addiction Flashcards
pharmacology of drugs of abuse: summarise the pharmacokinetics and pharmacology of the main drugs of abuse: cannabis, nicotine, cocaine, alcohol and opioids
4 commonest routes of administration for main drugs of abuse
snort (intra-nasal), eat/drink (oral), smoke (inhalation), inject (i.v)
intra-nasal administration: location and rate of absorption
mucous membranes of nasal sinuses; slow absorption (diffuses into venous system)
oral administration: location and rate of absorption
GI tract; very slow absorption
inhalation administration: location and rate of absorption
small airways and alveoli; very rapid absorption (minimal resistance to flow and already in pulmonary circulation)
i.v administration: location and rate of absorption
veins; rapid absorption
4 pharmacological classifications of drugs of abuse
narcotics/painkillers, depressants (‘downers’), stimulants (‘uppers’), miscellaneous
examples of narcotics/painkillers
opiate-like drugs e.g. heroin
examples of depressants
alcohol, benzodiazepines (valium), barbiturates
examples of stimulants
cocaine, amphetamine (‘speed’), caffeine metamphetamine (‘crystal meth’), nicotine
examples of miscellaneous (have other properties)
cannabis, ecstasy (MDMA)
forms of cannabis
cannabis/marijuana, hashish/resin (trichomes - glandular hairs), hash oil (solvent extraction)
number of compounds and cannabinoids in cannabis
> 400 compounds, >60 cannabinoids (n glandular hairs)
2 primary cannabinoids of cannabis, and onset of cannabis
cannabidiol and THC (most powerful); seconds->minutes
dosing in cannabis plant: reefer (60s-70s) vs skunkweed/netherweed (21st century) and relevance
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)
administration of cannabis bioavailablity (% into bloodstream)
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)
distribution of cannabis
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)
upon cannabis administration, what therefore builds up in fatty tissue
fatty acid conjugates of 11-OH-THC
concentration ratios of THC between fat and plasma
10^4 : 1
metabolism of cannabis: phase 1 metabolite location and name
liver to 11-hydroxy-THC (more potent than THC); liver can only conjugate (phase 2) so much per unit time
excretion of cannabis
65% GI tract into bile and faeces, 25% urine
what does cannabis undergo if excreted in bile as lipid-soluble
enterohepatic recycling
describe and explain correlation between plasma cannabinoid concentration and degree of intoxication
poor, as can measure plasma THC, but no info on 11-hydroxy-THC levels, levels in fat or enterohepatic recycling
describe cannabinoid diffusion to brain
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)
tissue half life of cannabis, and how long after smoking a cannabis cigarette will the effects persist in the body (remains in adipose tissue)
tissue half life of 7 days, but due to remaining in adipose tissue, effects persist for 30 days
what receptors does cannabis bind to
CB1, CB2 (cannabinoid receptor)
location of CB1 receptors
hippocampus, cerebellum, cerebral cortex, basal ganglia; most common G-protein coupled receptor in brain
location of CB2 receptors
immune cells
CB R type of receptor and hence type of drug and effect on IC enzymes
type 2 (G-protein coupled receptor), Gi/o (inhibitory) so depressant, depresing adenylate cyclase
CB R endogenous cannabinoid
endogenous anandamide
mesolimbic dopamine system resulting in euphoria
cannabis -> CB1 receptor on GABA interneurone -> reduction in GABA (natural suppressant) release to ventral tegmental area (disinhibition) -> high dopamine release from nucleus accumbens
5 central effects of cannabis
euphoria, psychosis (and schizophrenia), increased appetite, memory loss, psychomotor performance
what is the role of the anterior cingulate cortex
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)
what does cannabis do to anterior cingulate cortex, and what 2 conditions can result
hypoactivity, losing ability to change behaviour, resulting in psychosis, schizoprenia (especially if just THC vs THC and cannabidiol, which induces more euphoria)
cannabis effect on food intake
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
cannabinoid agonists as immunosuppressants: 4 immune cells with CB R expression, and effect of cannabis on cells
B-cell, macrophage, natural killer cells, T-cell; suppresses their effect, so more susceptible to illness and infection
why does cannabis cause memory loss
affects limbic regions (amnestic effects, reducing BDNF which normally improves hippocampal health)
which area does cannabis suppress psychomotor performance
cerebral cortex
2 peripheral effects of cannabis
immunosuppressant, tachycardia/vasodilation (conjunctivae - blood shot eyes; affects TRPV1 as opposed to CB R)
