GENERAL GENERAL PRINCIPLESPRINCIPLESGENERAL GENERAL

PRINCIPLESPRINCIPLESZenaida N. Maglaya, MD; FPSECPZenaida N. Maglaya, MD; FPSECP

Department of PharmacologyDepartment of Pharmacology

GENERAL PRINCIPLES• PHARMACOLOGY• DRUG• MEDICAL PHARMACOLOGY• PHARMACY• PHARMACOGNOSY• PHARMACOKINETICS• PHARMACODYNAMICS

PHARMACOKINETICS• ABSORPTION

• DISTRIBUTION

• BIOTRANSFORMATION/ METABOLISM

• EXCRETION

FACTORS AFFECTING ABSORPTION

• I. DRUG• II. TYPES OF TRANSPORT

1. SIMPLE DIFFUSION 2. FILTRATION3. ACTIVE TRANSPORT4. FACILITATED DIFFUSION5. PINOCYTOSIS

FACTORS AFFECTING ABSORPTION

• FICKS LAW OF DIFFUSION: Permeability CoefficientRATE = (C1-C2) ------------------------------ X AREA THICKNESS

III. DEGREE OF IONIZATION Protonated form Log ----------------------------- - = pKa – pH Unprotonated form

DEGREE OF IONIZATION

RNH3 -------------------> RNH2 + H • Protonated Unprotonated Proton• Weak Base Weak baseCharged more Uncharged more Water soluble lipid soluble

RCOOH -------------- RCOO - + H Protonated Unprotonated

Proton Weak Acid Weak AcidUncharged more Charged more Lipid soluble warer soluble

FORMULA• I 10 pH - pKa • Weak Acid = ----- = -----------• U 1

I 10 pKa - pH • Weak Base = ----- = -----------• U 1

EXAMPLE OF WEAK ACID WITH PKA OF 8

I 10 pH - pKa

• Weak acid = ------ = -------------- U 1 Stomach pH = 2 Plasma pH = 7.4 10 2 – 8 10 7.4 - 8

= ------------------ = -------------------- 1 1

10 - 6 10 - 0.6 = ---------------------- = -------------------- 1 1 0.000001 0.25 = --------------- = ----------------- 1 1

TOTAL DRUG IN STOMACH TOTAL DRUG IN PLASMA

1.000001 1.25

EXAMPLE OF A WEAK BASE WITH PKA OF 8

I 10 pKa - pH

• Weak Base = ----- = -------------- U 1 Stomach pH = 2 plasma pH = 7.4 10 8-2 10 8 - 7.4

= ------------------ = -------------------- 1 1

10 6 10 0.6 = ---------------------- = -------------------- 1 1 1000000 4 = --------------- = ----------------- 1 1

TOTAL DRUG IN STOMACH TOTAL DRUG IN PLASMA

1,000,001 5

ROUTES OF ADMINISTRATION• I. ENTERAL

1. ORAL2, SUBLINGUAL & BUCCAL3. RECTAL

II. PARENTERALA. INJECTIONS 1. INTRAVENOUS` 2. INTRAMUSCULAR

3. SUBCUTANEOUSB. INHALATIONC. TOPICALD. TRANSDERMAL

DISTRIBUTION OF DRUGS

• SIZE OF THE ORGAN• BLOOD FLOW• LIPID SOLUBILITY• TISSUE BINDING

• Vd = VOLUME OF DISTRIBUTION

METABOLISM OR BIOTRANSFORMATION OF

DRUGS• NEED FOR DRUG METABOLISM > TERMINATION OF DRUG

> ACTIVATION OF DRUGS. SITES OF DRUG METABOLISM. FACTORS AFFECTING METABOLISM > GENETIC FACTORS

> ENVIRONMENTAL FACTORS. TYPES OF METABOLIC REACTIONS > PHASE I REACTION > PHASE II REACTION

PHASE I METABOLISM• OXIDATIONA. OXIDATION P450 DEP

HYDROXYLATIONS:barbiturates, phenytoin, amphetamines

• N - ALKYLATIONS: morphine,caffeine, theophyllline• O --DEALKYLATION: codeine• N -OXIDATION: acetaminophen, nicotine• S-OXIDATION: cimetidine, chlorpromazineB. OXIDATION P450 INDEPENDENT AMINE OXIDATION:

epinephrine• DEHYDROGENATION: ethanol, chloral hydrate• REDUCTION: chloramphenicol, naloxone• HYDROLYSISA. Esters: procaine aspirinB. Amides: lidocaine, indomethacin

PHASE II METABOLISM• GLUCORONIDATION: morphine. Diazepam,

digitoxin• ACETYLATION: sulfonamides, isoniazid• GLUTATHIONE CONJUGATION: ethacrunic acid• GLYCINE CONJUGATION: salicylic acid,

nicotinic acid• SULFATE CONJUGATION: acetaminophen,

methyldopa• METHYLATION: dopamine. epinephrine

DRUG METABOLISM•

INDUCER DRUG INDUCEDPHENOBARBITAL Chloramphenicol,

Digoxin, Phenytoin Coumarin, Quinine, Testosterone

RIFAMPIN Coumarin, Digitoxin, Oral Contraceptives

Metoprolol, QuininePHENYTOIN Cortisol, Dexamethazone Digitoxin, TheophyllineGRISEOFULVIN Warfarin

DRUG METABOLISM• INHIBITORS• CIMETIDINE Diazepam, Warfarin• Chlordiazepoxide• ISONIAZID Antipyrine,

Dicoumarol, Probenecid

• PHENYLBUTAZONE Phenytoin, Tolbutamide

EXCRETION

• GLOMERULAR FILTRATION• TUBULAR EXCRETION• TUBULAR REABSORPTION

• ELIMINATIION• ZERO ORDER KINETICS• FIRST ORDER KINETICS

QUANTITATIVE PHARMACOKINETICS

VOLUME OF DISTRIBUTION amount of drug in the body Vd = ------------------------------------- plasma concentration

HALF LIFE• 0.693 x Vd 0.693 t ½ = ---------------- or- --------------

• Cl k

CLEARANCE 0.693 x Vd• Cl = ------------------------------ or Vd X k t 1/2

DOSAGE REGIMEN LOADING DOSE = Vd X desired plasma concentration MAINTENANCE DOSE = Cl X desired plasma concn

STEADY STATE PLASMA CONCENTRATION, OR PLATEAU 1ST HALF LIFE= 50% 4th half life = 94%

2ND HALF LIFE = 75 % 5th half life = 97% 3rd half life = 88% 6th half life = 99%

DRUG EVALUATIONI. PRECLINICAL PHASE

A. SAFETY & EFFICACYB. ANIMAL TESTING: Acute, Subacute, ChronicC. TYPES OF ANIMAL TEST: Pharmacologic Profile, Reproductive Toxicity, Carcinogenesis

II. CLINICAL PHASEa. PHASE Ib, PHASE IIc. PHASE IIId. PHASE IV

Thank You!If any of you lacks wisdom, let him ask of God, who gives to all, liberally and without reproach, and it will be

givento him.

James 1: 5