Addicition Flashcards
Dependence
progressive pharm adaption resulting in tolerance
-take more drug to get the same effect
dependence =/= addiction
-could be found in meds that are required for CV diseases, etc.
Tolerance
repeating the same dose = less of effect
Reasons Why?
- PK: same dose produces dec blood [ ], increased metabolism (inc. CYP activity with higher doses)
- PD: change response, receptor desensitization/density dec, dec efficiency in signal transduction
- Learned: compensate behaviours (manage drunk symptoms)
Addiction
compulsive, out-of-control behaviour of drug use
focus on immediate pleasure despite LT negative consequences
disease d/t NT imbalance
classified in DSM-5
most drugs act @ the striatum
-change brain activity + environmental conditions (turns use -> habit)
- not everyone that tries drugs = addicted
- d/t family history, genetics, environmental (social, risk seeking exposure, availability, drug action, drug metabolism, psychiatric diseases
Ex. Chewing Tobacco
- chew tobacco/coca in mountains
- not very potent & absorption =/= fast (compared to other routes of admin - smoking)
- way you take drugs impacts addiction
Ex. Psychosis
- chicken vs. egg
- take to self-med b4 disease
- drugs lead to disease (trigger?)
Withdrawal
adaptive response to loss of constant inputs -> neurons begin to fire like crazy
Reward + Addiction
Nucleus Accumbens
- involved in addiction
- drugs that inc dopamine here = likely to feel euphoria + be addictive
- hijacks the reward pathway
- accumbens projects info to other areas of the brain (cortex)
- dual feedback
Cocaine + Amphetamines
- General Info
- Toxicity
- Withdrawal
- Treatment
Sympathomimetic of A
- SNS stimulant
- inhibits DAT (blocks reuptake of DA)
- also blocks 5-HT + NA reuptake
- may also inc secretion of NT (amphetamines = likely inc dopamine release from vesicles - main effect)
Experiment (mouse blue light fluorescence)
- inc. dopamine, 1st day inc reward
- see sustained inc dopamine (hijacking dopaminergic system)
- also expect reward pre-emptively (classical conditions)
Toxicity (CV toxic)
- cardiac arrhythmias
- myocardial ischemia
- myocarditis
- aortic dissection
- cerebral vasoconstriction
- seizures
Withdrawal Symptoms
- dysphoria/depression
- fatigue/sleepiness
- cravings
- low BP
Treatment
-avoidance + behav mod (need to detox)
Alcohol
generally CNS depressant @ high doses
initially causes disinhibition (GABA sys)
-prob = modifies inhibitory NT (such as GABA)
Withdrawal = depress CNS so much that now you remove the depressant + get high SNS activity
Alcohol Withdrawal - Mild
Anxiety, tremor, insomnia, headache, heart palpitations + GI problems
Alcohol Withdrawal - Moderate
Mild + Inc systolic BP, inc HR, confusion, Inc T
Alcohol Withdrawal - Severe (Delirium Tremens)
Mod + disorientation + impaired attention, hallucinations + seizures
Treating Alcohol Withdrawal
Dec SNS activity
- Benzodiazepines
- Anti-convulsants
- Beta-blockers
- a-adrenergic receptors
risk of liver failure
Alcohol Metabolism
Ethanol -> Acetaldehyde -> Acetic acid -> Acetyl-CoA
Methanol -> Formaldehyde -> Formic Acid
Enzymes: Alcohol dehydrogenase/CYP2E1/Catalyase -> Aldehyde dehydrogenase -> Thiokinase
Dangerous to ingest methanol (formic acid = BAD)
Fomepizole = inhibits alcohol dehydrogenase Disulfiram = inhibits aldehyde dehydrogenase
Opioids
Short acting (high within a few minutes; lasts for couple of hrs - get early WD symptoms)
Highly addictive
Can become tolerant to diff side effects
-Tolerant to decreased breathing (respiratory depression)
-not tolerant to pupil constriction + GI constipation
Too high of a dose = respiratory depression
Overprescription = chronic use + addiction
Opioid Mechanism of Action
MOR found in GABA neurons
- When activated = close N-type Ca2+ channels & open calcium-dependent inwardly-rectifying potassium channels (when by binds from Gi/o complex)
- results in hyperpolarization of GABA neuron + dec of GABA NT release
- also a subunit binds to dec AC activity (dec PKA + cAMP)
- inhibition of inhibition (overall = excitation)
- inhibit GABA = inc dopamine, = inc reward pathway = inc pleasure
Desensitization with tolerance may be d/t internalization pathways (GRK +P & B-arrestin)
-Dec availability of receptors, dec amt that receptors can signal, dec signalling molecule outside cell/activity
(all contribute to addiction/tolerance)
-Results in…
-Inc AC, PKC, PKA, + NMDA (hyperalgesia)
Opioid Treatment + Detoxification
For Rapid Treatment
Ex. Naloxone (Narcan)
-Use nasal passages b/c lung = inc SA, very rapid admin
-Used for respiratory distress
-Antagonist -> kicks all the opioid off the receptor
Treatment = use partial agonist to treat WD symptoms
Methadone
- prototype, MOR partial agonist
- slow onset + long lasting
- cross tolerance -> stops heroin euphoria
LAAM
-lasts for 72 hours
Buprenorphine
- MOR partial agonist
- OD risk = lower
- Heroin action = dec
