Basic pronciples of psychopharmacology

Question 1

Absorption

Answer 1

Absorption is the movement of adrugfrom the site of administration to the plasma.

(e.g. ingestion, intravenous, intramuscular, oral)

Passive diffusion or membrane transport

Question 2

Distribution

Answer 2

Depends on the chemistry of the agents

Aminoglycosides are polar molecules, so their distribution is limited primarily to extracellular water and they tend not to enter extravascular spaces.

Polar molecle- unequal distribution of charges e.g. water is polar= not evenly distributed charges so other molecules like that are water-soluble

Diazepam is lipophilic (lipid loving), is able to penetrate more easily across cell membranes and therefore has more extensive intra-cellular uptake.

Volume of distribution also depends on plasma protein binding: When a drug is highly plasma protein bound it typically has a lower volume of distribution

Question 3

Metabolism

Answer 3

Breaking down the drug into metabolites so that it can eventually be eliminated from the body.

Drug metabolism is the biochemical modification of one chemical form of the drug to another, occurring usually through specialised enzymatic systems.

Can be affected by age, weight, size of the molecule, food

Question 4

Elimination

Question 5

Steps of delivering drug to the brain which are pharmacokinetics (6)

Answer 5

1. Absorption (e.g. ingestion, intravenous, intramuscular) Passive diffusion or membrane transport
2. Bound to plasma proteins ⇆ free in blood stream
3. Distribution - within systemic circulation and tissues
4. Metabolism (in liver, kidney or lungs)
5. Elimination (renal or biliary)
6. Free drug needs to cross the blood brain barrier

Question 6

Steps of delivering drug to the brain which are pharmacodynamics (1)

Answer 6

Drug binds to target receptors ➝ produce effect

Question 7

How can drugs cross blood-brain barrier

Answer 7

The molecule either needs to be lipid soluble or use membrane transporter (like a protain e.g. glucose)

1. Passive diffusion through the lipid bilayer (for lipid-soluble compounds)
2. Carrier-mediated transport
3. Diffusion through aqueous pores (for water soluble compounds)

Question 8

What pharmacokinetic factors influence effect of the drug?

Answer 8

Concordance
Dosing and medication errors
Absorption
Tissue and body fluid, mass and volume
Drug interactions
Elimination
Drug metabolism

Question 9

What pharmacodynamic factors influence effect of the drug?

Answer 9

Genetics
Receptor function
Drug interactions
Tolerance to effects (and side effects)

Question 10

Blood plasma

Answer 10

Yellow-coloured liquid componene of blood (other parts of blood are red blood cells and white blood cells)

Could be used as a proxy measure of how much the drug is in the brain

Question 11

Drug bound to plasma protein

Answer 11

Once in the systme circulation some of the drug may bind to the protains in the plasma=

only the unbound drug can pass through cell membranes and casue theraputic effect and get to the brain == unbound drug concentration is more closely related to activity of drug than is total concentration

Question 12

Free drug

Answer 12

If drug is lipid soluable then it can go further and pass the membrane

Ratio is an equilibrium depending on a drug (lipid soluble drugs will enter the membrain via equilibrium difusion (?)) [almost all anitipsychotics are lipid soluble]

Question 13

What is blood-brain barrier?

Answer 13

It is the endothelial cells, lining of blood vessel, which are everything outside of blood vessle in the brain so all drugs need to go out the blood streem and through Endothelial cell (barrier) to get to the brain

Question 14

First pass metabolism

Answer 14

Oral drugs go through the portal vein to the liver and are metabolised there before they are distributed to the general circulation–> it metabolised before even reaching the brain

This means that the dose will be different depending on mode of administration (e.g. oral vs IV)

Question 15

What does cytochrome P450 enzyme do?

Answer 15

Induces small changes to the drug molecule such as oxidation or reduction, producing metabolites. These are strucutrally similar to the ‘parent’ compound = still therapeutically active

Some antidepressants can inhibit this enzyme = the antipsychotics will not have really good results

Various drugs can act as inducers of CYP enzymes➝ increased activity and therefore increased metabolism and lower concentration of drug

Other drugs can act as inhibitors of CYP enzymes➝ reduced activity and therefore decreased metabolism and increased concentration of drug

Question 16

Genetic variations in CYP2D6

Answer 16

Genetic variation may result in CYP2D6 poor metabolisers, normal metabolisers or ultra-rapid metabolisers

Poor metabolisers – may have significant side effects to antidepressants at standard doses. They may respond to lower doses however.

Ultra-rapid metabolisers – drugs may be ineffective at standard doses. Genotyping usually is applicable to studies not clinical practise

Question 17

Caution

Answer 17

(1) Need to know what drugs people are taking to account for potential enzyme inhibition

(2) Smoking behvaiour- CYP1AD metabolises clozapine. Tobacco smoke induces CYP1AD which may partly explain why smokers need higher doses of clozapine BUT then if they quit the dose needs to be adjusted

(3) If someone has imparied metabolism we can even double the average steady state concentration of drug = side effects

Question 18

Lithium

Answer 18

The mechanism of action of lithium is not known. It is rapidly absorbed, has a small volume of distribution, and is excreted in the urine unchanged (there is no metabolism of lithium).

Question 19

Half-life

Answer 19

Is the time it takes for the plasma concentration to halve

Question 20

Effects of old age

Answer 20

• Reduced filtration rate of kidneys = less elimination of drugs
• Reduces volume = blood flow = less CYP2D6 activity = longer half-lifes of drugs
• Body composition changes: Increased body fat and decreased body water (may lead to changes in distribution of drug)

Question 21

Effects of pregnancy

Answer 21

Absorption: Nausea and vomiting during early pregnancy may lead to reduced absorption of drug

Distribution: Plasma volume can increase by 50% (reducing drug concentration) but there is also reduced protein binding (increasing unbound free form of the drug) which may offset this

Metabolism and elimination: Cytochrome P450 system induced (increased metabolism)
Glomerular filtration rate can increase by 50% (increased elimination)