cocaine.pdf

History: Cocaine - Plant based, indigenous cultural use - Pre-Columbian (2500 BC) - Spanish conquest 1500s introduced to Europe - Isolated concentration from plant (1860) - Medical use, late 1800s - Used to try to treat depression - Freud - First local anesthetic - Added to various beverages - Origi...

History: Cocaine - Plant based, indigenous cultural use - Pre-Columbian (2500 BC) - Spanish conquest 1500s introduced to Europe - Isolated concentration from plant (1860) - Medical use, late 1800s - Used to try to treat depression - Freud - First local anesthetic - Added to various beverages - Originally used as remedy drinks - Promoted as health tonic instead of alcohol - Vin mariani - Coca cola - Wine of cola - Became commonplace and used as a health tonic in NA - In place of alcohol during the prohibition - Became illegal due to recognition of addition potential and health issues and possibly racism - 1914 ban use - Cocaine use in African-Americans tied to crime History: Amphetamines - Plant based, indigenous cultural use - Ephedrine used in China for 5000 years and India traditional medicine and spiritual purposes - Leaves were used in teas to help with respiratory problems and as a stimulant - Amphetamine extracted from plant (1885) later synthesized (1887) - But effects not widely grasped until 1920s - Medical used sanctioned by American Medical Association (1937) - Marketed for respiratory use - Commonly used in wartime to help soldiers stay awake and remain vigilant, ‘pep pills’ which likely popularized these - After the war, used for many purposes - Weight reduction, antidepressants, stimulants, menstrual difficulties, etc - Fairly widespread use regularly prescribed - Recognition in the 70s of risk for dependence and a decline in prescription and use, late restriction - Currently used medically for narcolepsy and hyperactivity in children - Currently also illegally manufactured - MDMA - Can be grouped in with stimulants and hallucinogens - Influenced emotions and environment - Thus, different than these stimulants History: Cathinone (Khat) - Khat plant grown in Africa and other places - Leaves chewed to provide a mild stimulant effect - Like cocoa leaves, chewing history thousands of years in some indigenous populations - Alexander the Great - cure for melancholia - Various references by Arab physicians for many disorders historically - Early awareness in Europe (1600) but more recent use in western nations due to transport degradation of plant - Doesn’t travel well - Illegal in NA and some EU countries - Mephedrone (synthetic cathinones like active component of khat) was synthesized in 1920s and rediscovered in early 2000s (meow meow, bath salts, plant food) banned in 2012 in Canada Some Basics Cocaine - Cocoa leaf (low concentration) chewed for mild stimulant effect - Doesn’t produce the strong effects we normally see now - When it is exposed to chemical extraction it creates cocaine hydrochloride - Cocaine hydrochloride (high concentration, salt) snorted, injected - It is a salt so can be dissolved into a liquid - Coca cola - Can further process it and use solvent to release cocaine from hydrochloride - Freebase cocaine (stronger/faster effect) - solvents are used to release the cocaine from the hydrochloride - Cocaine hydrochloride is in an acid and a base so freebase releases it from that base - Use ether to do this (can explode) - End result is a power and if the ether hasn’t dried all the way can also explode - Smoke or inhale vapors - From heating the powder - Add another base substance and heat to produce ‘rocks’ - Usually add baking soda (another base) - Crack cocaine (stronger/faster effect) - Smoked or inhale vapors - Freebase and crack cocaine are stronger/faster than cocaine hydrochloride - Because the volume of lung tissue is greater than nose (snorting) - Strength is purely related to how to drug is administered Synthetic (Man Made) Sources - Amphetamines (treatment of ADHD and narcolepsy) - Dex-amphetamine - more potent CNS effects - Treatment for ADHD and narcolepsy - Levo-amphetamine - Combination of both found in dl-amphetamine - - Use - - Adderall used for ADHD and narcolepsy Methamphetamine - uncommonly used treatment of ADHD and obesity - more commonly in illegal trade - crystal, ice, crystal meth (smoked) Methylphenidate - Ritalin - treatment for ADHD, similar chemical structure to cocaine Pipradrol - Meratran - used some places to treat dementia Many synthetic derivatives of Cathinone from khat plant - ex. Bupropion - antidepressant and smoking cessation aid, bath salts used recreationally 2021 - canada prevalence of cocaine in general population in 2% (mid-range compared to other countries) - Increased in the previous years - Adults 25+ and youth 15-19 are under the 2% range - Young adults 20-24 are around 9% in 2019 - Was 3% in 2013 - One of the most commonly abused substances in the country - Along with alcohol, cannabis, and nicotine - Amounts to almost half of the total number of total amount of illegal