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Y2 LCRS Pharmacology and Therapeutics > addiction > Flashcards

addiction Flashcards

pharmacology of drugs of abuse: summarise the pharmacokinetics and pharmacology of the main drugs of abuse: cannabis, nicotine, cocaine, alcohol and opioids

1
Q

4 commonest routes of administration for main drugs of abuse

A

snort (intra-nasal), eat/drink (oral), smoke (inhalation), inject (i.v)

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2
Q

intra-nasal administration: location and rate of absorption

A

mucous membranes of nasal sinuses; slow absorption (diffuses into venous system)

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3
Q

oral administration: location and rate of absorption

A

GI tract; very slow absorption

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4
Q

inhalation administration: location and rate of absorption

A

small airways and alveoli; very rapid absorption (minimal resistance to flow and already in pulmonary circulation)

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5
Q

i.v administration: location and rate of absorption

A

veins; rapid absorption

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6
Q

4 pharmacological classifications of drugs of abuse

A

narcotics/painkillers, depressants (‘downers’), stimulants (‘uppers’), miscellaneous

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7
Q

examples of narcotics/painkillers

A

opiate-like drugs e.g. heroin

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8
Q

examples of depressants

A

alcohol, benzodiazepines (valium), barbiturates

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9
Q

examples of stimulants

A

cocaine, amphetamine (‘speed’), caffeine metamphetamine (‘crystal meth’), nicotine

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10
Q

examples of miscellaneous (have other properties)

A

cannabis, ecstasy (MDMA)

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11
Q

forms of cannabis

A

cannabis/marijuana, hashish/resin (trichomes - glandular hairs), hash oil (solvent extraction)

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12
Q

number of compounds and cannabinoids in cannabis

A

> 400 compounds, >60 cannabinoids (n glandular hairs)

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13
Q

2 primary cannabinoids of cannabis, and onset of cannabis

A

cannabidiol and THC (most powerful); seconds->minutes

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14
Q

dosing in cannabis plant: reefer (60s-70s) vs skunkweed/netherweed (21st century) and relevance

A

10mg THC vs 150-300mg THC; farmed to increase amount of THC in plant, so more powerful effect (if increase dose, hit ceiling of positive symptoms, but increasing risk of negative effects - cannabidiol moderates effects of THC, but with increased THC at expense of cannabidiol, elevation of negative effects)

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15
Q

administration of cannabis bioavailablity (% into bloodstream)

A

5-15% oral (delayed onset and slow absorption as fair amount of first pass metabolism by liver before entering blood stream), 25-35% inhalation (exhale about 50% back out again, and that 50% remaining must be deeply inhaled)

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16
Q

distribution of cannabis

A

diffuses freely from blood into organs, but overtime intensive accumulation occurs in less vascularised tissues and finally slowly accumulates in poorly perfused fatty tissues (long-term storage site as very lipid-soluble; reversible so slowly diffuses back into blood)

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17
Q

upon cannabis administration, what therefore builds up in fatty tissue

A

fatty acid conjugates of 11-OH-THC

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18
Q

concentration ratios of THC between fat and plasma

A

10^4 : 1

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19
Q

metabolism of cannabis: phase 1 metabolite location and name

A

liver to 11-hydroxy-THC (more potent than THC); liver can only conjugate (phase 2) so much per unit time

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20
Q

excretion of cannabis

A

65% GI tract into bile and faeces, 25% urine

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21
Q

what does cannabis undergo if excreted in bile as lipid-soluble

A

enterohepatic recycling

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22
Q

describe and explain correlation between plasma cannabinoid concentration and degree of intoxication

A

poor, as can measure plasma THC, but no info on 11-hydroxy-THC levels, levels in fat or enterohepatic recycling

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23
Q

describe cannabinoid diffusion to brain

A

structural fat in brain, so cannabinoids diffuse into and build up in brain, so 7-8x more THC in brain than blood (blood mainly has phase 2 conjugated form)

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24
Q

tissue half life of cannabis, and how long after smoking a cannabis cigarette will the effects persist in the body (remains in adipose tissue)

A

tissue half life of 7 days, but due to remaining in adipose tissue, effects persist for 30 days

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25
Q

what receptors does cannabis bind to

A

CB1, CB2 (cannabinoid receptor)

