Ok so starting off with the heavy stuff, let’s name the 1st two dopamine (DA) pathways from the ventral tegmental area (VTA) involved with reward
VTA–> nucleus accumbens
VTA–> prefrontal cortex
What’s the neural DA pathway from the substantia nigra? What is it associated with?
SN –> CPu
A/w with habit and compulsions
What’s the neural NE pathway from the locus coeruleus (LC) and what is it associated with?
LC –> forebrain, cerebellum
A/w with arousal and attention
What’s the neural serotonin (5HT) pathway from the raphe nucleus and what is it associated with.
Raphe nuc –> forebrain, cerebellum
A/w mood and visual
On to the actual drugs. Starting with Opiates. Name 4 opiates
What are the effects of opiates. Many many many options here.
nausea emesis “foam cone” euphoria (lasts~1hr), somnolence sedation (lasts 2-4hrs) dissociation analgesia resp depression LOC endocrine/immune disturbances constipation
What is the mechanism of opioids
- 1’ target: Mu opioid-R
- 1’ effect: Gi/o receptor that when stimulated causes hyperpolarization.
3: Result: disinhibition of DA release and euphoria.
What’s the most terrifying effect of opiates?
OD/Sudden Death: Profound respiratory depression, arrhythmia, cardiac arrest, severe pulmonary edema
What are the pulmonary effects of opiates?
- Pulmonary edema
- Septic embolism (from endocarditis)
- Lung abscess,
- Foreign body granulomas from Talc
- Opportunistic infections.
*Note, granulomas can be found elsewhere like spleen, liver and lymph nodes
Infections due to opiate use are likely to end up:
- Heart valves (Right sided tricuspid - S. Aureus)
What kind of skin shit happens when you take too many opiates?
- Cutaneous lesions from subQ injections
2. Hyperpigmentation over injection sites
What kind of kidney shit happens when you take too much opiate shit in your shit
- Amyloidosis from skin infections
- Segmental glomerulosclerosis
- Nephrotic syndrome
What will you see on labs when you have an opiate overdoser on your hands?
Talk me through the withdrawal process of opiates?
6-12h: lacrimation, rhinorrhea, yawning, sweating, goosebumps, anxiety
12-24h: restless sleep
16-96h: dilated pupils, goosebumps, tremor, weakness, anorexia, nausea, vomiting, intestinal spasms (cramps), diarrhea, muscle/back pain/spasms/jerks, CNS stimulation, depression, wt loss, acid-base change, dehydration, ketosis
Max sx at 48-72h; abate w/in 7-10d
What happens after detox of opiates?
- Relapse extremely common (80%)
- Craving for months-years
- Conditioned withdrawal syndrome – return to environment previously used shows features of withdrawal
What’s going on with drug tolerance?
- no change in opiate drug metabolism
- mu opioid receptor are desensitized (receptors are phosphorylated)
- NO/little reduction in # of receptors
- Signal transduction pathways are modified
- Gene expression altered
What’s going on with drug dependence?
- Compensatory changes are “unmasked” when drug is withdrawn aka there is withdrawal
- Withdrawal sx are often opposite to the acute drug effects
- Withdrawal is caused by giving a drug antagonist like naloxone or naltrexone for opiates
What is addiction?
Tolerance+Physical dependence+psychological dependance
May be considered a dz of maladapted learning
How do you treat a opiate addiction?
- Maintenacne therapy
More detail in next cards
What does detox for opiate addiction look like
- Cold turkey – not recommended
- Clonidine: suppression of sx by α2 R activation (inhibits firing of locus ceruleus neurons)
- Antagonist-accelerated withdrawal: naltrexone-precipitated withdrawal induces rapid transition to non-dependent state
What’s the maintenance therapy like for opiate addiction?
- Heroin maintenance (not legal in US) – replace illegal w/legal heroin
- Methadone maintenance – dose increased progressively, blocks assoc of high w/heroin, maintained daily for months-years, decrease when stable, significantly dec relapse rate
- Antagonist or partial agonist – after detox give naltrexone to block effects of any self-administered opiate
- Buprenorphine – mixed agonist-antagonist – blocks opiate effects, but induces high by itself
- Buprenorphine/Naloxone (Suboxone) – naloxone has poor oral bioavailability, but if injected naloxone is activated
What is fentanyl
Short acting synthetic opiate
Used for anesthesia
What is the mechanism for benzodiazepines?
1’ target: Acts allosterically on GABA(a) receptors
1’ effect: potentiates GABA
Result: hyperpolarization, sedation, mild euphoria, DA release
Where do we get cocaine from?
Extracted from coca leaves → water soluble powder. Mixed with Talcum powder or lactose. Snort or dissolve in water and inject.
What’s crack? Say crack again. Crack.
Crack = crystallized cocaine → Heat (causes it to crackle hence the name) and inhale vapors → far more potent than cocaine but same effects
What’s the mechanism of cocaine?
