FIRST PASS METABOLISM

INTESTINAL WALL
TYRAMINE
ISOPRENALINE
STILBESTROL
TESTOSTERONE
PROGESTERONE
CHLORPROMAZINE
LEVODOPA
ALFAMETHYLDOPA
 FIRST PASS METABOLISM CONTINUED
LIVER LUNGS
NITRATES ISOPRENALINE
OPIOIDS NICOTINE
Β –BLOCKERS (LIPID SOLUBLE)
LIGNOCAINE
CLARITHROMYCIN
SAQUINAVIR
VORICONAZOLE
VERAPAMIL
TCAD’s
 SIGNIFICANCE OF PLASMA PROTEIN BINDING
• SERVES AS A TEMPORARY DRUG RESERVOIR
• PHARMACOLOGICALLY INACTIVE. ONLY FREE FORM IS
ACTIVE
• NOT METABOLISED IN LIVER
• NOT FILTERED BY KIDNEY, BUT IS SECRETED FROM
PLASMA TO RENAL TUBULAR LUMEN
• DRUG-DRUG INTERACTIONS WITH HIGHLY PROTEIN
BOUND DRUGS
SIGNIFICANCE OF PLASMA PROTEIN BINDING
CONTINUED
• HIGHLY PROTEIN BOUND DRUGS ARE
DIFFICULT TO DIALYSE
• HIGH PROTEIN BOUND DRUG HAS POOR
ENTRY INTO CSF
• CAN DETERMINE HALF LIFE OF DRUG
 EXAMPLES OF PLASMA PROTEIN BINDING
HIGH BINDING LOW BINDING
WARFARIN SODIUM REGULAR INSULIN
PHENYTOIN HEPARIN
CARBAMAZEPINE METRONIDAZOLE
SODIUM VALPROATE DIGOXIN
PIROXICAM PENICILLIN-G
SULFADOXINE CHLORTHIAZIDE
CISPLATIN VANCOMYCIN
QUININE
 CONTINUED HIGH PROTEIN BINDING
SALICYLATES AZITHROMYCIN
INDOMETHACIN CLINDAMYCIN
MEFLOQUINE PHENYLBUTAZONE
DAPSONE TOLBUTAMIDE
CHLORPROPAMIDE
CHLORTHALIDONE
AMIODARONE
TEICOPLANIN
 DRUG IDIOSYNCRASY EXAMPLES
• CHLORAMPHENICOL APLASTIC ANEMIA
• SUCCINYLCHOLINE + HALOTHANE MALIGNANT
HYPERTHERMIA
• CHLORPROMAZINE CHOLESTATIC JAUNDICE
• THIAZIDE DIURETICS ERECTILE DYSFUNCTION
• VANCOMYCIN RED MAN SYNDROME
• ASPIRIN INDUCED LATE ONSET ASTHMA
 EXAMPLES OF PHARMACOGENETICS
• INH SLOW AND FAST ACETYLATORS (AR)
• SUCCINYLCHOLINE PROLONGED APNOEA DUE TO
ATYPICAL PSEUDOCHOLINE ESTERASE(AR)
• HEMOLYTIC ANEMIA IN G6PD DEFICIENCY (AR)
• PHENYTOIN SLOW HYDROLYSIS (AR)
• BARBITURATES CAUSING ACUTE PORPHYRIA (AD)
 COMPARISON BETWEEN TOLERANCE AND TACHYPHYLAXIS

