Drugs of Abuse 3: Alcohol

Question 1

pharmacokinetics- dosing

Answer 1

Absolute amount:

% ABV x 0.78 = g alcohol/100ml (ABV = alcohol by volume)
Units:
%ABV x volume (ml) 1 unit = 10ml or 8g of absolute alcohol
1000
No consistency!!

Question 2

alcohol safe level

Answer 2

Safe level?:

Men & Women;  14 units/week LOW RISK

Binge drinking i.e. > 8 units in one sitting; 18% (> 30%) ↓
(16-24 yrs)

Question 3

calculating blood alcohol levels

Answer 3

BLOOD LEVELS – 0.01% = 10mg/100ml blood

Question 4

routes of administration for alcohol

Answer 4

orally

Question 5

How does drinking on a full stomach influence your blood alcohol level?

Answer 5

alcohol on full stomach means- stays in stomach for longer, less absorbed.
has to wait until it enters the small intestine where more is absorbed.

but on an empty stomach- the alcohol passes straight through to the small intestines so it’s better absorbed (80% rather than 20%)

Question 6

pharmacokinetics- metabolism

-where does metabolism take place

Answer 6

85% liver
5% GIT
10% remains

Question 7

alcohol- liver metabolism

Answer 7

alcohol -> acetaldehyde
due to enzymes:
alcohol dehydrogenase
mixed function oxidase

these enzymes can be saturated, hence at a high dose not all alcohol is metabolised so there is higher blood alcohol levels

Question 8

what is the significance of the mixed function oxidase enzyme?

Answer 8

liver upregulates it as you drink alcohol more regularly- leads to faster alcohol metabolism and so builds tolerance

Question 9

alcohol- GIT metabolism

Answer 9

alcohol -> acetaldehyde

enzyme alcohol dehydrogenase

Question 10

A man and a woman of similar height and weight share a bottle of wine. Explain why the blood alcohol levels in the woman are likely to be higher.

Answer 10

women have less alcohol dehydrogenase and less body water (less ADH) so more alcohol enters the blood stream

Question 11

what happens to acetaldehyde?

Answer 11

turns to acetic acid

aldehyde dehydrogenase

Question 12

Explain why disulfiram can be effective as alcohol aversion therapy.

Answer 12

blocks the enzyme aldehyde dehydrogenase

this leads to acetaldehyde build up -> deterrent from drinking alcohol (since acetaldehyde is toxic)

Question 13

what impact does genetic polymorphism

Answer 13

lead to Asian flush

don’t break down acetaldehyde as well leading to a build up and the enzyme not as effective

Question 14

pharmacodynamics of alcohol

Answer 14

low pharmacological potency

since it is a simple molecule that binds to lots of targets but not v well hence lots more alcohol needed

Question 15

acute effects: CNS

alcohol

Answer 15

depressany effect
dependent on:
degree of CNS excitability
-environment -personality

environment

• non-social setting
• social setting

Question 16

acute effects: CNS

Answer 16

• can bind to GABA receptors, increases Cl- influx
• decreases excitability of NMDA receptors (decreases allosteric modulation)
• Ca2 channels: decreases neurotransmitter release

Question 17

acute effects: CNS

2 points

Answer 17

CNS is functionally complex

Ethanol has low potency low selectivity

Question 18

how does alcohol cause euphoria

Answer 18

alcohol/opiates bind to the opioid receptors, which inhibit the release of GABA stimulation and, and dopamine release

Question 19

impacts on the different parts of the brain with alcohol

Answer 19

Corpus Collosum - Passes info from the left brain (rules, logic)
to the right brain (impulse, feelings) and vice versa.

Hypothalamus - Controls appetite, emotions, temperature,
and pain sensation.

Reticular Activating System –
Consciousness

Hippocampus - Memory

Cerebellum - Movement
and coordination

Basal Ganglia –
Perception of time

Question 20

how does alcohol cause cutaneous vasodilation

Answer 20

Cutaneous vasodilation;

decrease Ca2+ entry (vessels cannot contract leading to Asian flush)

increase prostaglandins

Question 21

how does alcohol affect HR

Answer 21

alcohol suppresses the baroreceptors - (normally signals to the parasympathetic limb increase) but alcohol inhibits PNS and turns on SNS hence HR increases

Centrally mediated decrease in baroreceptor sensitivity leads to an acute increase in heart rate and chronic alcohol may be associated with an increased blood pressure.

Question 22

what impact does alcohol have on the endocrine system?

Answer 22

vasopressin suppressed to ability to retain water is suppressed
leads to diuresis (polyuria)

Question 23

effect on thiamine with alcoholism

Answer 23

thiamine reduced in alcoholics- most alcoholics get most calories from alcohol so lack thiamine from diet

The body can only store between 30–50 mg of thiamine, thus body stores of individuals on a thiamine deficient diet are likely to be depleted in four-to-six weeks. Further thiamine deprivation causes a significant decrease in the activity of many enzymes which play a key role in metabolism. Thiamine acts as an essential coenzyme to the TCA cycle and the pentose phosphate shunt.

