Drugs and Biology Introduction PDF

Drugs and Biology: An introduction Stuart Cruickshank Pharmacodynamics v’s Pharmacokinetics Pharmacodynamics is the effect of the drug on the body. Pharmacokinetics describes the time course of the movement of a drug into, around and out of the body.  Why is the study of pharmacokinet...

Drugs and Biology: An introduction Stuart Cruickshank Pharmacodynamics v’s Pharmacokinetics Pharmacodynamics is the effect of the drug on the body. Pharmacokinetics describes the time course of the movement of a drug into, around and out of the body.  Why is the study of pharmacokinetics important? If a drug is going to have an effect in the body it needs to be present: – In the right place – At the right concentration – For the right amount of time What do you think the effect of 50mg of diazepam will have on each of the following ? Knowledge of pharmacokinetic data about a drug tells you: What dose to give How often to give it How to change the dose in certain medical conditions How some drug interactions occur  PHARMACOKINETICS The study of the time course of the ABSORPTION DISTRIBUTION METABOLISM EXCRETION (elimination)  How does this sit with what I’m studying? Remember that lots of little things contribute to a bigger picture. Harder to remember the little things. Much easier to remember the big picture! Use your: experiences/knowledge/understanding to provide that bigger picture!  Absorption The movement of a drug from the site of administration to the bloodstream Three mechanisms by which drugs may cross membranes: Passive diffusion Facilitated diffusion Active transport (energy required, selectivity, against gradient) Influenced by: water and lipid solubility concentration gradients  P-glycoproteins P-gp in the apical cell Gut contents membrane (facing the gut contents). Substances are absorbed, Apical but then actively surface pumped back into the gut contents (Efflux). Intestinal ATP dependent. epithelial cell Basolateral surface  Location of P-glycoproteins A defensive mechanism against foreign substances Intestinal epithelium: into lumen of colon, jejunum … Liver: into bile duct Kidney: into collecting ducts Capillary endothelium (BBB): out of the CNS Some types of cancer cells: resistance to therapy  Induction and inhibition of P-gp Induction Rifampicin increase the amount of P-gp in the intestinal epithelium Reduces absorption of other substances Inhibition Verapamil will saturate the P-gp. Other substances then absorbed more easily Has been suggested as a means to increase absorption of problem molecules  BIOAVAILABILITY The percentage (or fraction) of the administered dose which reaches the systemic circulation  BIOAVAILABILITY Factors affecting: physico-chemical properties of drug; properties of dosage form; physiological factors; the “first pass effect”.  Avoiding the ‘first-pass effect’ Mouth General circulation Stomach Portal circulation Small intestine Large Liver intestine General Rectum circulation  DRUG DISTRIBUTION Reversible transfer from the systemic circulation to other body fluids & tissues Generally involves diffusion from region of high drug concentration to one of low concentration Rate & extent affected by drug & patient characteristics  DRUG DISTRIBUTION Drug factors affecting: dissociation constant (pka); oil/water partition coefficient; inert protein & tissue binding. Patient factors affecting: oedema; dehydration; obesity; pregnancy  Mammary Concentration in milk reflects free concentration in blood (apart from ion trapping) Milk is slightly acid (pH 7.0) compared to blood (pH 7.4)  Erythromycin in milk Blood (pH 7.4) Milk (pH 7.0) Non-ionised Non-ionised Ionised Ionised Lipid Erythromycin concentrations approx 8 times higher in milk than blood  Drugs in milk Diazepam: Accumulation and sedation Heroin: Prolonged neonatal dependence Methadone: Possible withdrawal syndrome if breast feeding stopped suddenly Tetracycline: Permanent staining of infant teeth  DRUG METABOLISM Biotransformation of drug molecules catalysed by enzymes. Main method of terminating action of drug in the body. Generally transformed into more hydrophilic compounds (metabolites) Metabolites may be active or inactive Metabolites may be more toxic than drug