ps333 exam #3

peripheral effects of nicotine

peripheral effects of nicotine

sympathomimetic = increased HR, increased BP, increased respiration, skin vasoconstriction (blood vessels are less active = cold to touch + skin wrinkles faster); increased smooth muscle activity; parasympathomimetic = stomach muscles will contract more (natural laxative)

central effects of nicotine

nausea (bc of activation of vomiting center), arousal (arousal of midbrain areas), + improvements in motor + cognitive performance (attention, short term episodic memory, + motor skills)

subjective effects of nicotine

stimulation, mood enhancement/pleasure, increased DA release in NAc tied to reinforcing effect (nAchRs are in mesolimbic pathway), + rapid blood absorption makes it more addicting

Tobacco Use Disorder (TUD)

3 major criteria; larger quantities of tobacco consumed than intended, tolerance for nicotine, + withdrawal symptoms after cessation of use

Nicotine withdrawal/dependence

complex because nicotine impacts many systems in the body + the brain; cognitive, emotional/psychological, + physical withdrawal symptoms; decreased HR, increased eating, insomnia, difficulty concentrating, craving, irritability, anxiety, etc.

nicotine physical dependence

most symptoms develop after several days, peak after a week; women experience stronger dependence bc they have more CYP2A6

nicotine psychological dependence

strong craving to return to nicotine use, no matter how many years they have been sober

harmful effects of smoking tobacco

increased risk of cardiovascular diseases (coronary heart disease + stroke), lung cancer, other forms of cancer, + respiratory diseases (chronic bronchitis + emphysema), nicotine can pass placental barrier = increases miscarriage, + stillbirth, baby’s risk of developing respiratory problems, birth defects

harmful effects of smokeless tobacco

cardiovascular risks, gum disease, damage to tooth enamel, loss of teeth, oral cancer, cancer of jaw, pharynx, + neck

negative effects of vaping

vapes contain carcinogenic properties + can damage lungs, breathing problems

psychomotor stimulants

drugs that enhance wakefulness and alertness, reduce fatigue + whose primary mechanism of action is to increase neurotransmission at monoaminergic synapses (dopamine, epinephrine, norepinephrine, + serotonin)

natural psychomotor stimulants

ephedrine (derived from an herb), cathinone (khat), cocaine (Erythroxylum coca)

Ephedra sinica

used in traditional chinese medicine for 5000+ yrs, ephedrine is chemically similar to epinephrine (sympathetic nervous system stimulant), originally used to treat asthma (bronchodilator + decongestant)

Catha edulis (Khat)

perinnial shrub found thru/out East Africa, cathinone is chemically similar to amphetamine, provides energy + reduces fatigue

Erythroxylum coca (cocaine)

dated back to 2500 BCE, sacred to Incas; chemically isolated in 1860 by Albert Neimann; extracted from leaves of coca bush in South America, produces euphoric effect

synthetic psychomotor stimulants

amphetamine, methamphetamine, + cathinone derivatives (bath salts)

cocaine in late 1800s

first local anesthetic, added to various beverages (Vin Mariani wine + Coca Cola until 1903); also thought to have therapeutic properties

Harrison Narcotics Tax Act (1914)

imposed taxes on sale, distribution, manufacturing, important, + distribution of coca leaves, opium, or any derived product; still allowed physicians to prescribe cocaine (could not use cocaine for pharmacotherapeutic purposes)

cocaine manufacturing

takes place in remote jungle labs where raw product undergoes a series of chemical transformations; Colombia produces 90% of cocaine powder reaching US

cocaine as local anesthetic

@ high local concentrations, cocaine inhibits voltage-gated sodium channels = blocking nerve signals for somatosensory/pain perception (procaine and lidocaine)

cocaine scheduling

cocaine is schedule 2 bc it has high misuse potential but still has some medicinal properties/uses (primarily topical local anesthetic for upper respiratory tract + reduce bleeding of mucous membranes in mouth, throat, + nasal cavities)

subjective/euphoric effects of cocaine

depends on how quickly cocaine reaches brain, faster it reaches = more rapid onset; IV (intravenous > INH/S (inhalation/smoking) > IN (intranasal) > PO (oral); improved mood, euphoria

