EXAM 3 Drugs of abuse Dr. Pond

Question 1

What are the two forms of Dependence?

Answer 1

Physical dependence = dependence (withdrawal when stopping the drug)

Psychological dependence = addiction (compulsive, relapsing drug despite negative consequences, cravings

all addictive drugs produce a strong feeling of euphoria and reward

Question 2

What are the forms of Tolerance?

Answer 2

reduced effect of drug over time

Pharmacokinetic tolerance: the drug is cleared faster

Pharmacodynamic tolerance: the body adapts to the drug (number of receptors is downregulated or less sensitive)

-sometimes both forms are seen

Question 3

What do all addictive drugs have in common?

Answer 3

a strong feeling of euphoria and reward

activation of the dopamine-reward pathway in some way

-> Mesolimbic pathway

Question 4

What is the Mesolimbic pathway

Answer 4

VTA (brainstem) -> Nucleus accumbens (limbic area)
other factors that activate this pathway: food, water, sex (surviving)

Question 5

Which substances have the highest risk for addiction?

Answer 5

RR = 5
-Cocaine
-Amphetamine

RR = 4
-Nicotine
-Opioids

Question 6

What are the enzymes involved in alcohol metabolism?

Answer 6

Alcohol dehydrogenase (ADH)
Ethanol -> Acetaldehyde

Aldehyde dehydrogenase (ALD)
Acetaldehyde -> Acetate

Question 7

What kinetics does alcohol metabolism follow?

Answer 7

Zero-order kinetics

Question 8

To which receptors does alcohol bind in the CNS?

Answer 8

-NMDA receptor - suppressing its activation
-GABA (A) activation (GABA(A) is inhibitory)

in total inhibitory

Question 9

Other short-term effects of alcohol

Answer 9

-Vasodilator - severe overdose -> hypothermia
-Diuresis: inhibits antidiuretic hormone (ADH)

-sour stomach: stimulates gastric acid secretion
-decreased sexual function
-inhibits REM: although it causes sedation, it disrupts normal sleep pattern

Question 10

Acute Tolerance of alcohol

Answer 10

reduced sensitivity of GABA(A) receptors
-> the first glass of wine has a greater effect than the last one

Question 11

Chronic tolerance of alcohol

Answer 11

-metabolic tolerance: induction of microsomal enzymes (MEOS) -> second way to metabolize Ethanol to Acetaldehyde

-pharmacodynamic tolerance:
decreased sensitivity of GABA(A) receptors
downregulation of GABA(A) receptors in some parts of the brain

Question 12

How does alcohol affect other drugs?

Answer 12

-additive or synergistic with other CNS depressants

-activation of MEOS -> build of toxic metabolites -> depletion of glutathione in liver cells -> acetaminophen toxicity

-increased risk of gastric bleeding when taking NSAIDs or aspirin

-cross-tolerance with other CNS depressants (fe benzos since the GABA(A) receptors become less sensitive)

Question 13

What are the early withdrawal symptoms?

Answer 13

Rum fits
-nausea
-anxiety
-shakes
-sweating, cramps
-nightmares, hallucination
-tonic-clonic seizure (can be life-threatening)

Question 14

What are the late withdrawal symptoms?

Answer 14

Delirium tremens
-confusion, disorientation
-agitation
-sweating
-hyperthermia
-cardiac collapse

Question 15

What is the treatment for alcohol withdrawal?

Answer 15

Sedative hypnotics are common
-> usually benzos like diazepam -> then gradually taper off

-the goal is to prevent seizures

Question 16

What are the long-term toxicities of alcohol?

Answer 16

-liver toxicity
-CNS dysfunction
-liver cirrhosis
-cardiomyopathy
-gastritis
-pancreatitis
-cancer risks

women at higher risk for HTN and the other toxicities

acute toxicities: nausea, vomiting, memory loss, passing out

Question 17

What are the long-term effects on CNS function?

Answer 17

-increases ventricular size, decreases in
grey matter (brain scan)
-> cognitive impairment, memory loss,
anxiety, depression

Question 18

What is the Wernicke-Korsakoff syndrome?