effect of cannabis on medulla
low CB1 receptor expression, meaning that cardiovascular and cardiorespiratory control not suppressed (can’t overdose to point of death)
medical use of cannabis: 3 conditions where regulatory elevation of CB1 R
multiple sclerosis, pain, stroke
medical use of cannabis: 2 conditions where pathology elevation of CB1 R
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)
medical use of cannabis ‘autoprotection’: what are dronabinol and nabilone (THC) used to treat
prevent nausea and vomiting caused by chemotherapy in those without good results using other medications
medical use of cannabis ‘autoprotection’: what is dronabinol used to treat
loss of appetite and weight loss in people with acquired immunodeficiency syndrome (AIDS)
medical use of rimonabant, and problem (hence taken off market)
anti-obesity agent as antagonist for CB R, decreasing weight; caused increased depression and suicide
medical use of cannabis: ‘autoprotection’ what is sativex (THC and cannabidiol) used to treat
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
what does high potency fatty acid amide hydrolase do inhibitor
increases concentration of endogenous anandamide (natural agonist of CB R)
epidemiology of alcohol
high in Europe, Russia and US; low in north Africa (Islam)
dosing of alcohol: absolute amount vs units, and consistency of units
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)
dosing of alcohol: safe level
men and women <14 units/week is low risk; binge drinking (>8 units in one sitting)
dosing of alcohol: what does a blood level of 0.01% mean
10mg/100ml blood
dosing of alcohol: blood levels based on weight and blood level
charts which show weight and number of drinks, and estimated blood level (can subtract 0.01% for each 40 minutes due to metabolism)
administration route of alcohol
oral
administration of alcohol and effect on stomach fullness
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
% of alcohol metabolised, and % metabolised in liver
90% metabolised (10% excreted unmetabolised), with 85% of 90% metabolised in liver
metabolism pathway of alcohol in liver to acetaldehyde
alcohol -> [alcohol dehydrogenase (75%) or mixed function oxidase (25%)] -> acetaldehyde (toxic compound)
why is there tolerance to alcohol
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)
metabolism of alcohol: role of first pass hepatic metabolism and breaking up alcohol dose over time
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
% of alcohol metabolism in GI tract (stomach)
15%
metabolism pathway of alcohol in GI tract to acetaldehyde
alcohol -> [alcohol dehydrogenase] -> acetaldehyde
metabolism pathway of alcohol in GI tract: female levels of alcohol dehydrogenase in stomach
50% less alcohol dehydrogenase in stomach vs men
distribution of alcohol: men vs women
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
metabolism of alcohol: metabolism of acetaldehyde in liver and GI tract
acetaldehyde (toxic compound) -> [aldehyde dehydrogenase] -> acetic acid
effect of disulfiram on aldehyde dehydrogenase, and clinical use
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
genetic polymorphism of aldehyde dehydrogenase
“Asian flush” -> less effective enzyme
potency of alcohol
low (ug/ml vs ng/ml for cocaine and nicotine) as simple chemical (binds to lots of targets, but not very well)
what chemical is alcohol, and hence pharmacological targets
ethanol (C2H5OH), so no pharmacological targets, so affinity and efficacy poor
acute effects of alcohol in CNS
primary effect is depressant, but CNS agitation might occur (low dose in certain situations)
what is degree of CNS excitability dependent on (low dose alcohol increases CNS excitability, but decreases at higher dose as depressant)
personality and environment (environment is non-social (low excitability) or social setting (high excitability))
acute effects of alcohol in CNS: direct and indirect effects on GABA receptors and Cl- influx
direct: increases GABA, promoting Cl- influx; indirect: increases release of allopregnenolone which binds to GABA receptors and promotes Cl- influx
acute effects of alcohol in CNS: effect on allosteric modulation of NMDA receptors
decrease
acute effects of alcohol in CNS: effect on neurotransmitter release, and reason
reduce, as Ca2+ channels decrease
2 factors influencing acute effects of alcohol on CNS
CNS is functionally complex, ethanol has low potency so low selectivity
how does alcohol cause an acute euphoric effect in CNS
opiates/alcohol bind to u-receptor on GABAergic neurone -> decrease in GABA release -> ventral tegmental area -> nucleus accumbens -> increase in dopamine release
6 locations acutely depressed in brain by alcohol, and normal functions
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)