mild/moderate effects of cocaine

mood amplification (euphoria + dysphoria), heightened energy, insomnia, motor excitement, talkativeness, hyperactive ideation, increased sexual interest, anger, mild to moderate anorexia, + inflated self-esteem

severe effects of cocaine

irritability, hostility, anxiety, extreme energy or exhaustion, total insomnia, compulsive motor stereotypies, rambling, disjointed flight of ideas, decreased sexual interest, possible extreme violence, total anorexia, + delusions of grandiosity

absorption of cocaine

cocaine is weak base (not good absorption), traditionally mixed with limestone so it raises pH of saliva which in turn increases absorption in the mouth

cocaine routes of administration

insufflation, IV (dissolved cocaine HCl), smoked (free base + crack)

cocaine distribution

readily crosses BBB, distributes to the brain

free base

cocaine HCl + ammonia and then extracted; more pure

crack

cocaine HCl mixed w/ sodium bicarbonate, dried into cakes; removes ionic charge = increased lipid solubility, lower melting point = allows vapor inhalation

absorption of amphetamines

amphetamines are weak base (not good absorption), depends on route of admin; two chemical forms active differently bc of chemical orientation

absorption of methamphetamine

compared to AMPH, more potent, more lipid soluble, chemically stable, + better BBB penetration

AMPH route of administration

amphetamines most potent by injection or inhalation; methamphetamines can be smoked, injected, or snorted

distribution of methamphetamine

more lipid soluble = can get into brain easily

metabolism of psychostimulants

all metabolized in the liver, although up to 40% of amphetamine may be excreted unaltered bc absorption is so low

excretion of psychostimulants

depends on pH of the urine (what is in the stomach), AMPH half-life 16-36 hours at basic pH, but as little as 7 hours w/ acidic pH; cocaine half-life 1 hour

presynaptic mechanism of cocaine

cocaine has binding site on dopamine transporter which blocks its activity, also blocks reuptake of norepinephrine + serotonin = more monoamine transmission in mesolimbic reward system; quickly binds + quickly comes off

presynaptic mechanism of apmhetamine

competitive substrate releasing agent; AMPH sneaks into cell, which allows it to sneak into vesicles, it causes vesicles to empty their contents, it reverses the transporter (release instead of reuptake), + inhibits enzymes (like MAO enzymes) that break down the neurotransmitter; massive increase in DA, NE, + serotonin

amphetamine vs methamphetamine

methamphetamine is more potent + faster acting, more lipid soluble + chemically stable, and has better BBB penetration; meth has additional methyl group

amphetamines in ADHD treatment

absorbed poorly from digestive system; slow/poor absorption creates more sustained lvl of amphetamine, advantage for medicinal use (d-Amphetamine = Adderall + Methylphenidate = Ritalin); increase NE + DA signaling in PFC = therapeutic effect (brings transmission lvls to “normal”)

animal models of psychostimulant reinforcement

rats will work on fixed ratio schedule + progressive ratio schedule to self-administer cocaine; depends on access; limited access = administer in steady manner, controlling cocaine intake; unlimited access = animals will binge; if provided w/ other rewarding behaviors, will decrease cocaine self-administration

cocaine “rush”

rapid onset of an acute/intense state of euphoria induced by cocaine reaching brain in seconds (via smoking or IV injection)

acute effects of cocaine

local anesthetic, activation of sympathetic nervous system, burst of energy + sense of wellbeing, rush that lasts b/t 20-30 minutes

acute effects of amphetamines

similar to cocaine; “rush” that can last up to 24 hours, increased wakefulness (insomnia), increased libido, increased HR + BP, enhanced mood (intense euphoria)

psychostimulant dependence + withdrawal

crash anhedonia, compensatory increases in sleeping + eating; anxiety, agitation, depression, + drug cravings that can last for a while depending on frequency + extent of use, + long term cognitive dysfunction (reduction in PFC)

crash/comedown anhedonia

period of depression + lethargy that usually begins 24 hours after drug cessation

monoamine psychosis

symptoms similar to schizophrenia; delusions, hallucinations, ‘formication’

psychological effects of psychosimulants

elevation of mood euphoria, increased vigilance, reduction of mental fatigue, sleep prevention; addictive properties, memory deficits

physiological effects of psychostimulants

increased HR, BP, vasocontriction, brochodilation, appetite suppression, over-driving fight or flight response, sleep prevention; neurotoxicity (death of neurons)