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26
Q

location of CB1 receptors

A

hippocampus, cerebellum, cerebral cortex, basal ganglia; most common G-protein coupled receptor in brain

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27
Q

location of CB2 receptors

A

immune cells

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28
Q

CB R type of receptor and hence type of drug and effect on IC enzymes

A

type 2 (G-protein coupled receptor), Gi/o (inhibitory) so depressant, depresing adenylate cyclase

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29
Q

CB R endogenous cannabinoid

A

endogenous anandamide

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30
Q

mesolimbic dopamine system resulting in euphoria

A

cannabis -> CB1 receptor on GABA interneurone -> reduction in GABA (natural suppressant) release to ventral tegmental area (disinhibition) -> high dopamine release from nucleus accumbens

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31
Q

5 central effects of cannabis

A

euphoria, psychosis (and schizophrenia), increased appetite, memory loss, psychomotor performance

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32
Q

what is the role of the anterior cingulate cortex

A

involved with performance monitoring with behavioural adjustment in order to avoid losses (error detection, and adapts behaviour by detecting and focusing on goal-relevant information, and selecting most appropriate behaviour to avoid losses)

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33
Q

what does cannabis do to anterior cingulate cortex, and what 2 conditions can result

A

hypoactivity, losing ability to change behaviour, resulting in psychosis, schizoprenia (especially if just THC vs THC and cannabidiol, which induces more euphoria)

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34
Q

cannabis effect on food intake

A

leptin, ghrelin etc signal from body into arcuate nucleus (unaffected by cannabis) -> cannabis binds to CB1 R which causes presynaptic inhibition of GABA to lateral hypothalamus, increasing MHC neuronal activity; also directly causes an increase in orexin production -> increased appetite

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35
Q

cannabinoid agonists as immunosuppressants: 4 immune cells with CB R expression, and effect of cannabis on cells

A

B-cell, macrophage, natural killer cells, T-cell; suppresses their effect, so more susceptible to illness and infection

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36
Q

why does cannabis cause memory loss

A

affects limbic regions (amnestic effects, reducing BDNF which normally improves hippocampal health)

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37
Q

which area does cannabis suppress psychomotor performance

A

cerebral cortex

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38
Q

2 peripheral effects of cannabis

A

immunosuppressant, tachycardia/vasodilation (conjunctivae - blood shot eyes; affects TRPV1 as opposed to CB R)

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39
Q

effect of cannabis on medulla

A

low CB1 receptor expression, meaning that cardiovascular and cardiorespiratory control not suppressed (can’t overdose to point of death)

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40
Q

medical use of cannabis: 3 conditions where regulatory elevation of CB1 R

A

multiple sclerosis, pain, stroke

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41
Q

medical use of cannabis: 2 conditions where pathology elevation of CB1 R

A

fertility (up-regulate and decrease testosterone and pituitary gland with regard to gonad function, as well as sperm function), obesity (up-regulated in liver and adipose tissue)

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42
Q

medical use of cannabis ‘autoprotection’: what are dronabinol and nabilone (THC) used to treat

A

prevent nausea and vomiting caused by chemotherapy in those without good results using other medications

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43
Q

medical use of cannabis ‘autoprotection’: what is dronabinol used to treat

A

loss of appetite and weight loss in people with acquired immunodeficiency syndrome (AIDS)

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44
Q

medical use of rimonabant, and problem (hence taken off market)

A

anti-obesity agent as antagonist for CB R, decreasing weight; caused increased depression and suicide

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45
Q

medical use of cannabis: ‘autoprotection’ what is sativex (THC and cannabidiol) used to treat

A

symptom improvement in adult patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other anti-spasticity medication, analgaesic

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46
Q

what does high potency fatty acid amide hydrolase do inhibitor

A

increases concentration of endogenous anandamide (natural agonist of CB R)

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47
Q

epidemiology of alcohol

A

high in Europe, Russia and US; low in north Africa (Islam)

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48
Q

dosing of alcohol: absolute amount vs units, and consistency of units

A

absolute amount is % alcohol by volume x 0.78 (g/100ml); units is % alcohol by volume x volume/1000, with 1 unit =10ml/8g of absolute alcohol; no consistency of units as volume changes (e.g. glass of wine)

