6.4 Drugs of abuse & alcohol Flashcards
The central reward pathway is part of the dopaminergic mesolimbic system, and facilitates the motivation and desire for rewarding stimuli and reinforcement:
• Dopaminergic neurones project from the ________________ → ventral striatum (includes nucleus accumbens and olfactory tubercle) → release dopamine into the ________________ → associated with feeling of reward
• Drugs of abuse increase the amount of dopamine released in the NAcc → euphoric feelings of reward (facilitates and maintains addiction)
ventral tegmental area (VTA);
nucleus accumbens (NAcc);
What are psychoactive drugs that is classified as narcotics?
heroin
What are psychoactive drugs that is classified as depressants (downers)?
Alcohol, benzodiapenes, barbituates
What are psychoactive drugs that are classified as stimulants (uppers)
cocaine, amphetamine (speed), nicotine, metamphetamine (crystal math)
what is the route the drug goes through if taken orally?
Gastrointestinal tract → hepatic circulation → venous system → heart → brain
what is the route the drug goes through if taken intranasal?
Mucous membranes of nasal sinuses → venous system → heart → brain
what is the route the drug goes through if taken intravenous?
Venous system → heart → brain
what is the route the drug goes through if taken inhalational?
Small airways/alveoli → heart → brain
[CANNABIS (MARIJUANA)]
Cannabis acts as a depressant and a hallucinogenic, which is found in all parts of Cannabis sativa (plant) with more than 60 types of cannabinoids:
• ________________ is the most potent of all the cannabinoids → high concentration in trichomes (hashish/resin on the glandular hair of leaves)
• Can be extracted (via solvent extraction) into
___________ (more concentrated than trichomes)
• Poor correlation between plasma cannabinoid concentration and the degree of intoxication → plasma concentration does not account for presence of toxic metabolite (from liver) and concentration of cannabinoid in fatty tissue
Δ9-THC (tetrahydrocannabinol);
hash oil;
[CANNABIS (MARIJUANA): Absorption]
Oral: delayed onset/slow absorption from the gut (first-pass metabolism before entering the systemic circulation)
• Bioavailability of _______________
Inhalation: onset in seconds to minutes
• Bioavailability of ______ (readily absorbed into the pulmonary circulation → _________________) → other 50% is breathed out or swallowed
10 – 15%;
50%;
brain and high perfusion tissues
[CANNABIS (MARIJUANA): distribution]
Very lipid soluble (slowly accumulates in fatty tissue as _______________) → lipid-soluble drug is normally cleared from high perfusion tissues within 48h:
• Cannabis clearance (accumulated in fat): slowly released back into bloodstream → remains in system for prolonged period
• Tissue t1/2: __________
fat receives very little cardiac output;
7 days
[CANNABIS (MARIJUANA): metabolism]
Metabolised into ____________ in the liver (more potent than cannabinoids → more effective at producing cannabinoid-like effects):
• 65% is metabolised in the GIT → feeds into _________________- (excreted as bile into gut then reabsorbed back into bloodstream)
• Highly potent metabolite is recycled from blood through the liver → gut → blood (cannabinoid effect lasts as long as metabolite is present in the system)
11-hydroxy-THC;
enterohepatic cycling
[CANNABIS (MARIJUANA): excretion]
________ is cleared in urine
25%
[CANNABIS (MARIJUANA): pharmacodynamics]
Cannabis and its metabolites interact with cannabinoid receptors (GPCRs negatively coupled to adenylate cyclase → depressant activity) in the brain and periphery:
• ___________ is the endogenous agonist of CB receptors (product of arachidonic acid)
Anandamide
Where are CB1 receptors located?
Brain (hippocampus, cerebellum, cerebral cortex, basal ganglia)
Where are CB2 receptors located?
Periphery (immune cells)
[CANNABIS (MARIJUANA): effects- euphoria]
Binding of cannabis to CB1 receptors inhibits ______________ (resulting in disinhibition) → increases rate of firing of reward neurones (VTA → NAcc → dopamine)
GABAergic interneurones
[CANNABIS (MARIJUANA): effects- psychosis/ schizophrenia]
_______________ is involved in error detection (controls inappropriate behaviour) → amplifier/filter to improve emotional processing and provide insight/response to emotional cues
• Inhibition of ACC causes poor insight/capacity to recognise error (inappropriate behaviours in psychotic/schizophrenic patients)
Anterior cingulate cortex (ACC)
[CANNABIS (MARIJUANA): effects- increased food intake/ appetite]
Positive effects on orexigenic (appetite stimulating) neurones in the _____________
lateral hypothalamic nucleus
[CANNABIS (MARIJUANA): effects- memory loss]
Reduced __________ → limbic system effects (reduced hippocampal density)
BDNF
[CANNABIS (MARIJUANA): effects- decreased psychomotor performance]
Depressant effect on ___________ causes reduced performance (e.g. balance)
cerebral cortex
[CANNABIS (MARIJUANA): effects- immunosuppressant]
Binding to _____________ on immune cells suppresses immune function
CB2 receptors
[CANNABIS (MARIJUANA): effects- cardiovascular effects]
____________ (esp. in the conjunctiva → bloodshot eyes): believed to be caused by _________________ receptor causing Ca2+ influx
Tachycardia and vasodilation;
TRPV1 (vanilloid)
[CANNABIS (MARIJUANA): effects- respiratory effects ]
Similar to cigarettes (since cannabis is smoked) → products in cigarette smoke (not the drug) that are toxic
What are physiological conditions in which CB receptors are upregulated?
