Basic Principles

Pharmacokinetics: The actions of the body on the drug, including absorption, distribution, metabolism, and excretion. Elimination of a drug may be achieved by metabolism or by excretion. Biodisposition is the same as pharmacokinetics. Relationship of drug concentration and time.

Drugs bind to receptors with a variety of chemical bonds (covalent, electrostatic, hydrogen)

Movement of drug in body:

    • Permeation

      • Aqueous

      • Lipid diffusion

      • Transport by special carriers

      • Endocytosis, pinocytosis

    • Bioavailability: The amount of absorbed drug divided by the amount administered.

    • Routes of administration

      • PO: subjected to first-pass effect, in which a significant amount of the drug is metabolized in the gut wall and liver before it reaches the systemic circulation. Bioavailability is low.

      • IV: 100% bioavailability

      • IM: 100% bioavailability

      • SC: 100% bioavailability

      • Buccal and sublingual: 100% bioavailability

      • PR

      • IH

      • Top:

      • TD

    • First-order elimination: It implies that the rate of elimination of the drug is proportionate to the concentration, i.e., the higher the concentration, the greatest the amount of drug eliminated per unit time. The drug's conc in plasma decreases exponentially with time. Drugs with first-order elimination have a characteristic half-life elimination that is constant regardless the amount of drug in the body. The conc. of such a drug decreases by 50% for every half-life. Most drugs follow first-order eliminations or kinetics.

    • Zero-order elimination or kinetics: The rate of elimination is constant regardless of concentration. The drugs conc. in plasma decreases in a linear fashion over time. This is typical of ethanol (over most of its plasma concentration range), phenytoin, and aspirin (in very high doses or toxic concentrations)

Urine pH and drug elimination:

    • Ionized species get trapped, as they are less water soluble and more lipid soluble.

    • Weak acids: phenobarbital, methotrexate, TCAs, ASA. Trapped in basic environments. Treat overdose with bicarbonate.

      • RCOOH (protonated weak acid - uncharged and more lipid soluble)

    • Weak bases: amphetamines. Trapped in acidic environments. Treat overdose with ammonium chloride.

      • RNH3+

    • Ionized or charged drugs are water soluble. Non-ionized or uncharged drugs are lipid soluble and less water soluble.

    • Many drugs are weak bases or weak acids. The pH of the medium determines the fraction of the molecules charged (ionized) versus uncharged (non-ionized). If the pKa of the drug and the pH of the medium are known, the fraction of the molecules in ionized state can be predicted by the Henderson-Hasselbach equation. The equation is clinically important when it is necessary to accelerate the excretion of the drug by the kidney, as in cases of drug overdose. Most drugs are filtered by the glomerulus, of the kidney. Lipid soluble drugs are reabsorbed quickly from the tubular urine. When a patient takes an overdose of a weak acid drug, like TCAs; its excretion is accelerated by alkalinizing the urine, by given bicarbonate. This is because the weak acid dissociates to its charged, polar form in alkaline solution. Essentially, the weak acid which is protonated gives off it proton to the basic pH environment created by HCO3. The unprotonated form of weak acid, thus formed charged and is ionized form. It is therefore, less lipid soluble and more water soluble. Conversely, excretion of a weak base may be accelerated by acidifying urine, eg. by administering ammonium chloride.

Synergy is when the combined effect is greater than the sum of the individual effects

Antagonism is when the activity of the combination is less than sum of their independent activities.

Pharmacodynamics: The actions of a drug on the body, including receptor interactions, dose-response, and mechanisms of therapeutic and toxic action. Relationship of drug concentration and effect.

Drug interactions must be considered in the DDx of any unusual response occurring during drug therapy.

A meticulous drug history should include examination of the patient's medications, OTC, herbal supplement, eye drops, and call to pharmacy to identify prescriptions.

    • PPI, H2 rcp antagonists decrease in absorption of weak bases such as ketonconazole.

    • Quinidine reduces analgesic efficacy of codeine.

    • TCA blunt anti-HTN effect of clonidine.

    • Reduced CNS penetration of multiple HIV protease inhibitors appears attributable to P-glycoprotein mediated exclusion of the drug from CNS.

      • P-glycoprotein inhibitors increase risk of digoxin toxicity.

    • Phenytoin blunts anti-HTN action of losartan.

    • Cyclosporine toxicity or rhabdomyolysis with statins.

    • Ritonavir decreases clearance of other anti-HIV agents and increases their efficacy.

    • Cyclosporine, some statins should avoid grapefruit juice.

    • 6-Mercaptopurine, the active metabolite of azathioprine + allopurinol > severe bone marrow suppression.

    • Salicylates + methotrexate > methotrexate toxicity.

    • Probenecid + PCN leads to reduced elimination of PCN.

    • Cimetidine reduces clearance of dofetilide and of procainamide.

    • Sildenafil inhibits PDE type 5 isoform that inactivates cyclic GMP in the vasculature. NTG and related nitrates produce vasodilation by enhancing cyclic GMP. Thus, coadministration of these nitrates with sildenafil can cause profound hypotension, which can be catastrophic in pts with CAD.