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49
Q

dosing of alcohol: safe level

A

men and women <14 units/week is low risk; binge drinking (>8 units in one sitting)

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50
Q

dosing of alcohol: what does a blood level of 0.01% mean

A

10mg/100ml blood

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51
Q

dosing of alcohol: blood levels based on weight and blood level

A

charts which show weight and number of drinks, and estimated blood level (can subtract 0.01% for each 40 minutes due to metabolism)

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52
Q

administration route of alcohol

A

oral

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53
Q

administration of alcohol and effect on stomach fullness

A

20% to stomach, 80% to small intestine, so drinking on a full stomach reduces blood alcohol level as joins food and can’t reach outer sides of stomach to be absorber (20%), and as most (80%) absorbed in small intestine, doesn’t reach there for longer, so speed of onset is proportional to gastric emptying

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54
Q

% of alcohol metabolised, and % metabolised in liver

A

90% metabolised (10% excreted unmetabolised), with 85% of 90% metabolised in liver

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55
Q

metabolism pathway of alcohol in liver to acetaldehyde

A

alcohol -> [alcohol dehydrogenase (75%) or mixed function oxidase (25%)] -> acetaldehyde (toxic compound)

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56
Q

why is there tolerance to alcohol

A

liver upregulates mixed function oxidase, so liver more effective at metabolising it (reversible so if stop drinking for long time, enzymes won’t be upregulated)

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57
Q

metabolism of alcohol: role of first pass hepatic metabolism and breaking up alcohol dose over time

A

enzymes are all saturable, so can only metabolise at certain rate, so if all in one go the alcohol leaks into systemic circulation, increasing blood levels, whereas if smaller doses, enzymes have more time to metabolise, so blood levels much lower

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58
Q

% of alcohol metabolism in GI tract (stomach)

A

15%

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59
Q

metabolism pathway of alcohol in GI tract to acetaldehyde

A

alcohol -> [alcohol dehydrogenase] -> acetaldehyde

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60
Q

metabolism pathway of alcohol in GI tract: female levels of alcohol dehydrogenase in stomach

A

50% less alcohol dehydrogenase in stomach vs men

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61
Q

distribution of alcohol: men vs women

A

women have lower body water (50%) vs men (59%), which corresponds to a lower plasma level, and as less stomach alcoholic dehydrogenase, so alcohol less diluted in women and have less capacity to metabolise

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62
Q

metabolism of alcohol: metabolism of acetaldehyde in liver and GI tract

A

acetaldehyde (toxic compound) -> [aldehyde dehydrogenase] -> acetic acid

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63
Q

effect of disulfiram on aldehyde dehydrogenase, and clinical use

A

inhibits aldehyde dehydrogenase, causing a build up of acetaldehyde (toxic compound) and producing an acute sensitivity to alcohol, so used as alcohol aversion therapy as symptoms of hangover occur much more quickly with less alcohol

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64
Q

genetic polymorphism of aldehyde dehydrogenase

A

“Asian flush” -> less effective enzyme

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65
Q

potency of alcohol

A

low (ug/ml vs ng/ml for cocaine and nicotine) as simple chemical (binds to lots of targets, but not very well)

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66
Q

what chemical is alcohol, and hence pharmacological targets

A

ethanol (C2H5OH), so no pharmacological targets, so affinity and efficacy poor

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67
Q

acute effects of alcohol in CNS

A

primary effect is depressant, but CNS agitation might occur (low dose in certain situations)

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68
Q

what is degree of CNS excitability dependent on (low dose alcohol increases CNS excitability, but decreases at higher dose as depressant)

A

personality and environment (environment is non-social (low excitability) or social setting (high excitability))

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69
Q

acute effects of alcohol in CNS: direct and indirect effects on GABA receptors and Cl- influx

A

direct: increases GABA, promoting Cl- influx; indirect: increases release of allopregnenolone which binds to GABA receptors and promotes Cl- influx

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70
Q

acute effects of alcohol in CNS: effect on allosteric modulation of NMDA receptors

