Basic Principles of Pharmacology

Core Concepts:

Pharmacodynamics:

1. Most drugs act by binding reversibly to receptors, which can be a variety of targets including enzymes, ion channels, G-protein coupled transmembrane proteins & DNA response elements.
2. Receptors have two fundamental characteristics: a) the ability to interact with a chemical ligand (drug); and b) to transduce the binding event into a biological signal.
3. Drugs can be divided into two broad categories - agonists and antagonists.
4. Agonists have the properties of affinity and efficacy.
5. The potency of different agonists can be compared using their EC50 values.
6. Classical antagonists have affinity for receptors, but little or no efficacy (ability to stimulate a response).
7. Antagonists can be divided into two subgroups, competitive and non-competitive.
8. Competitive antagonists compete for binding with the same site occupied by an agonist.
9. The antagonism produced by a competitive antagonist can be surmounted (overcome) by increasing the concentration of the agonist. The presence of a competitive antagonist produces a rightwards shift in the concentration-response relationship for the agonist.
10. Noncompetitive antagonists act by covalent binding to the agonist receptor site, or by binding to a secondary site that induces a conformational change in the agnonist receptor site that prevents the agonist from binding. The effects of a noncompetitive antagonist cannot be overcome by increasing the concentration of the agonist. The presence of a noncompetitive antagonist produces an apparent reduction in agonist efficacy.

Pharmacokinetics:

1. Drugs taken orally can undergo "pre-systemic clearance" in the GI tract and liver, resulting in a bioavailability of less than 100% (in some cases this can make the oral route of drug administration ineffective or undesirable).
2. Most drugs undergo elimination clearance by a first order process.
3. Clearance is a primary pharmacokinetic parameter defined as the volume of blood cleared free from drug per unit time.
4. Drugs distribute into different body compartments into a volume referred to as the "apparent volume of distribution".
5. Drugs undergoing first order elimination have a half-life that is determined by the drugs volume of distribution and elimination clearance.
6. When the clearance mechanism (metabolism or excretion) becomes saturated, drug elimination kinetics can become dose-dependent, and at high doses follow zero-order elimination kinetics.
7. Hepatic clearance is dependent upon 3 primary parameters - blood flow, extent of plasma protein binding, and the intrinsic hepatic clearance.
8. Renal clearance of charged drugs can be affected by changes in urine pH.
9. Pathophysiological events can alter a drug's clearance, volume of distribution, and/or half life of elimination.

Drug Metabolism:

1. Drug metabolism contributes to the maintenance of homeostasis.
2. Hepatic metabolism of drugs can be divided into two broad categories - phase I and Phase II.
3. Phase 1 metabolism of active drugs results in changes in drug structure which typically makes the product more water soluble and less pharmacologically active.
4. Phase 1 metabolism of prodrugs can convert them to biologically-active metabolites.
5. Phase 2 metabolism results in the covalent linkage between a parent compound and a another water soluble group that facilitates excretion in the urine.
6. Cytochrome P450 isozymes are responsible for metabolizing approximately half of all therapeutic drugs.
7. Cytochrome P450 isozymes can undergo both induction and inhibition due to the presence of a second drug.

Concept Maps:

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Sample Case-based Questions:
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