Drugs of abuse: Nicotine and Alcohol (Prof. Millar) Flashcards
How many chamicals make up tobacco smoke ?
Which one is responsible for its addictive and important pharmacological effects ?
About 4000.
Nicotine.
How long does it take for inhaled nicotine to reach the brain ?
How long does it take for the effects of nicotine to dissipate ?
Inhaled nicotine is absorbed into the bloodstream via the lungs and rapidly distributed throughout the body, reaching the brain within approx 10 seconds.
The effects of nicotine dissipate w/in a few minutes:
- an initial rapid fall due to redistribution between blood and other tissues (20mins)
- a slower decline due to oxidative metabolism in the liver (to cotinine) (30-100min)
Where are ionotropic nAChRs found ?
- NMJ
- Autonomic ganglia (in the sympathetic & parasympathetic NS)
- CNS
How many subunits make up the nAChR ?
5 (pentameric) –> α, β, γ, δ, ε
Which nAChR subunits have been implicated in mediating the addictive effects of nicotine ?
Why ?
The α4 and β2 subunits.
Self-administration of nicotine is attenuated in mice containing a deletion of the gene encoding the nAChR β2 subunit. [Picciotto et al. (1998) Nature 391, 173-177]
Where are nAChRs located at the NMJ ?
In the CNS and PNS ?
NMJ = post-synaptic CNS/PNS = pre- and post-synaptic
What effect does nicotine on other NTs ?
Nicotine stimulates the release of several NTs including: DA, NA, GABA, endorphins DA ⇒ psychoactive effects NA ⇒ increased attentiveness GABA and endorphins ⇒ anxiolytic effects
In which regions of the brain does nicotine stimulate DA release ?
Nicotine activates nAChRs in the brain causing
the release of DA in the mesolimbic DA pathway (or “reward centre”).
What are the three main areas of the mesolimbic pathway ?
VTA –> nucleus accumbens –> cerebral cortex
VTA (just above brainstem) = DA releasing neurons
Nucleus accumbens = relay messages about pleasure coming from the VTA and going to cerebral cortex
Cerebral cortex = where the message arrives
There are also reciprocal connections between the VTA and the tegmental pedunclopontine nucleus (TPP).
What are the effects of nicotine of the ANS ?
Mixture of sympathetic and parasympathetic effects:
- Increased heart rate
- Increased blood pressure
- Increased sweating
- Decreased gastrointestinal motility
- Release of AD and NA from adrenal medulla
What are the effects of nicotine on the CNS ?
Stimulatory and inhibitory effects:
- symptoms of stimulation and arousal
- can also alleviate stress and anxiety
- may enhance learning and sensory performance
What are the effects of nicotine on sk muscle ?
Relaxation (due to activation of nAChRs in spinal cord, rather than direct effect at NMJ)
What other negative effects can nicotine have ?
- Tolerance (higher doses required to produce the same effect)
- Physical withdrawal symptoms (days-weeks): irritability, restlessness, attentional deficits, sleep disturbances, hunger
- Craving (can persist for much longer)
How much does 1 unit of alcohol raise blood alcohol ?
15mg/100ml.
How fast do we metabolise alcohol ?
~15mg/100ml per hour (~1 unit/hour)
What are the different effects of alcohol (in rising blood alcohol concentrations) ?
Disinhibition < loss of motor coordination, judgement impaired < increased loss of coordination < amnesia < coma < death
What are the physiological effects of alcohol ?
Vasodilatation Gastric secretion Urine production Liver damage Male impotence --> "it provokes the desire, but it takes away the performance" W Shakespeare, Macbeth, Act II, Scene III
What is the main pathway that alcohol stimulates ?
The mesolimbic DA pathway.
What are the positive reinforcements induced by alcohol consumption ?
What about the negative reinforcements ?
+ve: due to pleaserable and eupohoric effects
-ve: to due the relief of stress
W/ which pathologies/dysfunctions is alcohol associated ?
- Primary effect = CNS depression
- Intellectual performance and sensory discrimination impaired
- Evidence for dementia with chronic abuse
- In pregnancy, associated with foetal alcohol syndrome
- Potentiates effects of other drugs (e.g. benzodiazepines)
What is “fatty liver” ?
What can this lead to ?
It is the first stage of liver deterioration in heavy
drinkers ==> chronic heavy alcohol consumption can lead to accumulation of fatty acids
This can lead to death of liver cells and the formation
of fibrous scar tissue (fibrosis), which can lead to
permanent damage (cirrhosis).
Is there an ethanol receptor ?
No, not specifically, but there is evidence for modulation of the functional properties of:
- nAChRs
- ATP receptors (P2XRs)
- 5-HT-3Rs
- GABA-ARs
- NMDARs
- GlyRs
- VGCCs (v-gated Ca2+ channels)
What is so special about the metabolism of alcohol ?
In marked contrast to many drugs, where the rate of drug
metabolism increases with blood concentration, the rate of metabolism of alcohol is linear and almost independent of concentration (~15mg/100ml per hour / 1 unit per hour)
Thus, blood concentration does not reach a plateau, but
continues to accumulate.
How long does it take for ethanol do produce its effects ?
Ethanol, being highly lipid soluble, is readily absorbed by the stomach and small intestine
Effects occur within 5-10 minutes and can last several hours
What are the 2 enzymes in the liver that oxidise ethanol to acetic acid ?
Alcohol dehydrogenase (coverts ethanol to acetaldehyde) + aldehyde dehydrogenase (converts acetaldehyde to acetic acid Both enzymes require the cofactor nicotinamide adenine dinucleotide (NAD)
Why is the rate of alcohol metabolism linear ?
It is due to the limiting supply of NAD (=cofactor for enzymes in liver)
Which of the 2 enzymes metabolizing alcohol can be blocked ?
Which drug can do this and why is it used ?
Disulfiram (Antabuse®) can block aldehyde dehydrogenase –> used for alcoholics
How is methanol metabolized ?
Why is this dangerous ?
It is metabolized by the same enzymes as alcohol, first to formaldehyde and then to formic acid.
This can lead to blindness.
What are the symptoms of an alcohol-induced hangover ?
- Headache
- Diarrhoea
- Nausea
- Fatigue
- Sensitivity to light & sound
- Tremor, sweating & increased pulse
Also diminished dexterity and visual-spatial skills, even after alcohol can no longer be detected in the blood
What negative effects are associated w/ excessive alcohol consumption ?
- Tolerance (greater quantity required to achieve desired
pharmacological effect) - Physical withdrawal symptoms (within hours, last few days): Tremor, Sweating, Nausea, Confusion, Hallucinations (delirium tremens)
- Craving (persists for much longer