performance effects of psychostimulants

increased endurance, reduced physical fatigue; banned in athletic competitions, creates narrowed focus (reduces driving performance), repetitive motor behavior in animals + humans

punding

compulsive + repetitive task by humans when under the influence of psychostimulants

chronic harmful effects of psychostiulants

physical consequences = severe weight loss + myriad of dental issues (mostly due to malnutrition + lack of hygiene, esp. if smoked); reduced cortical activity (death of neurons); pharmacodynamic tolerance (downregulation of receptors); cell death and/or reduced neurogenesis (loss of brain volume)

formication

sensation of bugs on the skin as a result of repetitive psychostimulant use

caine reaction

overdose on cocaine, 2 phases; severe headaches, nausea, convulsions; then respiratory depression + cardiac arrest (which ultimately causes death)

original use of opium

in Mesopotamia by the Sumerians, valued the poppy plant + probably used it medicinally for its analgesic effects

origins of opium

originated in Asia + later Mediterranean regions, traders brought it to China in 9th century, smoking opium created addictions fueled by British-owned opium from India; Greek physicians Hippocrates + Galen recommended opium for just about everything

opium in Europe + Americas

opium use was widespread in Britain + US at all lvls of society in mid-1800s, advertised as “cures”, available by mail order

source of opium

derived from latex (“opium milk”); scrapped off the seed pods of poppy plant, compressed into cakes + dried

psychoactive extracts of opium

morphine (10%), codeine (2.5%), + thebaine (1%)

opioid derivatives (semi-synthetic)

heroin (from morphine), hydrocodone (Vicodin, from codeine), oxycodone (Percoset, from thebaine), + buprenorphine (Suboxone, from thebaine)

synthetic opioids

methadone, meperidine (Demerol), fentanyl, carfentanil, + many more

countries that still produce illicit opioids

“The Golden Triangle”; Afghanistan; China ships base chemicals to Mexico where they are further processed + then fentanyl is smuggled into U.S via U.S-Mexico border

fourth wave of overdose crisis

more than just opioids, overdoses as a result of opioids mixed w/ other psychoactive substances (opioids + stimulants); cannot consider it “just” opioids

regional differences in stimulant-related overdoses

methamphetamine more prevalent in mississippi + southern states, cocaine is more prevalent in northeast, immigrant, Indian, + black communities affected disproportionately, + more men overdose on fentanyl than women

treatments for StimUDs

no treatment available right now

contingency management (CM)

behavior change technique based upon the principles of operant conditioning where reinforcement is provided contingent on the occurrence of a target behavior consistent with reduced cocaine and/or methamphetamine use; highly effective but expensive

challenges of contingency management

no regulated guidelines, ppl are generally resistant to the concept, expensive/difficulty financing, + regulatory obstacles

effectiveness of CM

more effective when reinforcer is provided @ higher rather than lower levels, provided more immediately, + highly probable of being delivered

methods to prevent misuse of opioids + overdoses

interventions, early screening, more accessible healthcare, more research on pain + addiction, better practices for pain management, non-addictive strategies to manage chronic pain, new medications + tech to treat OUDs, improved overdose prevention + reversal interventions, comprehensive

3 medications approved by FDA to treat OUD

methadone (full agonist at MOR), buprenorphine (partial agonist at MOR), + extended-release naloxone (antagonist at MOR); stigmatized bc people do not understand medicated-assisted treatments

naloxone

fundamental for reversing opioid overdoses, antagonist at MOR; rapidly + fully reverses opioid overdose

OUDs + criminal justice settings

60% of prison population has SUD, treating b/4 release can reduce risk of overdose + reincarceration, more likely to overdose after being released bc they take high dose + their body cannot handle it (behavioral tolerance)

routes of administration of opioids

pharmacological use = morphine + codeine usually oral administration bc no acute euphoric effect + easy to manage blood lvls; recreational use = usually injected, smoked, or snorted (not usually taken orally) bc it maximizes euphoric effect (intense euphoria + rapid onset)

designer opioids

modified versions of controlled substances (improves potency, easy to make + cheaper)

