Elizabeth Davis; Week 1 MED1022; Pharmacology
Efficacy without toxicity is the goal of drug therapy, therapeutic range is between minimum effective concentration and minimum toxic concentration. Pharmacokinetics helps plan amounts and timing of drug doses, enables decisions regarding route of administration, starting dose and frequency of drug administration. It allows avoidance of drug interactions, prevention of dose-dependant adverse effects and treatment and management of drug overdose. It enables attainment of a plasma concentration of drug in the therapeutic range.
The available amount transferring from the site of administration to the site of action is the drug bioavailability. Bioavailability is the proportion of drug that reaches the systemic circulation as intact drug. Movement of drug across membranes is altered by drug factors (lipid solubility, MW, shape), physiological factors such as thickness of membrane, surface area of membrane, pH of compartment, rate of removal of drug (dependent on blood flow, plasma protein binding, binding to tissues). Weak acids and bases can exist in two forms, bases are ionised in acidic conditions. Ionised forms have good lipid solubility.
If pH = pKa the drug is 50% ionised and 50% unionised. For a weak acid such as aspirin, ionisation is greatest at highest pH. Bioequivalence is where 2 formulations of the same drug attain similar concentrations in blood and tissues at the same time, meaning they have no clinically important differences in therapeutic or adverse effects. This is important for generic formulations.
Factors affecting distribution of drugs are penetration into extracellular and intracellular fluid, tissues, organs, fat, brain, binding to extravascular sites including tissues, binding to plasma proteins. The main plasma protein bound to is albumin, which decreases the amount of free drug in plasma. Drug molecules bound to plasma proteins are generally inactive, cannot enter cells or get to the brain and are not filtered by the glomerulus. Different drugs can displace each other from binding sites.
Volume of distribution is volume in which a drug appears to be distributed with a concentration equal to that of plasma, Vd = dose/[plasma]. <5L it is retained within vascular compartment (plasma volume 3.5L in 70kg person), <15L restricted to extracellular fluid (14L total ECF), >15L distributed throughout total body water (40L is TBW). Vd may affect dosing and elimination (t1/2).
Elimination can be by redistribution via circulation, can also be excreted from the body (urine, bile, faeces) or metabolised. Drug clearance is the amount of plasma cleared per unit time, indication of how well a drug is irreversibly removed from circulation. Rate of elimination = CL x [plasma] and can help maintain the dose-rate required to maintain [plasma]. Drugs can be eliminated unchanged through the kidneys; fraction excreted unchanged (fu) defines renal elimination. Metabolism in the liver changes it to an inactive product (metabolic elimination = 1 - fu). CL (total) = CL (renal) + CL (liver) + CL (other). Renal excretion is through glomerular filtration (drugs bound to plasma protein cannot cross), active tubular secretion can occur (penicillin, morphine), and passive reabsorption across tubular epithelium is also possible (polar molecules are trapped in tubules). Kidneys cannot readily excrete lipid soluble drugs. Molecules cannot cross barriers in an ionised state, ion trapping is where electrolytes will accumulate in the compartment where they are most highly ionised.