drug use in Canada - 2019 - prevalence of use of amphetamines and methamphetamines in general population is lowest in Canada compared to other western countries (.25%) - Highest use was in 2015 in young adults (5%) Overdose and Deaths - 2744 poisoning deaths (overdoses) caused by stimulants in 2020 (6 provinces) - Cocaine is frequently involved in overdose deaths - 63% of accidental opioid-related poisoning deaths in 2021 involved cocaine, while 53% involved methamphetamine - Polyuse of drugs or they just don’t all the components of the drug they are taking contribute to the increase of deaths - National Drug Driving Research Project collected data from 4976 injured drivers treated in 15 trauma centers across Canada between Jan 2018-May 2021 - Cocaine, amphetamines, or both were detected in 11% of drivers Neuropharmacology Administration, Absorption, Distribution - Cocaine - Water soluble, weak base - Easily absorbs into the body - From slowest to fastest routes - Stomach (beverage) - When taken orally, food and other contents play a factor in rate of absorption - Peak levels at around 30 min - Nasal membrane (powder, cocaine HCL) - Can somewhat slow absorption - Cocaine is a vasoconstrictor, this snorting it will have a reduced blood flow - Because it constricts the blood vessels in the nose - Makes it harder to use as a delivery route - Only 20-30% of what is sniffed is actually gets into the bloodstream - Peak levels 20-40 min - Lungs (smoke or vapor, freebase, crack) - Only absorb 5-30% but really fast absorption - Because lung has more surface volume - Peak reached in 5 min, but ends faster too - Injection (powder, cocaine HCL) - Fastest effect, near immediate - Most absorbed - Amphetamines - Oral route is typically used for medical delivery - For ADHD and sleep - To allow blood levels to remain more constant and to last in system longer - When used recreationally, use other faster administration routes - Want rapid peak blood level, strong effect - All of these drugs cross the BBB and are concentration in the spleen, kidneys, and brain - As with drugs from illegal markets, cocaine and other stimulants usually contains adulterants/impurities - It may also be mixed with other drugs often unknown to the user Excretion - Excretion of the amphetamines depends on the pH of the urine - It’s ionized at acid pH, so it is not reabsorbed from the nephron in acidic urine - But in more basic urine, more of the drug is going to be reabsorbed and be metabolized by the liver - Many roots and enzymes involved - Many metabolites of the drug remain active - Also excreted in sweat and saliva - Half life between 16-34 hours - For narcolepsy is beneficial, helps with sleep/stay asleep - Recreationally, not beneficiary, interrupts with daily life - Cocaine - Excreted much faster than amphetamines - Half-life about 40-75 min - Binge behaviour - Use it all up in one day until it's gone - Cathinone - Half-life about 90 min Stimulate Monoamines - All stimulant drugs stimulate monoamines - Making more active synapses that use epinephrine, norepinephrine, dopamine, and serotonin - Can also be called sympathomimetics - Because they stimulate sympathetic synapses - Mimicking the natural sympathetic arousal - Primarily due to their actions on epinephrine the primary NT in the sympathetic NS - Catecholamines - Epinephrine (EA) - Norephinepherine (NE) - Dopamine (DA) - Indolamine - Serotonin (5-HT) Neurophysiology - Effect on Monoamine Synapse - Note - monoamine action is terminated by the presence of enzymes: monoamine oxidase and COMT - These enzymes are in the synapse - Also terminated through reuptake/reabsorption back into the presynaptic neuron - Done by the monoamine transporters - Each monoamine has a specialized transporter (cert net) - These transporters will need something like sodium or chlorine to be bound in addition to the specific monoamine - Both need to be connected to the transporter in order for them to move back up into the presynaptic cell - Stimulant drugs alter the functioning of these transporter proteins in 2 ways - First - Cocaine acts as a reuptake inhibitor - Binds to the receptor site of the transporter and remains there, blocking the transport of monoamine into the cell (reptake) - Prevents the transporter from connecting to the monoamine - Monoamine remains in the synaptic cleft longer and at higher concentrations than it would normally be - Thus, continuing its effect on the postsynaptic membrane - Technically cocaine exaggerates the action potential - Allows prolonged activation of the postsynaptic cell resulting from an action potential bc it doesn’t allow for the transport molecules to bring monoamines back into presynaptic cell to terminate the signaling - Second - Amphetamines act as substrate-type releasers - Amphetamines are structurally similar to monoamines, so they can enter the presynaptic neuron by hitching a ride on the transmitter proteins (transporters) - Basically take the place of the monoamines during the reuptake process - The