Blocks DAT, NET and SERT (DA, NE and 5HT transporters) → inc extracellular DA, NE, 5HT → “high”
Are the withdrawal effects of cocaine just like nbd?
NO THEY SUCK: dysphoria, depression, hunger, craving
What are the CV effects of cocaine?
- Increase in NE/Epi → Tachycardia, HTN, peripheral vasoconstriction.
- Enhances platelet aggregation and thrombus formation → Coronary artery vasoconstriction → Myocardial ischemia.
- Enhanced sympathomimetic activity + ion transport disruption (Na+, K+, Ca2+) → Lethal arrhythmias
- Development of dilated cardiomyopathy (doesn’t say why)
What are the CNS effects of cocaine?
Blocks reuptake of Dopamine → euphoria and hyperpyrexia (very high fever due to dopaminergic pathways of body temperature control) and seizures
What about cocaine use in pregger ladies? JUST LIKE NBD RIGHT?
Acute decreases in blood flow to placenta → Fetal hypoxia, degeneration of neural development and potentially spontaneous abortion
What about your nose? Is your nose safe from cocaine?
NO NOTHING’s SAFE FROM COCAINE.
Perforation of nasal septum in snorters
What happens when you OD on cocaine?
- tachycardia/arrhythmias, HTN
- intracranial hemorrhage/stroke
What are some of the chronic effects of cocaine?
2. hunger and weight gain
What labs will be (+) for a cocaine user?
BE (benzoylecgonine, the major cocaine metabolite)
What is the mechanism of amphetamines?
blocks VMAT (displaces DA from vesicles into neuron endplate) → inc extracellular DA, NE & 5HT → “high”
What happens with chronic amphetamine use?
loss of stimulatory effects, depression, anxiety, hunger, weight gain
What happens to your MAO receptors with chronic amphetamine use?
MAO R downregulated (less stimulation) & MAO vesicular stores depleted (less DA release)
Now they went and OD’d on amphethamines. What’ll be going on with them now?
- tachycardia/arrhythmias, HTN
- intracranial hemorrhage/stroke,
- psychotic episodes, 6. paranoia
What are the withdrawal effects of amphetamines?
dysphoria, drowsiness, irritability, depression, hunger, weight gain, craving
What is the mechanism of MDMA (methylenedioxyamphetamine)
Mechanism: blocks SERT and DAT?–> inc extracellular 5HT → euphoria
What are the effects of MDMA?
taken orally, effects last 3-6hrs –> inc HR/BP, alertness; dehydration, mild hallucinogen
What are the effects at higher doses of MDMA?
- muscle brkdn=rhabdo, 3. kidney
- CV failure
- memory impairment
What are these newish bath salt things?
What is the mechanism of nicotine?
activate nACHN receptors, esp in VTA, Nuc accumbens & caudate putamen (regions where DA is a critical neurotransmitter –> inc cation currents –> inc extracellular DA
What happens with nicotine toxicity?
dysphoria; nicotine inc BP & HR , MI (green tobacco sickness).
Smoke can lead to CO poisoning, CV problems, lung/esophageal cancer
What is a major byproduct of nicotine metabolism?
cotinine made by liver metabolism. Inactive.
How do you treat a nicotine addiction?
nicotine patch/gum, bupropion/varenicline
What’s the mechanism of caffeine?
Adenosine receptor antagonists at A1 and A2 receptors
A1: normally inhibits Gi and Go receptors→ antagonist increases Gi/o activity
A2: normally activates Gs: antagonism reduces Gs activity
What’s the mechansim?
binds receptors CB1 and CB2 to dec neurotransmitter release. More specifically:
Gi and Go stimulated: inhibit Adenylyl Cyclase –> open K+ ch –> dec Ca2+ conductance → disinhibition of DA release and reduced transmitter release
What are the sx of weed?
tachycardia, dry mouth, hunger, peripheral vasodilation, euphoria, audio/visual distortions, altered perception of time, garrulousness, relaxation/sedation, psychomotor impairment
What are the sx at higher doses of marijuana?
confusion, delusions, hallucinations, anxiety, panic, paranoia
What do CB1 receptors usually do and where do we find them?
Many CB1 receptors in brain (hippocampus, cortex nuc accumb, striatum)
- retrograde signaling in hippocampus and cerebellum -> depression
- Extinction of fearful memories (amygdala)
- Regulation of appetite
- Control of pain
What about the CB 2 receptors?
High [CB2 R] in immune cells: Immunomodulation
What are some of the theraputic uses of marijuana?
- Tx nausea & vomiting in chemotherapy
- inc appetite in AIDS, chemo pts
- dec intra-ocular pressure in glaucoma (not 1st line)
- Pain relief
What are some of the chronic sx of marijuana use?
- respiratory problems (smoke),
- immune suppression
- dec secretion of gonadotrophins & sex steroids (inhib spermatogenesis & placental function);
- antimotivational syndrome
- memory loss
- impairment of mental performance