Answer 18

-paralysis of the eye muscle, ataxia, learning and memory deficit-> can progress to coma and death

-> lack of vitamin B1 (thiamine), malnutrition bc they get their calories from alcohol
-> loss of neurons in parts of basal forebrain

Question 19

Which drug is used for alcoholism?

Answer 19

Naltrexone (mu antagonist)

-reduces short-term cravings for alcohol

ADE: GI (N/V, diarrhea), dizziness, headache

Question 20

Why do we use opioid antagonists in alcoholism?

Answer 20

alcohol increases the release of endorphins -> which bind mu-opioid receptors on GABA neurons

so the release of GABA is blocked
GABA would have blocked the dopamine release in the reward pathway (nucleus accumbens)

so now we have more dopamine release due to endorphins blocking the GABA neuron -> we need to block the opioid in order to have more GABA

the opioid contributes to the feeling of euphoria -> that’s why we use naltrexone in alcoholism

Question 21

What are the risks associated with Naltrexone?

Answer 21

risks: hepatotoxicity, withdrawal in opioid-dependent patients

Question 22

Which drug is used for alcoholism treatment and is mimicking the effects of alcohol?

Answer 22

Acamprosate
-> reduces short and long-term relapses

alcohol is a GABA(A) agonist and NMDA antagonist
Acamprosate is a
-weak NMDA-receptor antagonist
-GABA (A) agonist

poorly absorbed and renally eliminated

ADE: GI, insomnia, itching, anxiety, depression

Question 23

Which drug is used for alcoholism and facilitates the side effects of alcohol?

Answer 23

Disulfiram (Antabuse)
-inhibits Aldehyde dehydrogenase (ALD)
-> accumulation of acetaldehyde (1st metabolite of ethanol) -> produces N/V, palpitation, blurred vision, flushing, dyspnea (SOB)

risks:
-hepatoxicity
-several DDI

Question 24

Which drugs for alcoholism are hepatoxic?

Answer 24

Naltrexone
Disulfiram

Question 25

How does Xylazine express its analgesic effect?

Answer 25

alpha-2 agonist on presynaptic neurons (autoreceptors in NE release) -> closes voltage-gated Ca2+ channels -> INHIBITORY -often used with fentanyl to prolong the euphoria -> risk for respiratory depression -ADE: drowsiness, amnesia, slow breathing and heart rate Antidote: Tolazoline (alpha-2 antagonist)

Question 26

What are the two pharmacologically active compounds in Kratom

Answer 26

7-α-hydroxymitragynine and mitragynine MOA not understood -has opioid and stimulant properties

Question 27

What is the main active ingredient in Cannabis?

Answer 27

Δ9-Tetrahydrocannabinol (THC) the main psychoactive Cannabinoid

Question 28

How does THC work?

Answer 28

Synthesized in response to Ca2+ -> they move retrogradely to the presynaptic neuron and bind to CB1 receptors -> blocking the release of NT same effect with body-made Endocannabinoids: -> anandamide and 2-arachidonylglycerol they may act on Glutamatergic neurons or GABA neurons (so different effects seen)

Question 29

Which neurons does THC bind to?

Answer 29

partial agonist of CB1 on GABA neurons -these GABA neurons would inhibit DA neurons in the VTA -> THC blocks GABA and thereby the inhibition of DA -> more DA effect (disinhibition of DA neuron) -> Opioids do the same

Question 30

MOA of Cannabidiol (CBD)

Answer 30

the drug itself is not psychoactive it blocks FAAH enzyme -it prevents the degradation of Endocannabinoids and it increases the amount of Endocannabinoids (anandamide)

Question 31

Other effects of THC

Answer 31

-Respiratory (irratation, infection) -Cardiovascular (increase in HR, MI risk) -IQ reduction in heavy users as teens (secondary effect since they are not so much engaged in learning events) -short-term antidepressive effects but long-term contributes to depression, anxiety -some addiction risk bc it works on the DA reward pathway

Question 32

How is Δ8-THC different from delta 9?