TOLERANCE TACHYPHYLAXIS
• DEFINITION • DEFINITION
• MOA: DOWNREGULATION • DEPLETION OF
OF RECEPTORS NEUROTRANSMITTER NOR-
ADRENALINE FROM
POSTGANGLIONIC
SYMPATHETIC NERVE
ENDINGS
• TAKES TIME TO DEVELOP
• CAN BE PRODUCED ACUTELY
 COMPARISON BETWEEN TOLERANCE AND
TACHYPHYLAXIS
TOLERANCE TACHYLPHYAXIS
• HAS CLINICAL SIGNIFICANCE • HAS NO CLINICAL
SIGNIFICANCE
• E.G’s: β2 AGONISTS, • INDIRECT
NITRATES, ALCOHOL, BDZ’s, SYMPATHOMIMETICS
BARBITURATES, OPIOIDS (TYRAMINE,
AMPHETAMINE,
EPHEDRINE)
 ANTIOXIDANTS
DRUGS MINERALS
• ACEI’s MELATONIN • MANGANESE
• ARB’s • SELENIUM
• CARVEDILOL ADENOSINE • COPPER
• NICOTINAMIDE
• NEBIVOLOL
• SELIGILINE
 DRUGS AS ANTIOXIDANTS
CONTINUED
• CHLOROQUINE
• TRIMETAZIDINE
• DESFERRIOXAMINE
• ALLOPURINOL
• LACTOFERRIN
 OTHER ANTIOXIDANTS
VITAMINS FOOD SUBSTANCES
• BETACAROTENE ( • ISOFLAVONES
VIT A) (SOYABEAN)
• VITAMIN C • LYCOPENE (TOMATO)
• CURCUMINOIDS
• VITAMIN E
(TURMERIC)
• SPIRULINA (BLUE-
GREEN ALGAE)
 SCHEDULE DRUGS
• SCHEDULE I : NOT USED CLINICALLY
E.G’s: LSD, HEROIN, MARIJUANA

• SCHEDULE II: NO PRESCRIPTION GIVEN

E.G’s: MORPHINE, PETHIDINE,
CODEINE,COCAINE,PENTOBARBITAL,
SECOBARBITAL,AMPHETAMINE,METHYLPHENIDATE
 SCHEDULE DRUGS CONTINUED
• SCHEDULE III: PRESCRIPTION IS GIVEN
E.G’s: NALORPHINE, GLUTETHIMIDE,
CHLORPHENTERAMINE
• SCHEDULE IV: REGULAR PRESCRIPTION GIVEN
E.G’s: BDZ’s , PHENOBARBITONE, PENTAZOCINE,
PROPOXYPHENE
• SCHEDULE V : OVER THE COUNTER (OTC)
 PLASMA HALF LIFE
• SIGNIFICANCE:
To know frequency of drug administration
To know plasma protein binding
To calculate hour at achieving Css
To know clinical situation for drug
administration
In clinical trials to avoid bias
 FORMULAE
T1/2 = 0.693/K : S = -K/ 2.303

Vd (L) = Total amt of drug administered

-----------------------------------------------
Desired plasma concentration ( Css )
 FORMULAE
Css : 41/2 HALF LIVES

LOADING DOSE = Vd X Css

MAINTENANCE DOSE = HALF THE LOADING

DOSE
 FORMULAE
CORRECTED DOSE

Normal dose X Patient’s creatinine clearance

---------------------------------------------------------------
Normal creatinine clearance
 COMPARISON BETWEEN COMPETITIVE AND NON-COMPETITIVE
ANTAGONISM

COMPETITIVE NON-COMPETITIVE
• REVERSIBLE • IRREVERSIBLE
• SURMOUNTABLE • UNSURMOUNTABLE
• MAX RESPONSE OF AGONIST • MAX RESPONSE OF AGONIST
IS OBTAINED IN IS NOT OBTAINED IN THE
PRESENCE OF ANTAGONIST PRESENCE OF ANTAGONIST
• SHIFT TO THE RIGHT • SHIFT TO THE RIGHT
• PARALLEL • NOT PARALLEL
 COMPARISON BETWEEN COMPETITIVE AND NON-COMPETITIVE
ANTAGONISM