A

decrease

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71
Q

acute effects of alcohol in CNS: effect on neurotransmitter release, and reason

A

reduce, as Ca2+ channels decrease

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72
Q

2 factors influencing acute effects of alcohol on CNS

A

CNS is functionally complex, ethanol has low potency so low selectivity

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73
Q

how does alcohol cause an acute euphoric effect in CNS

A

opiates/alcohol bind to u-receptor on GABAergic neurone -> decrease in GABA release -> ventral tegmental area -> nucleus accumbens -> increase in dopamine release

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74
Q

6 locations acutely depressed in brain by alcohol, and normal functions

A

corpus callosum (info left right, affecting behaviour), hypothalamus (appetite, emotions, temperature, pain sensation), reticular activating system (consciousness, affected at high levels), hippocampus (memory, affected at high levels), cerebellum (movement and coordination), basal ganglia (perception of time)

75
Q

effect of alcohol on cardiovascular system and how (“Asian flush”)

A

causes cutaneous vasodilation by preventing precapillary sphincters from remaining contracted, as acetaldhehyde decreases Ca2+ entry and increases prostaglandins in arterioles and capillaries

76
Q

why might chronic alcohol be associated with an increased BP and HR

A

centrally mediated decrease (depressant effect) in baroreceptor sensitivity leads to an acute increase in heart rate (inhibited CNS neurone not inhibited, so sympathetic activity to heart and arterioles and veins increases), increasing BP also

77
Q

acute effects of alcohol on endocrine system

A

diuresis (polyuria) due to decreased ADH release

78
Q

chronic effects of alcohol on CNS: thiamine (vitamin B1) pathway to cerebral energy utilisation

A

thiamine -> [cofactor] -> enzymes in energy metabolism -> cerebral energy utilisation (essential coenzyme to TCA cycle and pentose phosphate shunt)

79
Q

chronic effects of alcohol on CNS: effect of thiamine deficiency caused by alcohol (most calories in alcoholics from alcohol, which doesn’t contain thiamine) in brain regions with high metabolic demands

A

impaired metabolism, NMDA excitotoxicity, build up of reactive oxygen species

80
Q

chronic effects of alcohol on CNS: why does alcohol cause dementia

A

causes cortical atrophy, decreasing volume cerebral white matter, causing confusion (encephalopathy) and oculomotor symptoms

81
Q

chronic effects of alcohol on CNS: why does alcohol cause ataxia

A

ceberellar cortex degeneration, affecting gait

82
Q

chronic effects of alcohol on CNS: syndrome due to thiamine deficiency

A

Wernicke-Korsakoff syndrome

83
Q

chronic effects of alcohol on CNS: what is Wernicke’s encephalopathy (reversible)

A

acute neuropsychiatric condition due to an initially reversible biochemical brain lesion caused by overwhelming metabolic demands on brain cells that have depleted intracellular thiamine (vitamin B1)

84
Q

chronic effects of alcohol on CNS: effect of Wernicke’s encephalopathy on cells

A

imbalance leads to cellular energy deficit, focal acidosis, regional increase in glutamate, and ultimately cell death

85
Q

chronic effects of alcohol on CNS: what triad is Wernicke’s encephalopathy characterised by

A

ophthalmoplegia, ataxia, and confusion (only 10% of patients exhibit all 3, and other symptoms may also be present)

86
Q

chronic effects of alcohol on CNS: 3 causes of thiamine deficiency in Wernicke’s encephalopathy

A

oxidative damage, mitochondrial injury leading to apoptosis, and directly stimulating a pro-apoptotic pathway

87
Q

chronic effects of alcohol on CNS: what area does Wernicke’s encephalopathy affect

A

hypothalamus and thalamus

88
Q

chronic effects of alcohol on CNS: what is Korsakoff’s psychosis (irreversible)

A

impaired ability to acquire new information and by a substantial, but irregular memory loss for which patients often attempt to compensate through confabulation

89
Q

chronic effects of alcohol on CNS: what is Korsakoff’s psychosis associated with, and where does it affect

A

associated with polyneuritis, and affects deep brain e.g. hippocampus, causing irreversible neuronal cell death

90
Q

chronic effects of alcohol on liver: cofactor used by alcoholic dehydrogenase and substance produced

A

NAD+, producing NADH

91
Q

chronic effects of alcohol on liver: effect of increased NADH on liver

A

disrupt many dehydrogenase-related reactions in cytoplasm and mitochondria, suppressing energy supply (TCA) and fatty acid oxidation (acidosis), resulting in alcoholic fatty liver (not enough NAD+ to metabolise lipids)

