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M2 Pharmocology > 6.4 Drugs of abuse & alcohol > Flashcards

6.4 Drugs of abuse & alcohol Flashcards

1
Q

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)

A

ventral tegmental area (VTA);

nucleus accumbens (NAcc);

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2
Q

What are psychoactive drugs that is classified as narcotics?

A

heroin

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3
Q

What are psychoactive drugs that is classified as depressants (downers)?

A

Alcohol, benzodiapenes, barbituates

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4
Q

What are psychoactive drugs that are classified as stimulants (uppers)

A

cocaine, amphetamine (speed), nicotine, metamphetamine (crystal math)

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5
Q

what is the route the drug goes through if taken orally?

A

Gastrointestinal tract → hepatic circulation → venous system → heart → brain

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6
Q

what is the route the drug goes through if taken intranasal?

A

Mucous membranes of nasal sinuses → venous system → heart → brain

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7
Q

what is the route the drug goes through if taken intravenous?

A

Venous system → heart → brain

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8
Q

what is the route the drug goes through if taken inhalational?

A

Small airways/alveoli → heart → brain

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9
Q

[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

A

Δ9-THC (tetrahydrocannabinol);

hash oil;

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10
Q

[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

A

10 – 15%;

50%;

brain and high perfusion tissues

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11
Q

[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: __________

A

fat receives very little cardiac output;

7 days

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12
Q

[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)

A

11-hydroxy-THC;

enterohepatic cycling

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13
Q

[CANNABIS (MARIJUANA): excretion]

________ is cleared in urine

A

25%

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14
Q

[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)

A

Anandamide

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15
Q

Where are CB1 receptors located?

A

Brain (hippocampus, cerebellum, cerebral cortex, basal ganglia)

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16
Q

Where are CB2 receptors located?

A

Periphery (immune cells)

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17
Q

[CANNABIS (MARIJUANA): effects- euphoria]
Binding of cannabis to CB1 receptors inhibits ______________ (resulting in disinhibition) → increases rate of firing of reward neurones (VTA → NAcc → dopamine)

A

GABAergic interneurones

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18
Q

[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)

A

Anterior cingulate cortex (ACC)

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19
Q

[CANNABIS (MARIJUANA): effects- increased food intake/ appetite]

Positive effects on orexigenic (appetite stimulating) neurones in the _____________

A

lateral hypothalamic nucleus

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20
Q

[CANNABIS (MARIJUANA): effects- memory loss]

Reduced __________ → limbic system effects (reduced hippocampal density)

A

BDNF

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21
Q

[CANNABIS (MARIJUANA): effects- decreased psychomotor performance]

Depressant effect on ___________ causes reduced performance (e.g. balance)

A

cerebral cortex

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22
Q

[CANNABIS (MARIJUANA): effects- immunosuppressant]

Binding to _____________ on immune cells suppresses immune function

A

CB2 receptors

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23
Q

[CANNABIS (MARIJUANA): effects- cardiovascular effects]

____________ (esp. in the conjunctiva → bloodshot eyes): believed to be caused by _________________ receptor causing Ca2+ influx

A

Tachycardia and vasodilation;

TRPV1 (vanilloid)

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24
Q

[CANNABIS (MARIJUANA): effects- respiratory effects ]

A

Similar to cigarettes (since cannabis is smoked) → products in cigarette smoke (not the drug) that are toxic

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25
Q

What are physiological conditions in which CB receptors are upregulated?

A

Multiple sclerosis, pain, schizophrenia

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26
Q

What are pathological conditions in which CB receptors are upregulated?

A

Fertility, obesity, stroke

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27
Q

Name of CB receptor agonists used as appetite stimulant for AIDS patients (who were associated with weight loss)?

A

Dronabinol

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28
Q

Name of CB receptor agonists used as appetite stimulant for nausea associated with anti-cancer drugs?

A

Nabilone

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29
Q

Name of CB receptor agonists used as appetite stimulant for treatment of pain (e.g. multiple sclerosis)?

A

Sativex

30
Q

Name of CB receptor antagonists used as appetite stimulant for Anti-obesity treatment (via reduced hunger/appetite)

A

Rimonabant

31
Q

[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)

A

alkaline solution (baking soda);

non-polar solvent (e.g. ammonia + ether);

32
Q 
[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 = \_\_\_\_\_\_\_\_\_\_\_
A

8.7;

ecgonine methyl ester and benzoylecgonine;

20 – 90 minutes

33
Q

[Cocaine: excretion ]

Clearance of the drug is via ______________

A

plasma/liver cholinesterases

34
Q

[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

A

monoamine transport proteins;

35
Q

[Cocaine: psychodynamic- local anaesthesia ]

  • Reduces pain: blocks ___________ within peripheral nerves
  • Reduces risk of blood loss: good ____________
A

