Pharmacology
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Pharmacology . Pharmacokinetics Absorption Distribution Biotransformation (metabolism) Excretion Pharmacodynamics Receptor binding Signal transduction Physiologic effect. 59-291 Section 1, Lecture 3. Drug distribution.

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Pharmacology

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Pharmacology

  • Pharmacokinetics

    • Absorption

    • Distribution

    • Biotransformation (metabolism)

    • Excretion

  • Pharmacodynamics

    • Receptor binding

    • Signal transduction

    • Physiologic effect


59-291 Section 1, Lecture 3

Drug distribution

The transport of a drug in the body by the bloodstream to its site of action

  • Protein-binding

  • Water soluble vs. fat soluble

  • Blood-brain barrier

  • Areas of rapid distribution: heart, liver, kidneys, brain

  • Areas of slow distribution: muscle, skin, fat


-most drugs not uniformly distributed throughout the total body water

-can be trapped in interstitial fluid or in plasma

- if sufficiently lipophilic (hydrophobic) can get into cells

Circulation

cells

Interstitial fluid


-maybe concentrated by ion trapping

Consider a drug with a pKa= 2

pH =7.4

pH =2

HA

H+ + A-

-actively transported into liver cells and biotrnasformed

-intestines drugs (anticancer) are pumped from blood to lumen and excreted by the body’s natural detoxifying mechanisms


Volume of Distribution

Vd the volume of fluid in which drug would need to be dissolved in order to have the same concentration in that volume as it does in plasma

V (L)

PLASMA 4

INTERSTITIAL FLUID 10

INTERCELLULAT FLUID 28

Vd provides an indication of physiological distribution of a drug


Calculation of the Vd


If Vd = plasma volume or extracellular (interstitial) volume drug remains outside of cells (Plasma or interstitial fluid)

If Vd = total body water drug is evenly distributed (ie ethanol)

500mg/ 11.9 mg/L= 42 L

If Vd = >> total body water indicates drugs are concentrated in cells by ion trapping

(500mg /2mg/L= 250L)

Many weak bases have a large Vddue to intracellular ion trapping in the cells.

Intracellular pH is less than Plasma pH >> weak bases are more in ionized from inside the cells


Factors Affecting Distribution

  • Organ blood flow

    • Brain, heart, liver, kidney > skeletal muscle > skin, adipose tissue

  • Plasma protein binding

    • Albumin; Drug binding to albumin ranges from 10% to 99% of plasma concentration

    • Alpha1 acid glycoprotein

    • Corticosteroid binding globulin

    • Alb-DrugFree drugInterstitial fluid, cells

    • Albumin (plasma protein) binding is saturable. What does this mean??

  • Molecular size

    • High MW drugs stay only in plasma; Heparin

  • Lipid solubility

    • Blood Brain Barrier restricts the penetration of polar and ionized molecules into brain neurons


EXERCISE: A patient suffering from hyperalbumineuria requires 5 times the normal dose of an analgesic. Why?

What kind of a Vd would you expect this patient to have for this analgesic?


Drug Biotransformation(Drug metabolism)

  • Enzyme-catalyzed conversion of drugs to their inactive metabolites, more soluble forms, or a more potent metabolite

  • Main purpose: To detoxify and inactive drugs and other foreign substances

  • Liver (main site), Kidneys, lungs, plasma, intestinal mucosa

  • Metabolites are usually more water soluble and excreted by kidneys

  • Prodrugs are biotransfomed to active drugs

    • Prodrug is absorbed better than biotransformed

  • First-pass biotransformation


First-pass effect Inactivates many drugs

Alternatives:

Rectal or

sublingual


Phases of Drug transformation

Phase I- create a chemical functional group on the drug that can be recognized by Phase-II enzymes. Product of phase I enzymes still have biological activity

Phase II- no biological activity


Phase I Biotransformation

  • Oxidative reactions

    • Catalyzed by enzymes of microsomal fraction (ER) of liver

      • Microsomal cytochrome P450 monooxygenase

  • Hydrolytic reactions

  • Reductive reactions


Phase I reactions


Microsomal cytochrome P450 monooxygenase system is a family of enzymes that biotransforms many drugs

Monooxygenase reaction


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