92
Q

chronic effects of alcohol on liver: effect on cytochrome P450 2E1 of excess alcohol

A

leaks oxygen radicals which exceed cellular defence systems and result in oxidative stress (alcoholic steatohepatitis), increasing IL-6 and TNF-a, leading to cirrhosis if not reversed (stop drinking)

93
Q

chronic effects of alcohol on liver: effect of excess alcohol on glycolysis

A

alcohol uses up NAD+, so pyruvate converted to lactate (acidosis) to generate NAD+ for glycolysis, with acetyl CoA unable to enter TCA, so is transformed to ketones (ketosis)

94
Q

chronic effects of alcohol on liver: cirrhosis

A

fibroblasts increase and hepatocyte regeneration decreases, leading to decreased active liver tissue

95
Q

3 beneficial effects of low dose alcohol on CVS

A

decreased mortality from coronary artery disease (men drinking 2-4 units/day), polyphenols increase HDL and tPA levels, with low platelet aggregation

96
Q

chronic effects of alcohol on GI tract: acetaldehye

A

damage to gastric mucosa proportional to dose, exhibiting carcinogenic behaviour

97
Q

chronic effects of alcohol on endocrine system

A

increased ACTH secretion (Cushingoid) and decreased testosterone secretion

98
Q

5 symptoms of hangover (as [blood alcohol] reaches 0, symptoms at worse)

A

nausea, headache, fatigue, restlessness and muscle tremors, polyuria and polydipsia

99
Q

nausea pathway in hangover

A

acetaldehyde build-up in stomach is irritant -> vagus -> vomiting centre

100
Q

cause of headaches in hangover

A

vasodilation

101
Q

cause of fatigue in hangover

A

sleep deprivation, active when drinking

102
Q

cause of restlessness and muscle tremors in hangover

A

active when drinking

103
Q

cause of polyuria and polydipsia in hangover

A

decreased ADH secretion

104
Q

hangover cure

A

sleeping, drinking water to clear acetaldehyde (plus glucose for easier excretion)

105
Q

dosing of cocaine: 5 forms of cocaine and % of cocaine from extraction

A

leaves (0.6-1.8%), paste (80% cocaine in organic solvent), cocaine HCl (medicinal use occasionally; dissolved in acidic solution), crack (precipitate with alkaline solution e.g. baking soda), freebase (dissolve in non-polar solvent e.g. ammonia and ether)

106
Q

dosing of cocaine: administration of paste and cocaine HCl

A

i.v., oral, intranasal; can’t heat as breaks down

107
Q

dosing of cocaine: administration of crack and freebase

A

inhalation (heatable), so faster affect

108
Q

administration of cocaine: pKa of 8.7 so where is oral cocaine ionised and effect on absorption and action

A

oral cocaine ionised in GI tract, causing slower absorption and prolonged action as acidic environment in stomach so less likely to prefuse across membranes

109
Q

administration of cocaine: why is inhaled cocaine (e.g. crack) so low in bioavaliablity

A

pKa of 8.7 and pH of smoke is low (acidic), so ionises and doesn’t diffuse in mouth or lungs as well, but diffuses in alveoli

110
Q

metabolism of cocaine: 2 inactive metabolites, and excretion process

A

75-90% is ecgonine methyl ester or benzoylecgonine; excreted in urine

111
Q

metabolism of cocaine: onset and tissue half life

A

onset in seconds, with tissue half-life of 20-90 minutes

112
Q

what metabolises cocaine in blood to inactive metabolites

A

plasma/liver cholinesterases

113
Q

2 reasons as to what addictive potential of cocaine is due to (pharmacokinetics)

A

very quick speed of onset if administered i.v. or inhaled (and therefore fast reward); cleared quickly from system as metabolised in blood (and liver), driving drug seeking behaviour to restore euphoric effect

114
Q

how can cocaine be used as a local anaesthetic, and when is this better

A

blocks Na+ channels, stopping Na+ influx and disrupts action potentials (better if diffuses across nerve into cell, then enter channel; EC pH is 7.4, IC pH is 7.0 -> as pH closer to pKa EC, more unionised drug, so diffuse across plasma membrane more effectively -> becomes slightly more ionised in cell, so can access inside channel and is better at acting at target)

