GENERAL GENERAL PRINCIPLES PRINCIPLES Zenaida N. Maglaya, MD; FPSECP Zenaida N. Maglaya, MD; FPSECP Department of Pharmacology Department of Pharmacology
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