504 Pharm: Princ Of Drug Actions Ii

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504 PHARM: PRINC OF DRUG ACTIONS II

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504 PHARM: PRINC OF DRUG ACTIONS II

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Concentration of drug

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Determines ability of a drug to elicit a response.

Hard to calculate, therefore, drugs are delivered by DOSES.

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Dose response curves are used to assess:

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Effectiveness and safety of drugs.

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Dose and Responses axis

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Dose: X axis
Response: Y axis

Dose is plotted on a logarithmic scale.

Response is plotted as a percentage of maximum possible response.

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Graded dose response curve:

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Used when the physiological response of interest changes in magnitude in response to a drug.

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Quantal dose response curve

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Used when all that is needed to know is whether if response is "absent or present."

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Efficacy

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Measure of maximum effect produced by a drug.

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Potency

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Measure of conc or dose of drug required to produce 50% of maximal effect.

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ED50

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Means effective dose for 50% maximum response. (graded dose response)

or

Dose required to produce the desired therapeutic effect in 50% of pts. (Quantal dose response)

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TD50

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Dose required for toxicity in 50% of pts.

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LD50

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Dose required for lethality in 50% of experimental animals.

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Therapeutic Index

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A quantitative measure of drug safety.

Defined by the ratio: TD50/ED50

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The higher the TI, the _____

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Safer the drug

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What is the major drawback of the TI?

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Does not take acct the slopes of the therapeutic effect vs. toxicity curves.

Two drugs may have same TI, but differ in their safety.

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Competitive Antagonist

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Causes parallel rightward shifts in the dose response curve of agonists.

Alter potency of agonists but not their efficacy.

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How do you overcome the effect of competitive antagonist?

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Excess conc of agonist.

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Non-competitive Antagonist

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Interfere with agonist binding to its receptor.

1. dose response curve of full agonist is displaced DOWNWARD. Therefore, maximal effect is reduced.
2. cannot be overcome by an excess conc of a full agonist.

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Weak acids ionize at pH values above or below their pKa?

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Above

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Weak bases....?

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Below

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What is ion trapping?

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When pH gradients are used to distribute a drug between compartments.

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Metabolism of aspirin (acetysalicylic acid pKa 3.4)

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Dissolves in stomach

However, it's mostly in non-ionized form b/c pH of gastric juice is below that of aspirin. This means that if it's in an acidic environment, then the pH is below its pKa, therefore, it will not be ionized. However, once the nonionized form diffuse through the gastric epithelium and into blood where it is more basic, then aspirin becomes ionized.

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GI Epithelium

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Tight junctions means drugs can only be absorbed by lipid diffusion.

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Capillaries of Systemic Vasculature

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Can admit large molecules to cross by aqueous diffusion. Free diffusion of drugs between blood and ECF.

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Blood brain barrier

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Tight junctions and glial cell sheaths around brain capillaries.

Only lipid soluble drugs can pass into brain.

Polar and ionized drugs are excluded from CNS.

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Placenta

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Transfer of drugs via lipid or aqueous diffusion.

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Vd App (Vd)

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Apparent volume of distribution.

Volume that relates the plasma conc. of drug to amount of drug in the body at a given time.

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Eqtn of Vd

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Total amount drug in body/ plasma conc

= mg/mg/L = L

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What is Vd used to determine?

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To determine the dose required to attain a desired plasma concentration.

Dose (mg) = [Vd app (L) x Conc (mg/L)] / F (bioavailability)

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Bioavailability

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Fraction of adm. dose of drug reaching the systemic circulation.

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Drugs binding to macromolecules

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Only the free drug is pharmacologically active and available for metabolism.

Binding tends to reduce Vd app.

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Effects of blood flow

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1. affects conc gradients
2. influence initial tissue distribution, and thus, onset of action.

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Renal excretion =

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Amount filtered + amount secreted - amount reab.

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Renal clearance

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Vol of plasma in which drug is removed per unit time by kidney.

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Glomerular filtration

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Only the free drug (both ionized and non-ionized) is filtered.

Drugs with large Vd have low excretion rate.

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Tubular reabsorption

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Reab of Na and H2O concentrates the drug in the urine.

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Which form of drug gets reabsorbed?

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Lipid soluble
Non-ionized (unmetabolized)

NOTE: ionized form gets secreted.