115
Q

describe cocaine reuptake inhibition in SNS and effect on neurotransmitter and ANS

A

blocks NA reuptake transporter on pre-synaptic post-ganglionic neurone, meaning NA remains in synaptic cleft longer and produces more of an effect of SNS

116
Q

describe cocaine reuptake inhibition in dopaminergic neurones

A

blocks dopamine transporter, so dopamine remains in cleft for longer, so increases [dopamine] in cleft (doesn’t change dopamine affinity or efficacy for receptor)

117
Q

how does cocaine cause euphoria

A

mesolimbic dopamine system: ventral tegmental area to nucleus accumbens, where cocaine blocks dopamine transporter and causes dopamine released to last longer in synaptic cleft, increasing binding to D1 R

118
Q

positive/reinforcing mild-moderate effects of cocaine if acute or low dose

A

mood amplification, more energy, inflated self-esteem, talkative; can get anger and verbal aggression

119
Q

negative/stereotypic severe effects of cocaine if chronic or high dose

A

irritability, anxiety, fear, insomnia, rambling, total anorexia, exhaustion

120
Q

how are effects of cocaine partly due to tolerance

A

cocaine causes massive dopamine release but by blocking reuptake, neurone fails to replenish dopamine, so further cocaine use results in much lower euphoria, leading to other effects e.g. irritability

121
Q

how does cocaine affect the CVS: effect on SNS at low levels and why

A

stimulates SNS by inhibiting NA reuptake, stimulating central sympathetic outflow and increasing sensitivity of adrenergic nerve endings to NA -> increases platelet activation, coronary vasoconstriction, HR, contractility and BP

122
Q

how does cocaine affect the CVS: why, at high levels, does it depress CV parameters

A

acts like a local anaesthetic by blocking sodium and potassium channels

123
Q

how does cocaine affect the CVS: what does cocaine stimulate release of to cause vasoconstriction, and how does it do this

A

endothelin-1 from endothelial cells, inhibiting NO; also causes inflammation

124
Q

how does cocaine affect the CVS: how does cocaine promote thrombosis

A

activates platelets, increasing platelet aggregation, causing atherosclerosis -> MI

125
Q

progression of CVS effects of cocaine to sudden death

A

(heart rate and decreased left ventricular function ->) endothelial injury, platelet activation (-> atherosclerosis); coronary vasoconstriction -> decreased myocardial O2 supply; increased contractility, BP -> increased myocardial O2 demand; -> MI -> arrhythmias and sudden death

126
Q

how does cocaine overdose affect CNS: how does it cause hyperthermia

A

increased agitation, locomotor activity, involuntary muscle contraction - all in hot environent; increases central threshold for thermoregulation by sweat production and cutaneous vasodilation 3x, so increases sweat production and inhibits cutaneous vasodilation

127
Q

how does cocaine overdose affect CNS: how does it increase sweat production

A

enhances SNS ACh innervation to sweat glands

128
Q

how does cocaine overdose affect CNS: how does it inhibit cutaneous vasodilation

A

inhibits SNS NA innervation to vessels

129
Q

4 volatile (95%) contents of cigarettes

A

nitrogen, carbon monoxide/dioxide, benzene, hydrogen cyanide

130
Q

2 particulate (5%) contents of cigarettes

A

alkaloids, tar

131
Q

4 routes of administration for nicotine, dosing and bioavailability %

A

spray (1mg; 20-50%), gum (2-4mg; 50-70%), cigarettes (inhalation; 9-17mg; 20%), patch (transdermal; 15-22mg/day; 70%)

132
Q

given pKa of nicotine is 7.9 and cigarette smoke is acidic, is there buccal absorption

A

no as more ionised

133
Q

relationship of nicotine absorption in alveoli and pH

A

absorption in alveoli independent of pH

134
Q

how is nicotine from gum absorbed

A

fluid from gum diffuses across mucous membranes of mouth

135
Q

4 routes of administration: time plasma nicotine level peak from earliest to latest, and effect on addictivity

A

cigarette, spray, gum/inhaler/tablet; patch is steady; onset rapid but metabolised and excreted quickly, so addictive

