Basic pronciples of psychopharmacology Flashcards
Absorption
Absorption is the movement of adrugfrom the site of administration to the plasma.
(e.g. ingestion, intravenous, intramuscular, oral)
Passive diffusion or membrane transport
Distribution
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
Metabolism
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
Elimination
Steps of delivering drug to the brain which are pharmacokinetics (6)
- Absorption (e.g. ingestion, intravenous, intramuscular) Passive diffusion or membrane transport
- Bound to plasma proteins ⇆ free in blood stream
- Distribution - within systemic circulation and tissues
- Metabolism (in liver, kidney or lungs)
- Elimination (renal or biliary)
- Free drug needs to cross the blood brain barrier
Steps of delivering drug to the brain which are pharmacodynamics (1)
Drug binds to target receptors ➝ produce effect
How can drugs cross blood-brain barrier
The molecule either needs to be lipid soluble or use membrane transporter (like a protain e.g. glucose)
- Passive diffusion through the lipid bilayer (for lipid-soluble compounds)
- Carrier-mediated transport
- Diffusion through aqueous pores (for water soluble compounds)
What pharmacokinetic factors influence effect of the drug?
Concordance
Dosing and medication errors
Absorption
Tissue and body fluid, mass and volume
Drug interactions
Elimination
Drug metabolism
What pharmacodynamic factors influence effect of the drug?
Genetics
Receptor function
Drug interactions
Tolerance to effects (and side effects)
Blood plasma
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
Drug bound to plasma protein
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
Free drug
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]
What is blood-brain barrier?
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
First pass metabolism
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)
What does cytochrome P450 enzyme do?
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
Genetic variations in CYP2D6
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
Caution
(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
Lithium
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).
Half-life
Is the time it takes for the plasma concentration to halve
Effects of old age
- 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)
Effects of pregnancy
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)