Krokadil

derived from codeine, active ingredient = desomorphine, powerful analgesic, results in toxic byproducts that can cause scaly, gangrenous wounds

morphine vs heroin

morphine = acts directly on central opioid receptors; heroin = has additional acetyl groups which helps it to cross the BBB but no impact on receptor

heroin

schedule I drug; derived from morphine, has 2 additional acetyl groups that greatly improved lipid solubility; once heroin gets into brain, enzymes metabolize it back into morphine (which causes psychoactive effects)

pkA of morphine

pH = 8.5, makes it a base = poor absorption from the GI tract; only 15% gets to brain, significant first-pass metabolism via CYP3A4 enzymes in liver + gut break it down a lot

opioid absorption

morphine is base = poorly absorbed from GI tract (good for steady state levels); heroin is usually snuffed or smoked (IV fallen into disfavor)

opioid distribution

heroin passes BBB easily but must be metabolized back into morphine; morphine has poor lipid solubility but high affinity for receptors; many opioids are bound to blood proteins which extends their half-life

opioids well-absorbed in the gut

methadone, codeine, + oxycodone bc metaboized by different family of enzymes im GI tract which does not affect their bioavailability as much as other opioids

contemporary opioid use

1960s = Vietnam War vets brought back high grade opioid products with them + greater public acceptance of drug use + experimentation; present = opioids have become one of the most highly prescribed of all drugs (declining in recent years, peaked in 2012)

US drug overdose deaths per year

64% of ALL drug overdose deaths in US from April 2020 - April 2021 were specifically attributed to opioids (like fentanyl)

COVID-19 drug overdose deaths

increased drastically, 55% increase in opioid related overdoses + 47% increase in psychostimulant related overdoses

major opioid receptors

metabotropic; Mu (or MOR), Kappa, Delta, + ORL1 (nociception receptors; opioid-receptor like, in peripheral + spinal cord)

Mu opioid receptors (MOR)

primarily for analgesia + euphoric effect, all exogenous opioids bind to it; most important for sensing pain in spinal cord

distribution of opioid receptors

concentrated in midbrain (periaqueductal gray = pain perception), thalamus, hippocampus, ventral striatum, + olfactory bulbs; mu receptors thru/out brain + spinal cord

periaqueductal gray (PAG)

primarily for pain perception; can increase or decrease sensitivity to pain

presynaptic opioid receptor

inhibit VGCa2+ channels = decrease in neurotransmitter release (glutamate, GABA, etc)

postsynaptic opioid receptor

activate a variety of K+ channels to hyperpolarize neurons (K+ flows out of the neuron); opioid is inhibitory neuromodulator

endorphins

greatest affinity for mu receptors, “morphine within”, analgesia + reinforcement

enkephalins

greatest affinity for delta receptors, for analgesia + reinforcement

dynorphins

greatest affinity for kappa receptors, analgesia + dysphoria

nociceptin

greatest affinity for ORL1 receptors, regulate signals abt pain in peripheral + spinal cord (analgesia)

NAc opioid-induced DA release

beta endorphins bind presynaptically on GABAergic neuron in the VTA = blocked release of GABA; dopaminergic neuron is disinhibited = increased DA release to NAc = increased DA release in NAc to ventral pallidum (drive/motivated behavior)

mu opioid receptor competitive agonists

morphine, methadone, LAAM, fentanyl; mild-to-moderate binding affinity = heroin + codeine converted back into morphine in brain, short-acting forms = powerful “rush” (heroin, morphine, fentanyl), long-acting forms = weak “rush” (codeine, methadone)

mu opioid receptor competitive antagonists

work by competing for opioid binding sites + preventing exogenous opioid agonists from binding to MORs, no intrinsic efficacy of their own

Naloxone (Narcan)

high MOR binding affinity, short half-life + very rapid onset when given IV or intranasally; used to treat opioid overdose

Naltrexone

longer duration of action; blocks euphoric effect of opioids (and other drugs), used to treat many substance use disorders

opioids + analgesia

reduce sensation of physical pain (heat or cold, physical damage + organ damage) + emotional reaction to pain

physiological effects of opioids

nausea + vomiting (activation of MORs in brainstem region that controls vomiting), constipation (activation of opioid receptors in gut = inhibitory effect on motility), profuse sweating, pinpoint pupils, + sleep/sedation (produces drowsiness but long-term can cause insomnia)