transporters will transport the amphetamines back into the presynaptic cell into the axon terminal - Once at the axon terminal it will get packaged into the synaptic vesicles along with other monoamines - Repackage in order for the NTs to be released again at the next action potential - Because they are taking the place of some monoamines in reuptake, it slows reabsorption of the monoamines - Causes longer activation of postsynaptic cell - In axon terminal they also disrupt the pH balance in the presynaptic vesicle - Can trigger the release of monoamine into the cytoplasm of the axon terminal - Puts the vesicle in reverse (dumps contents of vesicle out) - By disrupting the pH, it inhibits the vesicle functioning and the repackaging process - Causes the transporter protein to work in reverse to manage the overload of monoamines in axon terminal - The transporter proteins will start to move monoamines into the extracellular space acting as though an action potential was triggered even though it wasn’t - Causes transporter to briefly open allowing monoamines to move into extracellular space - Inhibits the activity of monoamine oxidase enzyme (MAO) which degrades the monoamines that are floating in the cytoplasm - By inhibiting MAO, encourages longer survival of monoamines in the synapse and encourages their accumulation - Can block the vesicle and prevent the storage of monoamines in the vesicles - Increase amount if transmitter released in response to action potential - Last longer - Block reuptake Neurophysiology - Monoamine transporters - Dopamine transporters (DAT) - Norepinephrine transporter (NET) - Serotonin transporter (SERT) - Cocaine binds similarly to all three - Amphetamine and methamphetamine are most potent as NET, less as DAT, and even less as SERT - Methcathinone, and cathinone, similar to amphetamines Effects Effects in the CNS - In CNS, all monoamine systems are affected by stimulant drugs - Most of the effects are on the dopamine NT and dopamine transporter molecule (DAT) - Dopamine important for - motor activity control (by substantia nigra to striatum) - mesolimbic dopamine system (ventral tegmental area VTA circuit to the nucleus accumbens - reward circuitry - All stimulants are expected to increase the release of dopamine to these systems - Increased hindbrain activity = increased alertness, less sleep, more activity - Increased midbrain activity = more energy, more agitation - Increased forbrain activity/limbic system = positive emotions, increased motivation, and activity - Much of CNS activity is driven by DA Effects in the PNS - Stimulants activate the PNS - Do this by exciting synapses that use epinephrine - Epinephrine involved in activating the sympathetic NS - Leads to sympathetic arousal - When stimulants are used it activates fight-flight, stress response Acute Effects of Stimulants - Effects on body - Dilated pupils - Dry mouth - Increase in HR and BP - Vasodilation - Bronchodilation - useful for asthma - Indirect effect of food consumption (decrease) - Increased energy (adrenalin, glucose release) Acute Subjective Effects - Improved mood - Decreased fatigue - Increased energy - Improved concentration - Rushes - intense feelings of euphoria produced by rapid absorption procedures often sexual in nature (orgasmic) - Shows rapid tolerance - Crash - mild depression - Peak at 2 hours amphetamine, 3 h for methylphenidate, shorter for cocaine (23-30 min) - All 3 have same effects, but different durations - Reason why cocaine has binge users, want the high for longer because it doesn’t last as long like amphetamines - Influenced by expectation - Greater when blood levels are rising than falling - Showing acute tolerance effect - more effect on the high entering system than when leaving system Sensory Effects - Seen more with amphetamines - Increased visual acuity - Minor improvements of hearing - Passage of time is underestimated, so time is perceived to go by more slowly Stereotyped Behaviour - First described by Gosta Rylander (1965) - Repetitive performance of an act for extended length (in humans - punding) - Ex. taking apart things and putting them back together, organizing, cleaning - People get agitated it they are interrupted when doing this - Also observed in lab animals - More ‘complex’ species, more complex and varied the stereotyped behaviour - Usually same behaviour in one individual - Likely related to stimulation of nigrostriatal DA system Effects on Performance at Low Doses - Improved - RT - Attention (but possible deficits for divided attention tasks) - Due to amphetamines causing tunnel vision - Tasks that need flexibility or people being in tune with the environment might be inhibited - Ex. driving - Driving - 2.3x more likely to have a fatal car accident related to narrowing of attentional focus - Vigilance - STM - Athletic performance - bronchodilators, banned by sports feds - ADHD - correction of inattention related deficit in monoamine function in prefrontal cortex - Helps them focus their attention and zone