Multiple sclerosis, pain, schizophrenia
What are pathological conditions in which CB receptors are upregulated?
Fertility, obesity, stroke
Name of CB receptor agonists used as appetite stimulant for AIDS patients (who were associated with weight loss)?
Dronabinol
Name of CB receptor agonists used as appetite stimulant for nausea associated with anti-cancer drugs?
Nabilone
Name of CB receptor agonists used as appetite stimulant for treatment of pain (e.g. multiple sclerosis)?
Sativex
Name of CB receptor antagonists used as appetite stimulant for Anti-obesity treatment (via reduced hunger/appetite)
Rimonabant
[Cocaine: absorption]
Onset of action: within seconds → inhalational (50% lost on inhalation and some lost upon heating) > IV > intranasal > oral
IV/oral/intranasal (snorting) routes:
• Paste: mushing leaves with organic solvent → extracts 80% cocaine
• Cocaine HCl: dissolving organic solvent containing active cocaine in acidic solution like HCl → major therapeutic version of cocaine (heating activates cocaine and breaks it down → cannot be smoked or inhaled)
Inhalation (can be heated) route:
• Crack: precipitating cocaine HCl with ___________________
• Freebase: dissolve crack precipitate in _________________ then extract (more purified than crack → more expensive and dangerous)
alkaline solution (baking soda);
non-polar solvent (e.g. ammonia + ether);
[Cocaine: metabolism ] Oral cocaine (pKa \_\_\_\_\_\_) is ionised in the stomach (slower absorption, onset): • 75 – 90% is broken down in the liver within hours into \_\_\_\_\_\_\_\_\_\_\_\_ and \_\_\_\_\_\_\_\_\_\_\_\_\_\_ • Tissue t1/2 = \_\_\_\_\_\_\_\_\_\_\_
8.7;
ecgonine methyl ester and benzoylecgonine;
20 – 90 minutes
[Cocaine: excretion ]
Clearance of the drug is via ______________
plasma/liver cholinesterases
[Cocaine: psychodynamic- euphoria ]
Blockade of _____________ → monoamines remain in the synapse for longer → less dopamine reuptake in the central reward pathway → binds to dopamine receptors to cause euphoria
monoamine transport proteins;
[Cocaine: psychodynamic- local anaesthesia ]
- Reduces pain: blocks ___________ within peripheral nerves
- Reduces risk of blood loss: good ____________
Na+ channels;
vasoconstrictor
[Cocaine: psychodynamic- behavioural & subjective ]
Mild to moderate effects (positive/ reinforcing effects): ___________ cocaine use on semi-regular basis
- mood amplification: both ______________
- heightened energy
- sleep disturbance, insomnia
- motor excitement, restlessness
- talkativeness, pressure of speech, hyperactive ideation
- increased sexual interest
- anger verbal aggression
- mild to moderate anorexia
- inflated self esteem
Severe effects (negative/stereotypic effects): ____________
- irritability, hostility, anxiety, fear, withdrawal
- extreme energy or exhaustion
- total insomnia
- compulsive motor stereotypes
- rambling, incoherent speech
- disjointed flight of ideas
- decreased sexual interest
- possible extreme violence
- total anorexia
- delusions of grandiosity
low dose;
euphoria and dysphoria;
chronic abuse of cocaine/ overdose
[Cocaine: psychodynamic- cardiovascular ]
Blockade of monoamine transport proteins → increases ________________ → tachycardia, vasoconstriction, platelet activation → susceptible to MI
sympathetic stimulation
[Cocaine: psychodynamic- CNS ]
____________ and ____________ associated with epilepsy
Vasoconstriction and hyperpyrexia
[NICOTINE]
Nicotine is a stimulant derived from the plant Nicotana tabacum that is used in cigarettes:
• Cigarette smoke consists of particulate (5%) and volatile matter (95%)
Particulate (5%): Nicotine (alkaloid) dissolves in ____________ formed upon heating (effective delivery device) → tar droplets are inhaled into the lungs → nicotine diffuses across _________ into the bloodstream
Volatile matter (95%): Contains most of the ________________
tar droplet;
alveoli;
carcinogenic compounds (e.g. nitrogen, carbon monoxide, benzene, hydrogen cyanide)
[Nicotine: absorption] Nicotine spray (nasal): 1mg; bioavailability 20 – 50%
Nicotine gum (oral): 2 – 4mg; bioavailability 50 – 70%
Cigarettes (inhaled): 9 – 17mg; bioavailability 20% with onset in seconds