Na+ channels;

vasoconstrictor

36
Q

[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
A

low dose;

euphoria and dysphoria;

chronic abuse of cocaine/ overdose

37
Q

[Cocaine: psychodynamic- cardiovascular ]
Blockade of monoamine transport proteins → increases ________________ → tachycardia, vasoconstriction, platelet activation → susceptible to MI

A

sympathetic stimulation

38
Q

[Cocaine: psychodynamic- CNS ]

____________ and ____________ associated with epilepsy

A

Vasoconstriction and hyperpyrexia

39
Q

[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 ________________

A

tar droplet;

alveoli;

carcinogenic compounds (e.g. nitrogen, carbon monoxide, benzene, hydrogen cyanide)

40
Q 
[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%

A

7.9;

ionised;

buccal absorption

41
Q

[Nicotine: metabolism]

70 – 80% is metabolised by ________ into the metabolite cotinine:
• Tissue t1/2 = 1 – 4 hours (addictive properties

A

CYP2A6

42
Q

[Nicotine: effects- euphoria]
Nicotine binds to ________________ in the central reward pathway → increases dopamine release in ______ → increased euphoria

A

nAChR on dopaminergic neurones;

NAcc

43
Q

[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 ___________

A

HR, SV;

coronary arterioles and skin arterioles;

skeletal muscle arterioles;

TXA2;

endothelium-derived NO

44
Q

[Nicotine: effects- metabolic]

Increases metabolic rate → _________________ is seen in both males and females after stopping cigarette smoking

A

significant weight gain

45
Q

[Nicotine: effects- respiratory ]

Lung cancer and other respiratory effects (due to carcinogens like ____________ → not nicotine per se)

A

CO and hydrogen cyanide

46
Q

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 ________
A

brain CYP450 activity;

β-amyloid toxicity;

APP

47
Q

[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 ___________

A

20%; 80%;

4x higher (4x rate of absorption in intestines)

48
Q

[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

A

75%; 25%

aldehyde dehydrogenase (ALDH);

acetic acid (excreted);

Disulfiram

49
Q

What binding targets do the alcohol binds to in the CNS?

A

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

50
Q

what is the acute effect of alcohol on cortical brain?

A

Impairs both sensory and motor functions

51
Q

what is the acute effect of alcohol on corpus callosum?

A

Interferes with passing of information from left to right brain and vice versa

52
Q

what is the acute effect of alcohol on hypothalamus?

A

Interferes with appetite, emotional control, pain sensation, temperature

53
Q

what is the acute effect of alcohol on RAS?

A

Interferes with consciousness (esp. at high doses)

54
Q

what is the acute effect of alcohol on hippocampus?

A

Interferes with memory

55
Q

what is the acute effect of alcohol on cerebellum?

A

Interferes with movement and coordination

56
Q

what is the acute effect of alcohol on basal ganglia?

A

Interferes with perception of time

57
Q

how does alcohol cause facial flushing?

A

caused by reduced Ca2+ entry into smooth muscle → reduced constriction of precapillary sphincters (likely due to acetaldehyde rather than ethanol itself)

58
Q

how does alcohol increase heart rate?

A

depressed arterial baroreceptor function → reduced firing → less parasympathetic stimulation and reduced sympathetic inhibition

59
Q

what is the endocrine effect of alcohol

A

Polyuria/diuresis & dehydration: decreased K+ entry into cells and decreased ADH secretion (likely due to acetaldehyde rather than ethanol itself)

60
Q

What is wernicke- korsakoff syndrome?

A

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)

61
Q

What is korsakoff’s psychosis?

A

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)

62
Q

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

A

lactate conversion to pyruvate (used for gluconeogenesis);

lipogenesis;

β-oxidation;

acetaldehyde;

63
Q

What are the chronic endocrine effects of drinking alcohol?

A

Cushingoid symptoms: upregulates ACTH secretion → cortisol build-up Male feminisation: reduces testosterone secretion

64
Q

What are the chronic GI effects of drinking alcohol?

A
  • 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
65
Q

How does acute alcohol use cause euphoria?

A
  1. Decreases glutamate input → depresses GABAergic neurone
  2. Increases opioidergic input → depresses GABAergic neurone
  3. Positive effect on VTA dopaminergic neurones (from GABAergic neurone depression) → increased dopamine release into NAcc → increased reward sensation → euphoria
66
Q

What is the mechanism for alcohol dependence?

A

Neurones attempt to compensate for consistent alcohol inhibition (glutamate input ↑; GABA neurones more sensitive)

67
Q

What is the mechanism for alcohol withdrawal?

A

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

68
Q

What are the minor symptoms of alcohol withdrawal?

A

Begins 5 – 8 hours after last alcohol drink:
• Anxious, agitated, restless, nervous, shaky, trembling
• Problems sleeping, too much sweating, fast heartbeat, decreased appetite

69
Q

What are the major symptoms of alcohol withdrawal?

A

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

70
Q

What are the symptoms of delirium tremens?

A

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

M2 Pharmocology (20 decks)

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