PHARM; Lecture 13, 14 and 15 - Drugs of Abuse I, II and Alcohol Flashcards
Why are drugs of abuse used?
For euphoria -> cell bodies in the ventral tegmental area which project into nucleus accumbens, releasing DA to induce a euphoric high
What are the methods of admin of drugs of abuse?
Intra-nasal (Mucous membranes of nasal sinuses, slow absorption), oral (GIT, v. slow), inhalation (Small airways and alveoli = rapid), IV (veins, rapid)
What are the classes of drugs of abuse?
Narcotics (opiates - heroin), depressant (alcohol, benzodiazepines, barbiturates), stimulants (cocaine, amphetamine, caffeine, methamphetamine), misc. (cannabis, ecstasy)
What is cannabis?
- From the cannabis sativa plant;
- cannabinoids being the main compound (delta-9 THC is the main compound)
- main part of plant are the trichomes on the plant.
- Main aim of new versions of cannabis are to increase levels of delta-9 THC (seem to increase -ve consequences)
What are the methods of admin of cannabis?
Oral - 5-15% (delayed onset/slow absorption with 1st pass metabolism); inhalation - 25-35% to be absorbed in blood stream
Once in the blood stream, what occurs to cannabis?
- VERY lipid soluble
- Diffuses to highly perfused tissues first and slow accumulation in not well perfused tissues
- slowly accumulated in poorly perfused fatty tissues, with ratio 10^4 fatty tissue : 1 plasma, which will slowly release back into the plasma.
- Distributes also to the brain and sits in the brain tissues for a long time, with prolonged effect as it isn’t clearing from the tissues
What occurs to cannabis when broken down?
In the liver - a more potent cannabinoid is formed (11-OH-THC) from the cannabinoid; In the GIT (65%), most of it goes into the bile (to be excreted) so it is recycled in the enterohepatic circulation; excreted 25% via urine. Poor correlation between plasma cannabinoid concentration and degree of intoxication
How long after smoking a cannabis cigarette will the effects persist in the body? 5 hours 12 hours 7 days 30 days 10 years
30 days
What are the receptors that cannabis acts on?
- CB1
- hippocampus
- cerebellum
- cerebral cortex
- basal ganglia.
- CB2 - on immune cells.
- Acts on adenylate cyclase to inhibit it (hence depressant).
- Body’s cannabinoid = endogenous anandamide
What is the pharmacodynamics of euphoria?
- GABA maintains the pathway inhibited to prevent constant euphoria.
- Cannabis depresses the GABA inhibition, inhibiting the inhibition, to increase firing of VTA so NAcc releases more DA
What are the functions of cannabis?
- Euphoria,
- paranoia/schizophrenia,
- hunger,
- immunosuppressant,
- memory loss (limbic regions with amnestic effects with decreased BDNF),
- psychomotor performance (cerebral cortex),
- tachy/vasodilation (red eyes via vanilloid receptor),
- medulla (low CB1 receptor expression so it is very difficult to OD on cannabis so no decrease to cardioresp centre in medulla)
What does the Anterior cingulate cortex do and what occurs to it with cannabis?
- Involved with performance monitoring with behavioural adjustment in order to avoid losses
- hypoactivity in cannabis users;
- can increase psychosis and schizophrenia
What is the effect of cannabis on food intake?
- Positive effect on orexigenic neurones in lateral hypothalamus
- presynaptic inhibition of GABA increases MCH activity;
- inceased orexin production
How does cannabis cause immunosuppression?
What are the medical uses of cannabis?
- Increased regulation of CB receptors;
- MS/pain/stroke = regulatory;
- fertility = in males with upregulation of CB1 receptors interferes with sperm production;
- and in obesity there is an upregulation of CB1
What are the functions of the drugs that affect the CB receptors?
- Dronabinol/nabilone used as anti-emetic for cancer patients;
- sativex as analgesic for MS;
- rimonobant used for obesity as downregulates hunger but now withdrawn as instances of suicide associated
What is the t1/2 of cannabis and the elimination method?
t1/2= 7d; elimination = synth into 11OH THC - 65% in gut, urine 25%
What is cocaine and the different forms?
Plant derived (erythroxylum coca).
How do you admin cocaine?
Oral isn’t a good admin method
How do you metabolise cocaine?
How do cocaine pharmacokinetics contribute to the addictive potential of the drug?
Short elimination time means that it’s effects are short lived so want constant admin; also quick method of admin makes it more likely to be admin
What are the functions of cocaine?
- Local anaesthetic,
- reuptake inhibition,
- euphoria -> mild-moderate effects are positive/reinforcing effects and severe effects are negative/stereotypical effects;
- cardiovascular, MI
How does cocaine act as a local anaesthetic?
High dose -> blocks Na channels
How does cocaine act as a reuptake inhibitor?
- Blocks uptake systems so more DA in the synapse
- doesn’t affect affinity/efficacy,
- but increase DA in synapse,
- so more present to try to bind to the receptor to outcompete
How does cocaine cause euphoria?
Blocks DA transporter in the NAcc to increase DA in synapse which is released
How does cocaine cause MI/cardiovascular problems?
- With dose increasing as you go down;
- Releases endothelin-1 which increases vasoconstriction;
- CNS effects -> vasoconstriction and hyperpyrexia (caused by increase ANS activation) which can affect epilepsy
What is nicotine?
- From plant;
- present in cigarettes;
- tar droplets deposited in lung and nicotine diffuses through that into the alveoli.