• Nicotine has a pKa of ____, and since cigarette smoke is usually acidic, nicotine is _________- within the smoke → reduced capacity to cross mucous membranes (no ______________)
• Requires smoke to reach the alveoli → absorption in alveoli (thin-walled) is independent of pH
Nicotine patch (transdermal): 15 – 22mg/day; bioavailability 70%
7.9;
ionised;
buccal absorption
[Nicotine: metabolism]
70 – 80% is metabolised by ________ into the metabolite cotinine:
• Tissue t1/2 = 1 – 4 hours (addictive properties
CYP2A6
[Nicotine: effects- euphoria]
Nicotine binds to ________________ in the central reward pathway → increases dopamine release in ______ → increased euphoria
nAChR on dopaminergic neurones;
NAcc
[Nicotine: effects- cardiovascular]
Induces sympathetic stimulation:
• β1: increased ____, ___ (due to prostaglandins, NO) → increased BP
• α1: vasoconstriction in ________ and __________
• Vasodilatation in ______________
Deranged lipid profile: stimulates lipolysis, increases free fatty acids and LDL & decreases HDL
Increases platelet activity: increases ________ production and decreases ___________
HR, SV;
coronary arterioles and skin arterioles;
skeletal muscle arterioles;
TXA2;
endothelium-derived NO
[Nicotine: effects- metabolic]
Increases metabolic rate → _________________ is seen in both males and females after stopping cigarette smoking
significant weight gain
[Nicotine: effects- respiratory ]
Lung cancer and other respiratory effects (due to carcinogens like ____________ → not nicotine per se)
CO and hydrogen cyanide
nAChR is protective against progression of
- Parkinson’s disease: nAChR is linked to increased ____________ → increases brain capacity to metabolise neurotoxins
- Alzheimer’s disease: nAChR is linked to decreased ___________ and decreased ________
brain CYP450 activity;
β-amyloid toxicity;
APP
[Alcohol: absorption]
____ absorbed at the stomach; ______ absorbed at the small intestines:
• Speed of onset is directly proportional to gastric emptying
• Drinking on full stomach: alcohol is retained in stomach longer and absorbed at a slower rate
• Drinking on empty stomach: blood level of alcohol becomes ___________
20%; 80%;
4x higher (4x rate of absorption in intestines)
[Alcohol metabolism (90%)]
Hepatic metabolism (85%): ADH (____) and CYP450 (________):
Alcohol dehydrogenase (ADH): converts alcohol to acetaldehyde (toxic metabolite), which is then converted by _____________ into _____________
• _________ (aversion therapy for alcoholics): blocks ALDH to cause acetaldehyde build-up and negative side effects (more averse to drinking alcohol in future)
• Genetic polymorphism (especially among Asians → Asian flush effect): decreased effectiveness of ALDH causes acetaldehyde to build up rapidly → toxic side effects turn people off to alcohol
CYP450: the more the liver is exposed to alcohol → upregulation of mixed function oxidase system (more enzymes) → ability to metabolise alcohol increases → increased tolerance to alcohol
*First-pass metabolism: alcohol leaves the gut and passes the liver (with an appreciable quantity metabolised) → only a certain amount enters the systemic circulation to produce its effects
• Speed of drinking determines the speed of metabolism
• A lot drunk at one shot: liver metabolises certain amount of alcohol until saturated → large amount bypasses the liver to enter the systemic circulation
• Smaller doses spread out across time: allows liver to recover and metabolise the next shot of alcohol
75%; 25%
aldehyde dehydrogenase (ALDH);
acetic acid (excreted);
Disulfiram
What binding targets do the alcohol binds to in the CNS?
1) GABA: Enhances GABA effects → depressant effects:
• Presynaptic: increase presynaptic GABA release
• Postsynaptic: facilitate Cl- entry via GABA receptor
• Mediated by allopregnanolone (neuroactive)
2) NMDA: Binds via allosteric modulation → reduces excitation
3) Ca2+ channel: Reduces Ca2+ influx → reduces neurotransmitter release
what is the acute effect of alcohol on cortical brain?
Impairs both sensory and motor functions
what is the acute effect of alcohol on corpus callosum?
Interferes with passing of information from left to right brain and vice versa
what is the acute effect of alcohol on hypothalamus?
