Drugs of Abuse Flashcards
*hallmark of drug abuse?
compulsive drug use
drug abuse definition
- use of drugs without medical approval for euphoria and reward
- drug use in a manner that is detrimental to health and well being
*what is physical dependence?
what are 2 symptoms of physical dependence?
-when you need drug for normal physiological functioning
- development of tolerance (pharmacokinetic-changes in metabolism or pharmacodynamic-adaptations to presence of drug)
- withdrawal syndrome - symptoms are opposite of effects drug would usually produce
*what is physiological dependence?
ADDICTION
-compulsive drug use to induce pleasure or escape from reality despite negative consequences
HIGH RISK OF RELAPSE**
RR of 1=
RR of 5=
1-non addictive
2-highly addictive
mesolimbic dopamine reward system
- activated when?
- molecular targets?
- reward pathway - addictive drugs activate this system
- G-proteins
- inotropic receptors
- DA transporters
- path begins at the ventral tegmentum (VTA) - where all the DA hang out and activates the
- ->Nucleus accumbens (MAIN)
- ->prefrontal cortex
- ->amygdala
- ->hippocampus
How do opioids and THC affect the mesolimbic dopamine reward system?
Inhibit GABA receptors (g-proteins) which stimulates DA neurons to secrete more shit.
How do benzos, nicotine, ethanol affect the mesolimbic dopamine reward system?
bind to GABA_A (Cl channels?) ionotropic receptors = shut down GABA neuron = stimulation of DA neuron
How do cocaine, amphetamine, ecstasy affect the mesolimbic dopamine reward system?
blocking of DA transporters = accumulation of DA in target synapses
CNS depressants and Sedatives/hypnotics RR?
RR=3
Alcohol RR?
Ethanol
RR=3
Benzodiazepines RR?
Diazepam, alprazolam, flunitrazepam
RR=3
Barbiturates RR?
Pentobarbital
RR=3
gamma-hydrocybutyric acids (GHB) RR?
RR=3
ETOH effects @ high doses?
sedative and sleep
ETOH metabolism
-where?
Excretion where?
**90% liver
10 GI tract
**-excreted kidneys and lungs
ETOH metabolism
-which enzymes?
- Alcohol dehydrogenase (ADH)—ETOH to aldehyde
- Microsomal ethanol oxidizing system (MEOS)
- Aldehyde dehydrogenase (ALDH)— aldehyde –> acetate
**Elimination of ETOH follows what kinetics?
zero-order == depends on concentration of enzymes
What is rate limiting factor in ETOH metabolism/elimination?
ADH saturation is rate limiting bc zero order elimination = not dependent on time and concentration of ETOH
WHich enzyme system is activated to metabolize ETOH with chronic use?
Microsomal ethanol oxidizing system (MEOS)
What drug to give to treat methanol and ethylene glycol (anti-freeze) consumption?
give fomepizole - inhihibits ADH
Why is methanol toxic?
-converted to formaldehyde and oxalic acid by ADH - this is why we use fomepizole to block ADH
-formaldehyde is toxic to optic nerve and = metabolic acidosis
oxalic acid has kidney, lung, and CNS toxicity and = metabolic acidosis
**What drug to give to discourage alcoholics from drinking ETOH? WHY?
**-give Disulfiram - inhibits aldehyde dehydrogenase ALDH (second step of ETOH metabolism)
-results in high levels of aldehyde = unpleasant facial flushing, nausea, vomiting, dizziness, headache
What is disulfram used for?
blocks ALDH whcih causes accumulation of aldehyde in alcoholics who drink a lot of ETOH = they get sick when they drink
Males ETOH vs female ETOH effects:
same amount in females = greater blood alcohol bc less Vd (smaller/less water) and decreased first pass metabolism
ETOH MOA?
1) potentiates the effects of gamma-aminobutyric acid (GABA) at GABA_A receptors (INHIBITORY) = increased Cl ion flux and neuronal hyperpolarization
2) inhibits NMDA receptors (excitatory)
ETOH effects on glutamate activates NMDA receptors-
- what is part of NMDA functions?
- what does this translate to with ETOH?
- NMDA –> cognitive function, learning and memory
- relates to ETOH related memory loss = BLACKOUTS
- long term ETOH use results in?
- what does this contribute to?!
up-reg of NMDA receptors =====> CONTRIBUTES TO WITHDRAWAL SIGNS AND SEIZURES!!!!!!!!!
ETOH organ system effects?