- Nicotine in particulate side
How is nicotine admin?
Cigarettes are acidic and nicotine is alkaline, so is ionised in cig smoke, but then diffuses across the alveoli as the membrane is so thin.
How is nicotine metabolised?
Met by cytochrome P450 in liver (70-80%) into cotinine. T1/2= 1-4h Eliminated via urine
Where does nicotine act?
Acts on ANS nAChR
What are the functions of nicotine?
Euphoria, cardiovascular effects, metabolic effects, protective against neurodegenerative disorders
How does nicotine cause euphoria?
Increases firing rate of VTA so increases DA release from NAcc
What CV effects does nicotine cause?
No effect on lungs but increases CV disease risk but are long developing (unlike cocaine)
How does nicotine affect metabolism?
Increases metabolic rate and decreases appetite
How does nicotine affect neurodegenerative disorders?
Protection against development of: Parkinson’s (increases CYP in brain so decreases neurotoxins). Alzheimer’s (decreases beta-amyloid toxicity and amyloid precursor protein)
Does caffeine affect euphoria?
Caffeine is adenosine receptor antagonist so blocks inhibitory effects of adenosine, so increases DA release
What is a safe dose of alcohol?
Men/Women =< 14 u/wk.
Binge drinking > 8u in one sitting
How you administer alcohol?
Oral -> 20% absorbed from stomach, 80% absorbed from intestines. Speed of onset is proportional to gastric emptying so full stomach = slower absorption
How is alcohol metabolised?
90% is metabolised. 85% in liver -> mostly by alcohol DHase (75%) and mixed function oxidase (25%) which form acetaldehyde. In chronic alcoholism, mixed function oxidase is increased, so you become more tolerant. 15% in stomach (<50% capacity in females). Aldehyde DHase metabolises acetaldehyde into acetic acid
How can metabolism of alcohol be saturated?
By giving a high dose at once, rather than all at once - first pass metabolism
What is the difference in distribution between women and men?
- Women have higher fat levels so less water content, meaning that alcohol is less dilute in the blood
- less body water and less alcohol DHase in the stomach in women
What is a problem that can occur with aldehyde DHase?
Asian flush = polymorphism in the enzyme; also Disulfiram acts as an alcohol aversion therapy as it causes build up of acetaldehyde, increasing bad effects
What is the pharmacological potency of alcohol?
LOW -> less than nicotine and cocaine; this means that due to it having a non-selective target it can act on many targets with low potency, as it doesn’t activate/block targets
What are the acute effects of alcohol?
Depressant effect, slight euphoria, CNS effects, CVS effects, polyuria
How does alcohol cause a depressant effect on the CNS?
- Low dose -> with slight CNS agitation sometimes, can be difficult to see where it works as CNS is functionally complex and ethanol has low potency/selectivity.
- Dependent on:
What are the targets that alcohol influences?
Increases GABAa function via pre/post synaptic function (allopregnenlone increased in presynaptic region, enhancing GABAa function which increases Cl influx post synaptically); binds to NMDA receptors via allosteric site, reducing firing rate of that receptor; decreases Ca influx via Ca channels so decrease release of NT
How does alcohol cause a euphoric effect?
Via the same pathway as opiates
Which parts of the CNS does alcohol affect?
Which CV effects does alcohol cause?
- Cutaneous vasodilation (decreases Ca entry, increases Prostaglandin);
- centrally mediated HR as alcohol prevents baroreceptor control of HR, so increased HR
How does alcohol increase diuresis?
Prevents VP secretion, so prevents reabsorption of water, increasing need to go to toilet
What are the chronic CNS effects with alcohol?
- WKS: chronic alcoholics gain most calories from alcohol,
- so don’t gain enough thiamine in the diet.
- If energy metabolism is disturbed for long enough then it goes from
- reversible (Wernicke’s Ecephalopathy)
- to irreversible (Korsakoff’s psychosis)
What are the chronic liver effects from alcohol?
- NAD+ is being used up by alcohol metabolism (chronic alcohol),
- so kreb’s cycle is impaired (pyruvate met, TCA -> instead: pyruvate to lactate, ACoA to ketones,
- causing build up of TAG in the liver causing fatty liver, which causes an inflammatory stimulus,
- Inflammatory free radicals are released causing release of cytokines
- causing inflammation (IL-6 and TNFa),
- causing hepatitis (which can still be reversible) but if it continues long enough
- cirrhosis occurs (fibroblasts inflitrate the liver, deposite fibrous tissue, active liver tissue decreases, increases fibroblasts and decreases hepatocyte regeneration)
- Liver cannot manage met demands of body if it gets bad enough, so liver transplant/treatment needed
What are the beneficial effects of alcohol?
- LOW DOSES ->
- decreased mortality from coronary artery disease,
- increases HDL,
- increases tPA levels
- decreases platelet aggregation
How does alcohol affect the GIT?
Acetaldehyde is always present in stomach lining in chronic alcoholics which damage mucosa and can be carcinogenic (increase in stomach cancer in alcoholics)
What are some endocrine effects of chronic alcohol?
Increase ACTH secretion (alcohol stimulated so Cushing’s like syndrome) and decrease testosterone secretion (feminine characteristics)
How are the hangover effects caused?
Nausea is most profound when reaching blood alcohol conc of 0.
Rebound excitation occurs when reaching conc of 0.
Best cure: sleep it off until rebound effects have dissipated.