Interferes with appetite, emotional control, pain sensation, temperature
what is the acute effect of alcohol on RAS?
Interferes with consciousness (esp. at high doses)
what is the acute effect of alcohol on hippocampus?
Interferes with memory
what is the acute effect of alcohol on cerebellum?
Interferes with movement and coordination
what is the acute effect of alcohol on basal ganglia?
Interferes with perception of time
how does alcohol cause facial flushing?
caused by reduced Ca2+ entry into smooth muscle → reduced constriction of precapillary sphincters (likely due to acetaldehyde rather than ethanol itself)
how does alcohol increase heart rate?
depressed arterial baroreceptor function → reduced firing → less parasympathetic stimulation and reduced sympathetic inhibition
what is the endocrine effect of alcohol
Polyuria/diuresis & dehydration: decreased K+ entry into cells and decreased ADH secretion (likely due to acetaldehyde rather than ethanol itself)
What is wernicke- korsakoff syndrome?
Wernicke-Korsakoff syndrome refers to dementia associated with alcoholics (due to thiamine deficiency/poor diet; not toxic effect of alcohol)
Wernicke’s encephalopathy: problems with balance, leaky capillaries within 3rd ventricle and aqueduct → reversible (if alcohol is stopped)
What is korsakoff’s psychosis?
toxic effect on dorsomedial thalamus & mamillary bodies of hypothalamus → anterograde/retrograde amnesia, amnesia of fixation, confabulation (making up memories), poverty of speech, lack of insight, apathy → irreversible (due to continued alcohol use when patient has Wernicke’s)
Chronic alcoholism involves excessive use of NAD+ stores to metabolise alcohol with build-up of NADH → prevents ______________ → lactic acidosis + hypoglycaemia
- NADH accumulation tricks the body into thinking that it is still producing sufficient energy → stores energy instead of producing
- Increased ______________ → triacylglycerol → more ketones produced
- Interference of ______________ → generates more fat and reduces fat metabolism to generate acetyl CoA → less acetyl CoA entering Krebs cycle → less ATP generated (worsens lack of energy)
Liver damage: fatty liver → hepatitis → cirrhosis → liver failure
• Fatty liver: easily reversible after abstinence (fat metabolised)
• Hepatitis: chronic alcoholism and build-up of ____________ → tissue damage → free radicals, infiltration of inflammatory cells, increased cytokines (IL-6, TNF-α)
• Cirrhosis: fibroblasts lay down connective tissue to repair the liver → accumulation of connective tissue replaces active hepatocytes over time → hepatocyte regeneration decreases
• Liver failure sets in after cirrhosis reaches a certain level
lactate conversion to pyruvate (used for gluconeogenesis);
lipogenesis;
β-oxidation;
acetaldehyde;
What are the chronic endocrine effects of drinking alcohol?
Cushingoid symptoms: upregulates ACTH secretion → cortisol build-up Male feminisation: reduces testosterone secretion
What are the chronic GI effects of drinking alcohol?
- Gastric ulceration: build-up of acetaldehyde damages the gastric mucosa (proportional to the dose of alcohol)
- Gastric cancer: build-up of acetaldehyde is also carcinogenic
How does acute alcohol use cause euphoria?
- Decreases glutamate input → depresses GABAergic neurone
- Increases opioidergic input → depresses GABAergic neurone
- Positive effect on VTA dopaminergic neurones (from GABAergic neurone depression) → increased dopamine release into NAcc → increased reward sensation → euphoria
What is the mechanism for alcohol dependence?
Neurones attempt to compensate for consistent alcohol inhibition (glutamate input ↑; GABA neurones more sensitive)
What is the mechanism for alcohol withdrawal?
Alcohol withdrawal causes sudden full stimulant effect of enhanced glutamate production and ↑ sensitivity of GABA neurones → strongly inhibits dopaminergic neurones
Decreases dopamine production in NAcc → → reduced reward sensation → dysphoria (massive reduction in mood
What are the minor symptoms of alcohol withdrawal?
Begins 5 – 8 hours after last alcohol drink:
• Anxious, agitated, restless, nervous, shaky, trembling
• Problems sleeping, too much sweating, fast heartbeat, decreased appetite
What are the major symptoms of alcohol withdrawal?
Begins 24 – 72 hours after last alcohol drink:
• Confused/more restless, agitated, shaky, trembling
• Frequent rapid eye movements, excessive cold sweats, nausea, vomiting, fast heartbeat, high BP, problems thinking clearly, seizures, hallucinations
What are the symptoms of delirium tremens?
May occur 48 – 96 hours after last alcohol drink:
• Fever, very high BP or fast HR
• Excessive sweating, delirium (manic/hysterical), shaking very badly
• Seizures, heart attacks, breathing problems, strokes may occur