effect of alcohol on cardiovascular system and how (“Asian flush”)
causes cutaneous vasodilation by preventing precapillary sphincters from remaining contracted, as acetaldhehyde decreases Ca2+ entry and increases prostaglandins in arterioles and capillaries
why might chronic alcohol be associated with an increased BP and HR
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
acute effects of alcohol on endocrine system
diuresis (polyuria) due to decreased ADH release
chronic effects of alcohol on CNS: thiamine (vitamin B1) pathway to cerebral energy utilisation
thiamine -> [cofactor] -> enzymes in energy metabolism -> cerebral energy utilisation (essential coenzyme to TCA cycle and pentose phosphate shunt)
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
impaired metabolism, NMDA excitotoxicity, build up of reactive oxygen species
chronic effects of alcohol on CNS: why does alcohol cause dementia
causes cortical atrophy, decreasing volume cerebral white matter, causing confusion (encephalopathy) and oculomotor symptoms
chronic effects of alcohol on CNS: why does alcohol cause ataxia
ceberellar cortex degeneration, affecting gait
chronic effects of alcohol on CNS: syndrome due to thiamine deficiency
Wernicke-Korsakoff syndrome
chronic effects of alcohol on CNS: what is Wernicke’s encephalopathy (reversible)
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)
chronic effects of alcohol on CNS: effect of Wernicke’s encephalopathy on cells
imbalance leads to cellular energy deficit, focal acidosis, regional increase in glutamate, and ultimately cell death
chronic effects of alcohol on CNS: what triad is Wernicke’s encephalopathy characterised by
ophthalmoplegia, ataxia, and confusion (only 10% of patients exhibit all 3, and other symptoms may also be present)
chronic effects of alcohol on CNS: 3 causes of thiamine deficiency in Wernicke’s encephalopathy
oxidative damage, mitochondrial injury leading to apoptosis, and directly stimulating a pro-apoptotic pathway
chronic effects of alcohol on CNS: what area does Wernicke’s encephalopathy affect
hypothalamus and thalamus
chronic effects of alcohol on CNS: what is Korsakoff’s psychosis (irreversible)
impaired ability to acquire new information and by a substantial, but irregular memory loss for which patients often attempt to compensate through confabulation
chronic effects of alcohol on CNS: what is Korsakoff’s psychosis associated with, and where does it affect
associated with polyneuritis, and affects deep brain e.g. hippocampus, causing irreversible neuronal cell death
chronic effects of alcohol on liver: cofactor used by alcoholic dehydrogenase and substance produced
NAD+, producing NADH
chronic effects of alcohol on liver: effect of increased NADH on liver
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)
chronic effects of alcohol on liver: effect on cytochrome P450 2E1 of excess alcohol
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)
chronic effects of alcohol on liver: effect of excess alcohol on glycolysis
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)
chronic effects of alcohol on liver: cirrhosis
fibroblasts increase and hepatocyte regeneration decreases, leading to decreased active liver tissue
3 beneficial effects of low dose alcohol on CVS
decreased mortality from coronary artery disease (men drinking 2-4 units/day), polyphenols increase HDL and tPA levels, with low platelet aggregation
chronic effects of alcohol on GI tract: acetaldehye
damage to gastric mucosa proportional to dose, exhibiting carcinogenic behaviour
chronic effects of alcohol on endocrine system
increased ACTH secretion (Cushingoid) and decreased testosterone secretion
5 symptoms of hangover (as [blood alcohol] reaches 0, symptoms at worse)
nausea, headache, fatigue, restlessness and muscle tremors, polyuria and polydipsia
nausea pathway in hangover
acetaldehyde build-up in stomach is irritant -> vagus -> vomiting centre
cause of headaches in hangover
vasodilation
cause of fatigue in hangover
sleep deprivation, active when drinking
cause of restlessness and muscle tremors in hangover
active when drinking
cause of polyuria and polydipsia in hangover
decreased ADH secretion
hangover cure
sleeping, drinking water to clear acetaldehyde (plus glucose for easier excretion)
dosing of cocaine: 5 forms of cocaine and % of cocaine from extraction
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)
dosing of cocaine: administration of paste and cocaine HCl
i.v., oral, intranasal; can’t heat as breaks down
dosing of cocaine: administration of crack and freebase
inhalation (heatable), so faster affect
administration of cocaine: pKa of 8.7 so where is oral cocaine ionised and effect on absorption and action
oral cocaine ionised in GI tract, causing slower absorption and prolonged action as acidic environment in stomach so less likely to prefuse across membranes