Low dose
High dose?
low=excitation, loss of inhibitions, euphoria follwed by impaired judgements and reaction time; slurred speech and ataxia - intoxication or drunkeness
high=drowsiness, amnesia, unconsciousness (blackout) respiratory depression
What drugs does ETOH interact with? effects?
other CNS depressants (barbs, benzos, marijuana)
-sedative effects of all ingested are additive = potentially fatal
- Wernicke Korsakoff Syndrome
- another name for this condition?
- what is it?
- “wet-brain” or “alcoholic encephalopathy”
- neurological condition associated with thiamine B1 deficiency due to excessive ETOH intake
*Symptoms of Wernicke Korsakoff syndrome?
1) occular disturbances - nystagmus and paralysis of EOM
2) Changes in mental state - confusion cognitive defects (execute function)
3) memory impairment - amnesia
4) movement difficulties- ataxia, apraxia
Fetal Alcohol syndrome (FAS)
- what are signs of FAS?
- how much alcohol causes FAS?
- mental retardation, hyperactivity, antisocial behavior
- no safe level of alcohol intake
most common cause of preventable birth defects?
alcohol - FAS!
Long term ETOH use=
1) ETOH tolerance - altered margin of safety bc they can have more in their blood without apparent sedation or intoxication
2) ETOH Withdrawal - physical dependence -hyperexcitability, seizures, toxic psychosis, delirium tremens
3) ETOH addiction-seeking reward
**Stages of liver damage due to ETOH?
alcoholic fatty liver (reversible)
alcoholic hepatitis
liver cirrhosis (IRREVERSIBLE)
liver failure
**What does the liver do with cocaine and ETOH? What happens to body/person?
makes cocaethylene=intensification of cocaine effects = most common two drug combo that results in drug related death
Organ system effects of ETOH?
liver damage
cardiovascular
kidney
GI tract
What happens to cardiovascular system with chronic ETOH abuse?
1) dilated cardiomyopathy with ventricular hypertrophy and fibrosis
2) atrial and ventricular arrhythmias
3) reversible HTN
ETOH effects on the kidney:
diuretic effects = inhibit ADH
ETOH GI tract effects:
acute gastritis
bleeding ulcers
cancers of upper GI
Drug options to use for chronic alcoholism and why?
- Disulfiram - inhibis ALDH = produces acute sensitivity to ETOH = hangoer like symptoms
- naltrexone-opioid antagonist that blocks reinforcing properties of ETOH and reduces rate of relapse
Long term use of sedative/hypnotics results in?
- metabolic tolerance = inc metabolism
- pharmacodynamic tolerance= down reg of DA receptors
most commonly abused benzodiazepines?
diazepam
alprazolam
- **Flunitrazepam
- what is it?
date rape drug
- *flumazenil
- what is it?
- what does it treat?
- benzodiazepine receptor antagonist
- useful in treating OD and reversing the effects of long acting benzos used in anethesia
- *phenobarbital
- abused often?
not as often anymore – easier to just use benzos
Benzo and barbs MOA?
positive modulators of GABA_A chloride ion channels = potentiate GABAergic inh at all levels ==> disinhibition of the VTA dopamine (DA) neurons and activation of mesolimbic reward pathway
gamma-hydroxybutyric acids (GHB)
- How does it affect reward path?
- what effect?
- what is it used for?
- disinhibition of DA neurons in VTA via GABA_B receptors (metabotropic) (G-protein K channels?)
- produces AMNEISA in addition to euphoria, sedation, social closeness
- odorless, tasteless, readily dissolves == DATE RATE DRUG
What are the psychostimulants and what is RR of addiction?
- cocaine
- amphetamine
- methamphetamine
- MDMA
-RR=5!
Cocaine -
- how affects reward system?
- how acts as local anesthetic?
- increased DA release in the nucleus accumbens (VTA-mesolimbic reward path)
- inh Na channels = block of action potentials
What is “speedballing?”
IV use of heroin and cocaine mix
cocaine + ETOH in the liver makes:
cocaethylene = mixture with intensification of cocaine effects = most common 2 drug related death
Cocaine effects:
- intense euphoric effect
- increase energy
- increase libido
Cocaine toxicity?
cardiovascular tox=
intracranial hemorrhage
ischemic stroke
MI
OD=
hyperthermia
coma
death
What is special about cocaine withdrawal symptoms?
mild withdrawal and no specific tx/antidote for cocaine addiciton
Which drug has the strongest physiological dependence of any drug - even after only a few exposures?
cocaine
- *Methamphetamine
- why is this dug used a lot?
- easily burned/smoked
- effects last 6-24 hrs while cocaine hgih lasts only 20-30 minutes
**What happens when amphetamines activate autonomous nervous system?
sympathomimetic effect = DUE TO VESICULAR RELEASE OF NE
mydriasis
tachychardia
HTN
Serious side effects of amphetamine use?