136
Q

metabolism of nicotine to inactive metabolite

A

hepatic CYP2A6 (70-80%) -> cotinine; metabolised only in liver, not in blood

137
Q

onset and tissue half life of nicotine

A

onset seconds, with tissue half life of 1-4 hours

138
Q

pharmacodynamic effect of nicotine: receptors affected

A

agonises nicotinic ACh receptors (pre-ganglionic ANS, post-ganglionic PSNS and SNS sweat gland)

139
Q

how does nicotine cause euphoria

A

binds to nicotinic receptor on ventral tegmental area, directly stimulating nerve -> nucleus accumbens releases more dopamine

140
Q

CV effects of nicotine

A

same effects as, but slower than, cocaine (stimulates release of catecholamines and increases SNS output, and all subsequent effects on heart and vessels); also increases free fatty acids, VLDL and LDL, causing atherosclerosis

141
Q

metabolic and appetite effects of chronic nicotine, and effect on weight gain

A

increases metabolic rate and decreases appetite, so weight gain reduced

142
Q

nicotine and neurodegenerative disorders: effect on Parkinson’s disease

A

increase brain CYPs (cytochrome P450) enzymes, so increased ability for brain to metabolise neurotoxins

143
Q

nicotine and neurodegenerative disorders: effect on Alzheimer’s disease

A

decrease B-amyloid toxicity, decreasing amyloid precursor protein (APP)

144
Q

how could caffeine cause euphoria

A

caffeine inhibits adenosine binding to A1 receptors on nucleus accumbens and D1 R; adenosine blocks reward pathway

145
Q

what is an opiate

A

natural alkaloid derived from poppy (opioid has some synthetic property which exerts opiate-like activity)

146
Q

4 examples of opiates

A

morphine, thebaine, codeine, papaverine

147
Q

describe morphine structure-activity relationship

A

tertiary nitrogen (gives affinity and efficacy so crucial to analgesia of morphine by allowing anchorage to receptor)

148
Q

morphine structure-relationship

A

permits receptor anchoring

149
Q

what happens if extend morphine side chain of tertiary nitrogen to 3+ carbons

A

generate antagonist, decreasing analgesia

150
Q

describe how heroin/codeine are transformed to morphine, and hence what they are

A

for heroin OH groups at positions 3 and 6 altered; for codeine OH group at position 3 altered; as OH on position 3 is required for binding to receptor (affinity), codeine is therefore a prodrug

151
Q

what happens to lipophilicity if the OH at position 6 of morphine is oxidised (e.g. add sometheing less water soluble) e.g. heroin, codeine

A

increases 10x, therefore morphine binds more effectively but heroin and codeine more lipid soluble so accesses tissue better

152
Q

describe the old morphine rule

A

must have aromatic ring, spacer, quaternary carbon centre and basic nitrogen for effect; now just tertiary nitrogen and aromatic ring

153
Q

old morphine rule: methadone

A

conforms to morphine rule where tertiary nitrogen, quaternary carbon and phenyl group

154
Q

old morphine rule: fentanyl

A

moving away from morphine rule generates more potent opioids (has tertiary carbon no quaternary carbon)

155
Q

routes of administration of opioids

A

i.v., oral

156
Q

are opioids strong/weak acids/bases

A

weak bases (pKa > 8)

157
Q

as opioids are weak bases, describe oral route of administration

A

heavily ionised in acidic stomach and poorly absorbed, but in small intestine will be unionised and more readily absorbed (but first pass metabolism will decrease bioavailability)

158
Q

as opioids are weak bases, describe distribition in blood and access to tissues

A

best absorbed in blood, despite pH = 7.4 (so most opioid still ionised in blood, with <20% unionised which can access tissues)

159
Q

what can opioid potency depend on

A

administration, effect (e.g. euphoria vs analgesia vs respiratory depression), lipid solublity

160
Q

what is the general rule of thumb for opioid potency, and order of opioids

A

the more lipid soluble, the more potent: methadone/fentanyl&raquo_space; heroin > morphine

161
Q

why is codeine less potent than morphine even though it is more lipid soluble

A

prodrug so less potent due to metabolism

162
Q

duration of action of opioids

A

hours (2-32), with methadone being longest acting

163
Q

active metabolite of morphine, and ability

A

M6G (10% of all metabolites), causing euphoria as opposed to respiratory depression