administration of cocaine: why is inhaled cocaine (e.g. crack) so low in bioavaliablity
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
metabolism of cocaine: 2 inactive metabolites, and excretion process
75-90% is ecgonine methyl ester or benzoylecgonine; excreted in urine
metabolism of cocaine: onset and tissue half life
onset in seconds, with tissue half-life of 20-90 minutes
what metabolises cocaine in blood to inactive metabolites
plasma/liver cholinesterases
2 reasons as to what addictive potential of cocaine is due to (pharmacokinetics)
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
how can cocaine be used as a local anaesthetic, and when is this better
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)
describe cocaine reuptake inhibition in SNS and effect on neurotransmitter and ANS
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
describe cocaine reuptake inhibition in dopaminergic neurones
blocks dopamine transporter, so dopamine remains in cleft for longer, so increases [dopamine] in cleft (doesn’t change dopamine affinity or efficacy for receptor)
how does cocaine cause euphoria
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
positive/reinforcing mild-moderate effects of cocaine if acute or low dose
mood amplification, more energy, inflated self-esteem, talkative; can get anger and verbal aggression
negative/stereotypic severe effects of cocaine if chronic or high dose
irritability, anxiety, fear, insomnia, rambling, total anorexia, exhaustion
how are effects of cocaine partly due to tolerance
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
how does cocaine affect the CVS: effect on SNS at low levels and why
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
how does cocaine affect the CVS: why, at high levels, does it depress CV parameters
acts like a local anaesthetic by blocking sodium and potassium channels
how does cocaine affect the CVS: what does cocaine stimulate release of to cause vasoconstriction, and how does it do this
endothelin-1 from endothelial cells, inhibiting NO; also causes inflammation
how does cocaine affect the CVS: how does cocaine promote thrombosis
activates platelets, increasing platelet aggregation, causing atherosclerosis -> MI
progression of CVS effects of cocaine to sudden death
(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
how does cocaine overdose affect CNS: how does it cause hyperthermia
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
how does cocaine overdose affect CNS: how does it increase sweat production
enhances SNS ACh innervation to sweat glands
how does cocaine overdose affect CNS: how does it inhibit cutaneous vasodilation
inhibits SNS NA innervation to vessels
4 volatile (95%) contents of cigarettes
nitrogen, carbon monoxide/dioxide, benzene, hydrogen cyanide
2 particulate (5%) contents of cigarettes
alkaloids, tar
4 routes of administration for nicotine, dosing and bioavailability %
spray (1mg; 20-50%), gum (2-4mg; 50-70%), cigarettes (inhalation; 9-17mg; 20%), patch (transdermal; 15-22mg/day; 70%)
given pKa of nicotine is 7.9 and cigarette smoke is acidic, is there buccal absorption
no as more ionised
relationship of nicotine absorption in alveoli and pH
absorption in alveoli independent of pH
how is nicotine from gum absorbed
fluid from gum diffuses across mucous membranes of mouth
4 routes of administration: time plasma nicotine level peak from earliest to latest, and effect on addictivity
cigarette, spray, gum/inhaler/tablet; patch is steady; onset rapid but metabolised and excreted quickly, so addictive
metabolism of nicotine to inactive metabolite
hepatic CYP2A6 (70-80%) -> cotinine; metabolised only in liver, not in blood
onset and tissue half life of nicotine
onset seconds, with tissue half life of 1-4 hours
pharmacodynamic effect of nicotine: receptors affected
agonises nicotinic ACh receptors (pre-ganglionic ANS, post-ganglionic PSNS and SNS sweat gland)
how does nicotine cause euphoria
binds to nicotinic receptor on ventral tegmental area, directly stimulating nerve -> nucleus accumbens releases more dopamine
CV effects of nicotine
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
metabolic and appetite effects of chronic nicotine, and effect on weight gain
increases metabolic rate and decreases appetite, so weight gain reduced
nicotine and neurodegenerative disorders: effect on Parkinson’s disease
increase brain CYPs (cytochrome P450) enzymes, so increased ability for brain to metabolise neurotoxins
nicotine and neurodegenerative disorders: effect on Alzheimer’s disease
decrease B-amyloid toxicity, decreasing amyloid precursor protein (APP)
how could caffeine cause euphoria