out distracting environment Dissociation and Drug State Discrimination - Animals trained under the influence of amphetamine cannot completely remember what they learned when the drug was worn off - Discrimination learning difference - When given amphetamines, were able to do the task well, but when given other drugs, they tanked Chronic High-Level Use - Monoamine psychosis - Psychosis can occur when using high doses repeatedly of all these stimulants - Auditory and visual hallucinations, delusion, hostility, depression and axiety - Linear relationship - More use more likely/stronger psychosis is - Paranoid schizophrenia - Formication - tactile hallucinations - Hallucination of something touching skin - Ex. bugs crawling on/under the skin ‘crack bugs’ - Lead to people picking their skin, leads to sores - Violence/hostility - Not frequent and not the same and monoamine psychosis - Anxiety and depression - Dependence Tolerance - Acute tolerance - Related to subjective effects - Sniffing every 20-30 min for 10-13 hours of cocaine eventually will lose the rush and ability to boost the mood - People will stop by then - After around 24 h this tolerance will dissipate - Chronic tolerance - Appetite suppressant - Can tolerate after a few weeks use - Heart and blood pressure - Lethal effects - Doses can increase lethal effect - What would originally kill the person not anymore - Sensitizations (increased sensitivity of mesolimbic DA system) - reverse tolerance - Stereotype behaviour - Psychotic behaviour - Increased sensitivity cues Withdrawal - Not associated with a severe or medically serious withdrawal - Crash - Depression - Most common even after acute tolerance withdrawal - Related to dose and duration - Stronger for higher/longer dose - Symptoms - depression, insomnia, decreased appetite - Opposite effect of initial effects of the drug Amphetamine for ADHD - Why do stimulants work for ADHD? - Increased DA activity (especially in frontal cortex) may help individuals pay attention to what is important among small stimuli - Help amplify the environment signal to noise ratio - Can increase motivation and have more drive to to the things they are focusing on - Side effects - reduction in growth rate - Suppression of height and weight gain - Lack of motivation, depression, lack of energy - May be given inappropriately - Ex. may suffer from depression, anxiety, learning disabilities, conduct disorders for which other treatments would be more appropriate - Is interpreted as ADHD - Overdiagnosis - Drugs can be misused - Crushed up and used recreationally Harmful Effects of Stimulants - Physical damage related to chronic use - Cocaine can interact with nasal mucous to produce hydrochloric acid and dissolve nasal tissues, anesthetic properties of cocaine may encourage further use - Can develop ulcers or lose nostril - Damage liver - Heart damage - Stimulants rev up the heart, and more extended periods of time at a high rate can cause potential risk for heart attack - Stroke risk - Impacts vascular system - Especially in brain, can lead to a stroke - Parkinsonian-like tremors - Sleep disturbances - Broken, discolored, rotting teeth - Usually attributed to meth (stronger) - Stimulants activate sympathetic nervous system - Causes salivation to be reduced, dry mouth causes mouth acids to increase = damages teeth - Can also grind their teeth on meth - Impact their diet - Eat sugary food and not care about brushing when on stimulants - Skin picking - Psychological - Anxiety - Depression - Paranoia, psychosis Harmful Effects - Indirect - Hepatitis - Needles - AIDS - Needles - Infection - More prone to infection - Skin picking, snorting - Inability for body to even fight off the infection - Prone to violence - Cant think through consequences - Increased energy - High death rate - Related to interaction of chronic effects and lifestyle - Addiction and their impact on social lives - Lose support circle Fetal Exposure - Abnormalities typically observed in infants of cocaine exposure in utero - Low birthweight - Smaller head circumference - Tremors - Excessive crying - Disturbed sleep patterns - Diminished responsiveness - Long-term effects are difficult to study but generally show a small effect on mental and cognitive function with boys at a greater disadvantage than girls Harmful Effects - Overdose - Those who take large doses commonly experience muscle weakness and respiratory depression - They just stopped breathing - Lethality depends on route of administration - Needle vs inhalation - Caine reaction (cocaine overdose) - Initial excitement followed by severe headache, nausea, vomiting and severe convulsions - Followed by loss of consciousness, respiratory depression, and cardiac failure resulting in death Treatment - Behavioral therapies - Contingency management, CBT - Counseling, group therapy - Any support system - Immunization - Pharmacotherapies - Modafinil - Bupropion - Methylphenidate - Oral d-amphetamine - Naltrexone - No clear drug that is used to specifically help