Exam 1 ( Pharmacokinetic -pharmacodynamics) exam1

Pharmacokinetics (PK)

The branch of pharmacology concerned with the movement of drugs within the body

•In layman's terms: "What the body does to the drug"

Four components of PK (ADME):

•Absorption

•Distribution

•Metabolism

•Elimination (or Excretion)

Absorption

•Dependent on the environment where the drug is absorbed, chemical characteristics of the drug, and the route of administration

Absorption Environment

pH, blood flow to the absorption site, surface area available for absorption, contact time with the absorption surface

Absorption Chemical Characteristics

molecule size, solubility, weak acid or weak base,

Route of Administration

inHALTION

Intranasal

introcular

intrthecal = injected into spine

intravenous

otic= to the ear

rectal

subcutaneous

sublingual

transdermal

Bioavailability

•The rate and extent to which an administered drug reaches the systemic circulation.

Absorption Interactions (Chelation)

•results in the formation of a complex of a drug to a di- or trivalent cation (Ca, Al, Fe, Mg, Zn)

-Example: Fluoroquinolones/tetracyclines with minerals, bisphosphonates

Absorption Interactions (Adsorption)

•adhesion of molecules to the surface of another substance, as opposed to absorption, in which the molecules actually enter the absorbing medium.

-Example of a beneficial interaction: Activated charcoal is used to adsorb many poisons and drug overdoses following oral ingestion.

Absorption Interactions(Altered GI pH)

•the acidity of the environment frequently determines if the drug is in it's protonated or unprotonated form

-Example: Antacids, H2 blockers, and proton pump inhibitors increase gastric pH.

Distribution of drug

•The process by which a drug leaves the bloodstream and enters extracellular fluid and tissues

•Dependent upon cardiac output and local blood flow, capillary permeability, protein binding, and lipophilicity of the drug

Volume of Distribution

•The fluid volume that is required to contain the drug in the body at the same concentration measured in the plasma.

• How much drug is required to fill up the tank?

•

Distribution Interactions

•Protein binding

•Bound drug vs unbound (free) drug

•Most are usually self-correcting and not clinically significant.

•Clinically Significant Example:

-Phenytoin and warfarin

Metabolism

•Biotransformation of a drug to facilitate elimination from the body

•Largely the responsibility of the liver

•Generally necessary for lipophilic drugs

Metabolism of drug is assure largely by ?

Liver

Metabolism drug is generally neccesary for

•lipophilic drugs

Metabolism Interactions

•CYP - one of the most common targets for DI

•Inducers

Inhibitors

•Enzyme inhibition

•Competitive & non-competitive inhibition

•Inducers role

•Increase the synthesis or enhance the action of CYP

•Increased metabolism:

•$plama conc. of the parent drug

•Examples:

•phenobarbital, carbamazepine, phenytoin, and rifampin

• slow onset: 2-4 days to 1-3 weeks

Inhibitors

•Decrease the synthesis or diminish the action of CYP

•Decreased metabolism:

•# plama conc. of parent drug

•Enzyme inhibition

Rapid Onset

CYP

Cytochrom p450

Cytochrom P450 Interaction( ISOZYME : CYP1A2) = substrate

Gingko

warfarin

clopipramine

diazepam

Cytochrom P450 Interaction( ISOZYME : CYP1A2) = Inducers

Charbroiled

cigarette smoke

Cytochrom P450 Interaction( ISOZYME : CYP1A2) = inhibitors

Grapefruit

Cytochrom P450 Interaction( ISOZYME : CYP2C9) = substrate

Rosiglitazone

warafarin

Cytochrom P450 Interaction( ISOZYME : CYP2C9) = Inhibitors

fluvastatin

Elimination

•Irreversible removal of drug from the body

•Largely the responsibility of the kidneys

Elimination step

1- free drug enter glomerular filtrate

2-Active secretion of drugs

3- Passive reabsorption of lipid solublr -un-ionized .