caffeine inhibits adenosine binding to A1 receptors on nucleus accumbens and D1 R; adenosine blocks reward pathway
what is an opiate
natural alkaloid derived from poppy (opioid has some synthetic property which exerts opiate-like activity)
4 examples of opiates
morphine, thebaine, codeine, papaverine
describe morphine structure-activity relationship
tertiary nitrogen (gives affinity and efficacy so crucial to analgesia of morphine by allowing anchorage to receptor)
morphine structure-relationship
permits receptor anchoring
what happens if extend morphine side chain of tertiary nitrogen to 3+ carbons
generate antagonist, decreasing analgesia
describe how heroin/codeine are transformed to morphine, and hence what they are
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
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
increases 10x, therefore morphine binds more effectively but heroin and codeine more lipid soluble so accesses tissue better
describe the old morphine rule
must have aromatic ring, spacer, quaternary carbon centre and basic nitrogen for effect; now just tertiary nitrogen and aromatic ring
old morphine rule: methadone
conforms to morphine rule where tertiary nitrogen, quaternary carbon and phenyl group
old morphine rule: fentanyl
moving away from morphine rule generates more potent opioids (has tertiary carbon no quaternary carbon)
routes of administration of opioids
i.v., oral
are opioids strong/weak acids/bases
weak bases (pKa > 8)
as opioids are weak bases, describe oral route of administration
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)
as opioids are weak bases, describe distribition in blood and access to tissues
best absorbed in blood, despite pH = 7.4 (so most opioid still ionised in blood, with <20% unionised which can access tissues)
what can opioid potency depend on
administration, effect (e.g. euphoria vs analgesia vs respiratory depression), lipid solublity
what is the general rule of thumb for opioid potency, and order of opioids
the more lipid soluble, the more potent: methadone/fentanyl»_space; heroin > morphine
why is codeine less potent than morphine even though it is more lipid soluble
prodrug so less potent due to metabolism
duration of action of opioids
hours (2-32), with methadone being longest acting
active metabolite of morphine, and ability
M6G (10% of all metabolites), causing euphoria as opposed to respiratory depression
what enzyme converts morphine to M6G
not cytochrome P450 (uridine 5 diphosphate glucoronosyltransferase)
relative clearances, and therefore rates of metabolism, of methadone compared to fentanyl
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
active metabolite of codeine and heroin
morphine (5-10%; hence prodrugs)
how is codeine metabolised to morphine
in liver by CYP2D6, which is slow O-dealkylation
what enzyme in liver deactivated codeine to norcodeine (90%), and hence relative potency of codeine and morphine
CYP3A4 (fast so 90% metabolised to norcodeine), hence codeine less potent than morphine
3 useful effects of opioids
analgesia, euphoria, depression of cough centre (anti-tussive)
4 unuseful effects of opioids
depression of respiration (medulla), stimulation of cheoreceptor trigger zone (nausea/vomiting), pupillary constriction (miosis), GI effects
describe tussive (cough centre) pathway
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
where do ACh/NK C-fibres relay stimulation from mechano/chemo-receptor up to medulla via
vagus
what receptors do afferent impulses act on in cough centre (medulla)
5HT1A
central effects of opioids on tussive pathway
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
peripheral effects of opioids on tussive pathway
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
how do opioids cause respiratory depression in central chemoreceptors
inhibit central chemoreceptors, which provide tonic drive to respiratory motor output by sensing changes in pH
how do opioids cause respiratory depression in medulla
inhibit pre-Botzinger complex in ventrolateral medulla to prevent respiratory rhythm
how do opioids cause vomiting/nausea
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)
how do opioids cause miosis (pin-point pupils indicator of heroin overdose)
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
sensory stimulation pathway in enteric nervous system of GI
chemical/tension in GI -> mucosal chemo/stretch receptors -> sensory neurone -> submucosal and myenteric plexus via interneurones
motor response pathway in enteric nervous system of GI
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
location of opioid receptors in GI, causing GI disturbance
myenteric neurones
how do opioids cause urticaria (hives)
some cause histamine release from mast cells under skin (N-methyl group and 6-OH group in opioid induces non IgE mediated histamine release)