164
Q

what enzyme converts morphine to M6G

A

not cytochrome P450 (uridine 5 diphosphate glucoronosyltransferase)

165
Q

relative clearances, and therefore rates of metabolism, of methadone compared to fentanyl

A

fentanyl has fast metabolism as clearance is 30x faster than methadone (accumulates in adipose tissue, so long duration of action; given as even though more potent, than heroin, released longer and titrate down), which therefore has a slow metabolism (both don’t have active metabolites); clearance of M6G is faster than fentanyl

166
Q

active metabolite of codeine and heroin

A

morphine (5-10%; hence prodrugs)

167
Q

how is codeine metabolised to morphine

A

in liver by CYP2D6, which is slow O-dealkylation

168
Q

what enzyme in liver deactivated codeine to norcodeine (90%), and hence relative potency of codeine and morphine

A

CYP3A4 (fast so 90% metabolised to norcodeine), hence codeine less potent than morphine

169
Q

3 useful effects of opioids

A

analgesia, euphoria, depression of cough centre (anti-tussive)

170
Q

4 unuseful effects of opioids

A

depression of respiration (medulla), stimulation of cheoreceptor trigger zone (nausea/vomiting), pupillary constriction (miosis), GI effects

171
Q

describe tussive (cough centre) pathway

A

stimulation of mechano/chemo-receptors (throat, respiratory passages or stretch receptors in lungs) -> afferent impulses to cough centre (medulla) -> efferent impulses via PSNS and motor nerves to diaphragm, intercostal muscles and lung -> increased contraction of diaphragmatic, abdominal and intercostal muscles -> noisy expiration (cough) to eject blockage

172
Q

where do ACh/NK C-fibres relay stimulation from mechano/chemo-receptor up to medulla via

A

vagus

173
Q

what receptors do afferent impulses act on in cough centre (medulla)

A

5HT1A

174
Q

central effects of opioids on tussive pathway

A

reduce 5HT1A receptor function -> increase in 5HT levels -> depress discharges from inspiratory motor neurones; NTS is cough centre, with opioids directly inhibiting cough responses from here

175
Q

peripheral effects of opioids on tussive pathway

A

u-opioid receptors (on ACh/NK C-fibres) in airway vagal sensory neurone and opioids inhibit eNANC nerve activity and cholinergic contraction of smooth muscles

176
Q

how do opioids cause respiratory depression in central chemoreceptors

A

inhibit central chemoreceptors, which provide tonic drive to respiratory motor output by sensing changes in pH

177
Q

how do opioids cause respiratory depression in medulla

A

inhibit pre-Botzinger complex in ventrolateral medulla to prevent respiratory rhythm

178
Q

how do opioids cause vomiting/nausea

A

low doses activate mu (m) opioid receptors in chemoreceptor trigger zone (samples blood for noxious stimuli) by decreasing GABA release, which stimulate medullary vomiting centre (also stimulated by vagus, vestibular system and cerebral cortex)

179
Q

how do opioids cause miosis (pin-point pupils indicator of heroin overdose)

A

optic nerve - > pretecal nucleus -> Edinger-Westphal nucleus -> oculomotor nerve -> ciliary ganglion; switch off GABA in Edinger-Westphal nucleus (u), so causes on PSNS nerve to fire more

180
Q

sensory stimulation pathway in enteric nervous system of GI

A

chemical/tension in GI -> mucosal chemo/stretch receptors -> sensory neurone -> submucosal and myenteric plexus via interneurones

181
Q

motor response pathway in enteric nervous system of GI

A

motor neurones -> prevent release of ACh or substance P for smooth muscle contraction, and instead cause release of vasoactive intestinal peptide or NO for smooth muscle relaxation; as opioids suppress, gut motility slows down and constipation occurs

182
Q

location of opioid receptors in GI, causing GI disturbance

A

myenteric neurones

183
Q

how do opioids cause urticaria (hives)

A

some cause histamine release from mast cells under skin (N-methyl group and 6-OH group in opioid induces non IgE mediated histamine release)

Y2 LCRS Pharmacology and Therapeutics (68 decks)

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