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
caudate/putamen)
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
- Heroin
- Morphine
- Oxycodone
- Hydrocodone
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:
- Skin
- Heart valves (Right sided tricuspid - S. Aureus)
- Liver
- Lungs
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
- Proteinuria
- Nephrotic syndrome
What will you see on labs when you have an opiate overdoser on your hands?
6-MAM
monoacetylmorphine
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?
- Detox
- Maintenacne therapy
More detail in next cards
What does detox for opiate addiction look like
- Cold turkey – not recommended
- Methadone
- 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.