MI, cerebrovascular hemorrhage, seizures, death
Cocaine MOA:
blocks DA reptake transporter (DAT) = inc synaptic DA
amphetamine MOA?
1) taken up into DA and NE terminals
2) cause vesicular release of DA and NE
3) reverse DA transporter (DAT) = increased release of DA
What is methylphenidate used for?
Tx for ADHD and narcolepsy
- **MDMA - methylene dioxymethamphetamine-
- MOA?
- what happens with prolonged use?
- interferes with 5HT transporters (SERT) to release 5HT from presynaptic terminals
- can cause permanent 5HT depletion
**Acute toxicity of MDMA?
hyperthermia
dehydration
=== death!
**What are the psychedelic drugs?
What is the RR of addiciton?
hallucinogens
- lysergic acid diethylamine (LSD)
- psilocybin (magic mushroom
- ketamine (special K)
- phencyclidine (PCP)
RR=1
So why are psychedelic drugs NOT addictive?
they dont effect the mesolimbic reward pathway! RR=1!
also means NO WITHDRAWAL!
*LSD MOA?
- release of glutamate in cortex via thalamic excitation
- target 5HT_2A receptors - Gq proteins –> IP3 –> inc in Ca
*Psilocybin MOA?
- release of glutamate in cortex via thalamic excitation
- target 5HT_2A receptors - Gq proteins –> IP3 –> inc in Ca
*Effects of LSD & psilocybin:
disturbances in perception (hallucinogens)
- hallucinations
- illusions
- thought paranoia
- euphoria or depression
What is one risk of LSD and psilocybin=
- severely impaired judgement = risk to harm self or others
- *-FLASHBACKS
- *-BAD TRIP-panic, anxiety, suicidal thoughts
**Ketamine & PCP MOA?
block NMDA-type glutamate receptors –> decrease activity of cortex and limbic system
Long term use of ketamine and PCP?
RR =1 but prolonged use can cause psychosis similar to schizophrenia
Which hallucinogen has anesthetic properties?
ketamine = dissociative anesthetic (the patient is under but eyes are open but they dont remember or know whats going on) & analgesic
emergence phenomenon too
***opioids that are commonly abused?
***What is RR of addiciton?
morphine
codeine
heroin
hydroxycodone
RR=4
Opioids MOA?
- inh of GABAergic neurons via activation of Mu opioid receptors = disinhibition of the VTA DA neurons = euphoria
- inh of VTA DA neurons via activation of kappa-opioid (KAPPA RECEPTORS ARE ON THE DA NEURON) receptors (inhibitory) = dysphoria
*****What drug is used for emergency opioid overdose??
Naloxone - Mu opioid receptor competitive antagonist reverses effects of morphine or heroin within minutes
what is withdrawal of oipids called?
opioid abstinence syndrome - lasts 5 days
-intense dysphoria, nausea, vomiting, rhinorrhea, lacrimation, awning, chills, flu-like musclar aches, goosbumps…. some more shit
methadexone:
- what is it used for?
- what does it do?
- used to treat opioid withdrawal and addiction
- long acting opioid agonist = immediate suppression of withdrawal symptoms
- prevent opiate craving and opiate induced withdrawal = longer half-life!
**WHat is naltrexone used for? how does it work?
- mu opioid receptor antagonist
* -primarily used for maintenance therapy
What two drugs would be used FOR LONG TERM opioid withdrawal/therapy? Explain how and why this works for an addict?
methadone
naltrexone
used for patient who is in rehab and just maybe had his last drug use recently –> the methadone will ease the symptoms of craving and withdrawal while the naltrexone will block the receptors that the drug is hitting at the moment
give naltrexone without methadone and your addict will go into a shitty withdrawal soon after
cannabinoids-
1) active substance?
2) what is synthetic THC drug name for chronic pain?
3) RR?
1) THC - tetrahydrocannabinol
2) dronabinol
3) RR=2
Cannabinoid MOA?
THC disinhibits DA neurons in the VTA via pre-synaptic cannabinoid receptors –> inh GABAergic interneurons = +++ on DA neurons
cannabinoid therapeutic effect?
**relief of chronic pain
nicotine
1) MOA?
2) TX?
1) Activation of nicotinic ach receptors (nACHR) on VTA projection neurons results in DA release in nucleus accumbens and PFC
2) Tx:
Bupropion
transdermal nicotine patch
-varenicline - high affinitiy nACHRs agonist that compete with nicotine binding
