angina pectoris or MI may be treated w/ nitrates

monitor vital signs and ECG for several hours

t/f: beta blockers are a solid choice to treat cocaine toxicity

F!!

normally bb would help w/ HTN, tachycardia, etc, but will leave alpha unopposed which makes it worse

agent to be avoided w/ treatment of cocaine-related MI or infarction

which agents are ok

propranolol

specific drugs and antidotes for cocaine

none

propranolol- produces worsening of HTN, via blockade of beta-2 vasodilation,

propranolol or esmolol may be used in combination w/ an alpha-blocking vasodilator such as phentolamine

labetalol- weak alpha blocker- 5X>beta-blocking power than alpha blocking power

carvedilol- 10:1 ratio

NTG, nitroprusside ok

treatment for cocaine body packers

give repeated doses of activated charcoal and consider whole bowel irrigation

if ingested packets are not removed by these procedures- laparotomy and surgical removal may be necessary

cocaine may be contaminated with " " to make it heavier

lead

cocaine: long-term use of cocaine binges of a few days- abrupt stopping of drug results in these withdrawal sx

physiological disruptions?

anxiety

depression and craving followed by fatigue and sleep

upon waking- hyperphagia, continued sleepiness, depression and anhedonia

mood returns over a period of days while anhedonia may last weeks. cause unknown

no grossly observable PHYSIOLOGICAL disruptions necessitating gradual withdrawal of the drug

t/f: cocaine cessation should be done gradually due to the risks of abrupt cessation

F

no grossly observable PHYSIOLOGICAL disruptions necessitating gradual withdrawal of the drug

just stop that sh!t

these drugs may be used to help cocaine relapse

antidepressants:

imipramine and desipramine

bupropion

fluoxetine

this drug may prevent neuronal kindling in cocaine relapse

carbamazepine

hypothesized to reduce cocaine craving

not enough support for the use of carbamazepine

BUT NO EFFECTIVE TREATMENT EXISTS

"you cannot handle this drug"

amphetamines are used for the treatment of:

narcolepsy

ADD or ADHD

adjunct in pain treatment

prescription anorectic medication for use in weight reduction

"ice"

a smokable form of methamphetamine

only way users can tell difference from cocaine and amphetamines

duration- amphetamines longer

amphetamines- paradoxical response seen in:

children- tx of ADD

amphetamines- stimulant pharmacology

same as cocaine

elevation of mood (euphoria)

sense of increased self-esteem and well-being

mental and physical performance enhancement

decreased appetite and need for sleep

increased socialization

heightened sexual interest

disinhibition, grandiosity and impaired judgement

amphetamines: absorption high or low?

metabolized where?

T1/2?

drugs well absorbed orally

extensively metabolized by the liver

amphetamine- 10 hours

methamphetamine- 5 hours

amphetamines: largely excreted unchgd?

what may increase elimination

up to 30% of amphetamines excreted in urine unchgd

acidifying urine may increase elimination but increase myoglobin ppt in renal tubule (amphetamines are weak bases)

what is the risk of acidifying urine to increase amphetamine excretion?

increases myoglobin precipitation and renal failure so not worth it

amphetamines- this route of 20-40 mg is sufficient for pleasurable effects

what may be done to achieve a rush

IV amphetamine or methamphetamine

IV users may dissolve oral tablets or use crystalline methamphetamine to achieve a rush similar to crack cocaine

amphetamines: when is rush not achieved

rush is not appreciated following intranasal or oral use

describe an amphetamine "run"

stopping use results in:

binges- user may continue to inject drug q2-3 hours around the clock and go for days w/o sleeping or eating

stopping use followed w/in few hours by a deep sleep "crashing" that lasts 12-18 hours depending on duration of the run

amphetamine mechanism of action

Indirect general agonist, released stored catecholamines.

dopamine and NE are released into the synapse

t/f: toxic syndrome seen with cocaine = amphetamines

T

amphetamines- really increase these two neurotransmitters

high doses can release this:

dopamine and NE

serotonin (weak effect)

amphetamines- main MOA is release of catecholamines from presynaptic terminal but also have this minor mechanism

inhibition of neuronal re-uptake

(cocaine is only inhibiting re-uptake. amphetamines can inhibit re-uptake and promote release)

s/sx of amphetamine toxicity

anxiety

hyper vigilance

suspiciousness

fear of persecution

impaired insight, paranoia

amphetamine toxicity- permanent degradation of:

seen in animals at high doses- thought to be due to formation of a neurotoxin, 6-hydroxydopamine

in high doses- inhibition of " " can occur

dopaminergic neurons

high doses- inhibition of MAO can occur and autoxidation of dopamine may produce the neurotoxin 6-hydroxydopamine

6-hydroxydopamine

destroys adrenergic nerve terminals

seen in amphetamine toxicity

what might prolonged anhedonia in amphetamine toxicity be due to

induced damage to dopaminergic elements in the reward system

amphetamines: cardiac effects similar to

acute intoxication more likely in who?

cocaine

inexperienced users- dizziness, tremor, irritability, confusion, hallucination, chest pain, palpitation, HTN, sweating, cardiac arrhythmias. hyperpyrexia, convulsions and shock usually precede death

amphetamines- low or high TI

low TI

high degree of tolerance can develop after repeated use

acute ingestion of more than 1 mg/kg of dextroamphetamine (or eq. dose of other drugs) potentially life-threatening

amphetamines- CNS effects of intoxication include

euphoria

talkativeness

anxiety

restlessness

agitation

seizures

coma

ICH may occur 2'2 HTN or cerebral vasculitis

amphetamines- acute manifestations include

sweating

tremor

muscle fasciculation and rigidity

tachycardia

HTN

acute myocardial ischemia

infarction- even w/ normal coronary aa.

amphetamines- inadvertent intra-arterial injection may cause:

vasospasm resulting in gangrene

amphetamines: hyperthermia frequently results from:

risk of this?

seizures and muscular hyperactivity

may cause brain damage, rhabdomyolysis and myoglobinuric renal failure