Answer 32

change in location of the double-bond it is psychoactive and not regulated right now (delta 9 is psychoactive too)

Question 33

What are the targets of Gamma-Hydroxybutyric Acid (GHB)?

Answer 33

-high-affinity on protein of unknown function (GHB receptor) -low-affinity binding site on GABA(B) receptor (weak agonist) -> main target (studies have shown that blocking GABA (B) you will block most effects of the drug

Question 34

What are the effects of GHB?

Answer 34

Euphoria, enhanced sensory perception, feeling of social closeness, and amnesia (synergistic with alcohol) -rapidly absorbed, short half-life (30 min, hard to detect) -Liquid ecstasy, rape drug

Question 35

To which neurons does GHB bind?

Answer 35

GABA(B) receptors are present on GABA neurons which would inhibit DA neurons (like opioids and THC) and on DA neurons -it prefers to bind to the GABA(B) receptors on the GABA neuron at lower doses-> Disinhibition of the DA neurons -at high doses it will also hit GHB receptors on DA neurons -> agonist -> IPSP -> decrease in firing -> less DA effect

Question 36

Which receptors are targeted by LSD, Mescaline, and Psilocybin?

Answer 36

their structure resembles Serotonin -they target 5-HT(2A) receptors (agonist/(partial agonist) -G-protein coupled -closing K+ channels -> ESPS

Question 37

What are the effects of LSD, Mescaline, and Psilocybin?

Answer 37

Hallucination -Synesthesia (experiencing one than one sense?) -awareness of sensory input, feeling of clarity -spectator ego -autonomic activation, increase in HR and BP -GI distress with the natural products

Question 38

Which receptor is targeted by Ketamine and PCP?

Answer 38

NMDA (antagonist) -PCP is more potent than Ketamine -dissociative drug, ego perspective -similar effects with high doses of Dextromethorphan (DXM)

Question 39

What are the effects of Ketamine and PCP?

Answer 39

autonomic: increase in BP and HR, hyperthermia, impaired memory function effects can be unpredictable -excitement, agitation -hallucinations, euphoria, dysphoria PCP is addictive -> DA and NE release

Question 40

Which receptor does Salvia bind to?

Answer 40

Kappa receptor (like opioids) -> Kappa receptor causes dysphoria, but it is still used because it also causes psychotomimesis (hallucinations)

Question 41

Which receptors does Nicotine bind to?

Answer 41

agonists of Nicotinic ACh receptors (ionotropic, Na+/K channels -> Na+ comes in -> EPSP) they hit NiACh receptors on DA neurons in the mesolimbic pathway (VTA to nucleus accumbens)

Question 42

Which drugs to treat nicotine addiction?

Answer 42

-Nicotine substitution (Nicorette, Nicoderm) Spray, chewed, inhaled -Bupropion (Zyban) -Varenicline (Chantix)

Question 43

Which receptors are targeted by Bupropion?

Answer 43

-inhibits NE and DA uptake (weak) since nicotine activates DA neurons and stopping smoking causes DA withdrawal -> blocking DA reuptake makes more DA available to reduce withdrawal -nicotine receptor antagonist smoking when on Bupropion will prevent that high sensation, bc it prevents nicotine from binding and the DA release

Question 44

BBW of Bupropion

Answer 44

suicidal ideation particularly in children and adolescents ADE: aggravation of psychosis (drugs that increase DA have this effect), dizziness, tremor, insomnia, some sympathomimetic: dry mouth, constipation, increased HR and BP -> since it increases NE

Question 45

Which receptors are targeted by Varenicline?

Answer 45

partial agonist of α4β2 nicotinic acetylcholine receptor (major receptor in the VTA) -partial agonist in the presence of the (stronger) agonist, in this case, nicotine will reduce the effect of nicotine (in the presence of no other agonist (nicotine) the partial agonist will give a reduced effect of dopamine) -insomnia, sleep disturbance (dreams), nausea, constipation, flatulence

Question 46

Which chemicals are contained in inhalants?

Answer 46

nitrates, ketones, aliphatic and aromatic hydrocarbons -inhalants produce a rapid high (like alcohol intoxication)