Elimination Interactions step

1-•Reduced renal excretion of one drug by another

2-•Active secretion in the renal tubule

3-•Alteration of urinary pH

•Active secretion in the renal tubule

•Carrier-mediated system

•Example:

•Probenecid $ tubular secretion of MTX

•Alteration of urinary pH

•Urinary pH influences the ionization of weak acids and bases and thus affects their reabsorption back into the bloodstream and excretion via the nephron.

Weak acid drug dominantly in nonionized form in acidic urine

More weak acid drug diffuses back into the bloodstream

Weak base drug dominantly in nonionized form in alkaline urine

•More weak base drug diffuses back into the bloodstream

Clearance (CL)

•Measurement of the volume of plasma from which a substance is completely removed per unit of time.

Total body clearance

•is the sum of all clearance from drug-metabolizing and drug-eliminating organs.

Factors Affecting Drug Safety/Efficacy

1-Age

2-Disease

3-Pregnacy and lactation

Factors Affecting Drug = AGE

-Neonates & elderly have decreased capacity to metabolize & excrete drugs due to low levels of biotransformation enzymes

-In elderly, oxidative rxns decline more than conjugation rxns

Factors Affecting Drug Safety/Efficacy = Disease

-Kidney & liver dz $ metabolism & excretion

-Heart failure/intermittent claudication may $ blood flow to liver

Factors Affecting Drug Safety/Efficacy = pregnacy and lactation

-Teratogenic fx are greatest during the 4th to 10th week of gestation

-After 10th week, the major risk is brain/spinal cord

Pharmacodynamics

Definition: A branch of pharmacology concerned with the action of drugs on the body or on microorganisms within or on the body

•In layman's terms: "What the drug does to the body"

Intrinsic Activity

Agonist

antagonist

Agonist

•a substance activates the receptor to produce a biological response

Antagonist

a substance that binds to the receptor and produces NO response

What is the biological response of Agonist?

-Full

-Partial

What is the biological response of antagonist?

-Competitive

-Irreversible

-Allosteric

-Functional

Receptors types

-Ligand-gated channels

-G protein-coupled receptor

-•Membrane-bound Enzymes

•Intracellular Receptors

• Ligand-gated Ion Channels

-Regulate the flow of ions across cell membranes

-Critical regulators in excitable (nerve & muscle) and non-excitable cells

-Once a ligand is bound to an ion channel, response is rapid (a few milliseconds)

-Ex. Nicotinic receptors & GABA receptors

activation of G protein-coupled receptors

•When the GPCRs binds to a signal molecule, the receptor is activated and changes shape, thereby allowing it to bind to an inactive G Protein

•When this occurs, GTP displaces GDP on the α-subunit which activates the G Protein

•Membrane-bound Enzymes

-The ligand binds to the receptor resulting in a conformational change and increased enzyme activity

-Duration of response is minutes to hours

Membrane-bound Enzymes includes

1.Receptor guanylyl cyclases

2.Receptor tyrosine phosphatases

3.Tyrosine kinase-associated receptors

4.Receptor serine/threonine kinases

Intracellular Receptors

-Ligand must diffuse into the cell to interact with the receptor

-Once bound, the activated ligand-receptor complex migrates to the nucleus where it binds to specific DNA sequences resulting in the regulation of gene expression

-Duration of response is hours to days

-These are targets for sex hormones, glucocorticoids, and vitamins A & D

Signal Transduction

1-Down-regulation - diminished effect from

2-•Up-regulation - increased response due to repeated exposure to an antagonist

Additive Interactions

•Produce the same biologic response by:

•binding to the same receptors

•through another mechanism entirely

Example of Additive Interactions

•Ephedrine (an agonist at a1-adrenoceptors) produces effects that resemble the action of norepinephrine ð ð vasoconstriction

•Albuterol (an agonist at b1,2-adrenoceptors) produces effects that resemble the action of epinephrine ð ð increasing heart rate >>>>> Elevated blood pressure

Antagonistic Interactions

Two drugs with opposing actions can interact, thereby reducing the effectiveness of one or both.

Antagonistic Interactions : example

•NSAIDS can cause sodium and fluid retention

•Given with a diuretic, may reduce the effectiveness of diuresis >>>> Edema