Question 24

what is thiamine needed for?

Answer 24

thiamine is a cofactor for enzymes in energy metabolism
which leads to cerebral energy utilisation
Brain regions with high metabolic demand – impaired metabolism, NMDA excitotoxicity, ROS.

Question 25

chronic effects due to alcohol

Answer 25

Dementia – Cortical atrophy/ volume cerebral white matter confusion (encephalopathy), oculomotor symptoms
Ataxia – Cerebellar cortex degeneration - gait

Wernicke-Korsakoff syndrome (due to thiamine deficiency)
Wernicke’s encephalopathy – (hypothalamus/thalamus)
Korsakoff’s psychosis – (deep brain e.g. hippocampus)

Question 26

what are the effects on the liver

Answer 26

*alcohol needs NAD+ to be metabolised, but alcoholics use it all up for other processes in the liver. therefore it is not metabolised properly causing lipid and fat build up hence there is more ketosis and lactic acid build up. Fatty liver.

In the liver, alcohol is primarily metabolized by cytosolic alcohol dehydrogenase (ADH) to acetaldehyde, which is further metabolized to acetate by mitochondrial aldehyde dehydrogenase (ALDH2). Both enzymes use NAD+ as a cofactor, producing a reducing equivalent NADH in both steps. Increased production of NADH was implicated in the disruption of many dehydrogenase-related reactions in the cytoplasm and mitochondria [i.e. the tricarboxylic acid cycle (TCA) and β-oxidation of fatty acids], thereby suppressing energy supply and fatty acid oxidation, which in turn results in alcoholic fatty liver.
Cytochrome P450 2E1 (part of the microsomal ethanol oxidising system) leaks oxygen radicals as part of its operation and when they exceed the cellular defense systems they result in oxidative stress with its pathologic consequences. This is true when excess alcohol has to be metabolized, as in alcoholic steatohepatitis, or when CYP2E1 is confronted by an excess of ketones and fatty acids associated with diabetes, obesity, or both, resulting in nonalcoholic steatohepatitis.
Alcohol related problems for Glycolysis – Glucose to pyruvate (requires 2 x NAD+), pyruvate into acetyl coA (requires 2 x NAD+), acetyl coA into Krebs Cycle (requires 6 x NAD+). With alcohol using up NAD+, then pyruvate must be converted to lactate to generate NAD+ for glycolysis. Acetyl coA unable to enter citric acid cycle are transformed to ketones.

Question 27

how does hepatitis emerge from alcohol?

Answer 27

acidosis and ketosis -> inflammatory changes -> hepatitis and cirrhoisis

The oxidative stress caused by CYP2E1 induction and mitochondrial injury results in lipid peroxidation and membrane damage. In addition, the acetaldehyde produced by the oxidation of ethanol has toxic effects, decreasing the activity of key enzymes, and markedly reducing oxygen use in mitochondria damaged by long-term ethanol consumption. The impaired oxidation capacity of the mitochondria may, in turn, interfere with the oxidation of acetaldehyde leading to a vicious circle of progressive acetaldehyde accumulation and greater mitochondrial injury. Moreover, acetaldehyde promotes cell death by depleting the concentration of reduced glutathione (GSH), inducing lipid peroxidation, and increasing the toxic effect of free radicals. Oxidative stress promotes inflammation, which is aggravated by an increase of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) in the Kupffer cells. Kupffer cells are a major source of cytokines.
Acetaldehyde, the first metabolite of ethanol, can upregulate transcription of collagen I directly as well as indirectly by upregulating the synthesis of transforming growth factor-beta 1 (TGF-beta1).

Question 28

cirrhosis and alcohol

Answer 28

Fibroblasts (connective tissue cells) – Supportive framework

Hepatocyte regeneration- decreases
Fibroblasts - increases
Active liver tissue - decreases

Question 29

beneficial effects of alcohol

Answer 29

decrease Mortality from coronary artery disease (Men 2-4 units/day);

increase HDLs
increase tPA levels/ platelet aggregation

Question 30

how does alcohol affect the GIT

Answer 30

the acetaldehyde produced leads to damage to gastric mucosa- which is carcinogenic

Question 31

chronic effects on the endocrine system with alcohol

Answer 31

increase ACTH

decrease testosterone secretion

Question 32

how does hangover occur

Answer 32

because symptoms peak as blood alcohol conc tends to 0

Question 33

signs of hangover

Answer 33

Nausea Irritant  Vagus  Vomiting center

Headache Vasodilation

Fatigue 1. Sleep deprivation, 2. ‘Rebound’

Restlessness and muscle tremors ‘Rebound’

Polyuria and polydipsia ↓ ADH secretion

Question 34

hangover cure

Answer 34

Sleep
Water drinking – does it help clear toxins (e.g. acetaldehyde?)
Kidney Int 67 : 613 –621, 2005 – 15min water load is largely excreted
Water mixed with an easily absorbed sugar is largely excreted