COMPETITIVE NON-COMPETITIVE
• D-TC AND • PAPAVERINE /
NEOSTIGMINE ACETYLCHOLINE
• CHOL/ANTICHOL • PHENOXYBENZ/α -
• MORPHINE/NALOXONE RECEPTORS
• HIST/ANTIHISTAMINE • OP COMPS AND
CHOLINE ESTERASE
 PHARMACOPOEIA
OFFICIAL BOOK CONTAINING DRUGS
PRESENT IN THE COUNTRY
IP (INDIAN PHARMACOPOEIA)
BP (BRITISH PHARMACOPOIEA)
USP (UNITED STATES PHARMACOPOIEA)
 ESSENTIAL DRUG LIST CRITERIA (WHO)
• STANDARD QUALITY
• COST EFFECTIVE
• GOOD BIOAVAILABILITY
• LONG SHELF LIFE
• AVAILABLE 24 HRS
• WITHIN REACH (PROXIMITY)
• MEET MAJORITY OF PEOPLES NEEDS
• USED FOR MOST PREVALENT DISEASES
• COMMON INTERNATIONAL NON- PROPRIETARY NAMES
• INVESTIGATED IN HUMANS AND ANIMALS
 FORMULAE FOR CHILD DOSE
YOUNG’S: AGE (YRS)
------------------ X ADULT DOSE
AGE + 12

DILLING’s: AGE (YRS)

----------------- X ADULT DOSE
20

CLARK’s: WT (LBS)
--------------- X ADULT DOSE
150

WT (KG) X ADULT DOSE

----------------
70

CHILD’s DOSE = BSA (M2)/ 1.8 X ADULT DOSE

 COMPARISON BETWEEN SYNERGISM AND ADDITIVE
EFFECT
SYNERGISM ADDITIVE
• MECH OF A & B IS DIFF • MECHANISM IS THE SAME
• FINAL EFFECT AB IS MORE • AB IS SAME

EXAMPLES: SMX + TM EXAMPLES:

TYRAMINE + MAOI’s EPHEDRINE + SALBUTAMOL
LEUPROLIDE + FLUTAMIDE IBUPROFEN + PARACETAMOL
SALBUTAMOL+ THEOPHYLLINE
ASPIRIN + CODEINE
ESTROGEN + PROGESTOGEN
 PRODRUGS
• BULAQUINE ----- PRIMAQUINE
• METRONIDAZOLE --- NITRATE/NITRITE RADICALS
• RIBAVIRIN ----- RNA NUCLEOTIDES
• INH ---- INH-NADPH COMPLEX
• PYRAZINAMIDE ----- PYRAZINOIC ACID
• PROGUANIL ---- CYCLOGUANIL
• 5-FU ---- 5-FUMP---- 5-FUDP----5-FUTP
• CAPECITABINE --- 5-FU
• PIVMECILLINAM ----- MECILLINAM
• METHENAMINE MANDELATE ----- FORMALDEHYDE
• VALGANCICLOVIR ------ GANCICLOVIR
ACTIVE ------ ACTIVE METABOLITE
• MORPHINE • MORPHINE 6
GLUCURONIDE
• METRIFONATE • DICHLOROVOS (DDVP)
• CLARITHROMYCIN • 14-OHYCLARITHROMYCIN
• CHLORAL HYDRATE • TRICHLOROACETIC ACID
COMPARISON BETWEEN ACTIVE TRANSPORT AND
FACILITATED DIFFUSION
ACTIVE TRANSPORT FACILITATED DIFFUSION
• FROM LOWER TO • FROM HIGHER TO
HIGHER GRADIENT LOWER GRADIENT
• REQUIRES ENERGY • NO ENERGY NEEDED
• NEEDS A CARRIER • NO CARRIER NEEDED
• GETS SATURATED • GETS SATURATED
 EXAMPLES OF ACTIVE TRANSPORT
• UPTAKE OF SYMPATHOMIMETIC
AMINES BY NEURAL TISSUE
• CHOLINE BY CHOLINERGIC NEURON
• DIGITALIS GLYCOSIDES BY LIVER
• 5-FU BY INTESTINE
• NITROGEN MUSTARD BY LYMPHOCYTES
EXAMPLES OF FACILITATED DIFFUSION
• TRANSPORT OF AMINOACIDS IN BRAIN
• ANTIMETABOLITE ANTICANCER DRUGS
• ANTIVIRAL DRUGS
• ADENOSINE LIKE DRUGS
• VITAMINS (RIBOFLAVIN, THIAMINE, B12)
CHARACTERISTICS OF PASSIVE DIFFUSION
• PASSAGE THROUGH A SEMI-PERMEABLE
MEMBRANE
• LIPID SOLUBLE/ WATER SOLUBLE
• DOSE DEPENDENT
• DOES NOT NEED A CARRIER
• NO ENERGY NEEDED FOR PASSAGE
• DOES NOT GET SATURATED
 FACTORS AFFECTING BIOAVAILABILITY
• PHARMACEUTICAL
-SOLID, LIQUID, GAS
-LIPID/WATER SOLUBLE
-PARTICLE SIZE
-DISINTEGATION TIME
-DISSOLUTION RATE
-FORMULATION
-pH
 CONTINUED BIOAVAILABILITY FACTORS
• PHARMACOLOGICAL
- ENTEROHEPATIC CIRCULATION
-RAPID FIRST PASS METABOLISM
-MALABSORPTION SYNDROMES
-FOOD, GASTRIC EMPTYING TIME
-ROUTE OF ADMINISTRATION
-CIRCULATION
-PHARMACOGENETIC FACTORS
-DRUG-DRUG INTERACTIONS
-BIOEQUIVALENCE/ THERAPEUTIC EQUIVALENCE/ CHEMICAL
EQUIVALENCE
 EXAMPLES OF ENTEROHEPATIC CIRCULATION
• PIROXICAM
• MEFLOQUINE
• DAPSONE
• DOXYCYCLINE
• MINOCYCLINE
• AMPICILLIN
• CIPROFLOXACIN
• CHLORAMPHENICOL
• DIGITOXIN
• COLCHICINE
EXAMPLES OF PHASE I BIOTRANSFORMATION
• OXIDATION
MICROSOMAL:
AROMATIC HYDROXYLATION: Phenobarbitone, Phenytoin,
Propranolol
ALIPHATIC HYDROXYLATION:Tolbutamide, Meprobamate,
Ibuprofen, Secobarbital, Cyclosporine, Midazolam
N,S,O DEALKYLATION: Amitryptiline --- Nortriptiline
DEAMINATION: Amphetamine --- Phenylacetone
derivative
DESULFURISATION: Parathion ---- Paraxon
 Continued biotransformation examples
• OXIDATION:
NON-MICROSOMAL: MAO
(Mitochondria) Epinephrine ---- VMA
ADH
(Cytoplasm) Alcohol -------- Acetaldehyde
Histaminase
(Plasma) Histamine -- 4-imidazole aceticacid
Xanthine oxidase
Xanthine ------ uric acid
CONTINUED BIOTRANSFORMATION EXAMPLES
• REDUCTION:
MICROSOMAL:
NITRO: Chloramphenicol ------ Arylamine
AZO: Prontosil ------- Sulfanilamide
KETO: Cortisone ----- Hydrocortisone

NON-MICROSOMAL:
Chloralhydrate ----- Trichloroethanol
 CONTINUED BIOTRANSFORMATION EXAMPLES
• HYDROLYSIS: MICROSOMAL:
Pethidine ----- Pethidinic acid

NON-MICROSOMAL:
Ester local anaesthetics (Procaine etc.) ------PABA
Atropine ---- Tropic acid
Hydrolysis of β lactam ring
 PHARMACOKINETICS
FIRST ORDER ZERO ORDER
• FRACTION OF DRUG • FIXED AMOUNT OF DRUG
ELIMINATED PER UNIT TIME ELIMINATED PER UNIT TIME
• INDEPENDENT OF DOSE • DOSE DEPENDENT
• DOES NOT ACCUMULATE • DRUG ACCUMULATES
• ENZYMES ARE INTACT • ENZYMES ARE SATURATED
• GRAPH PLOTTED IS A STRAIGHT • GRAPH PLOTTED IS A
LINE HYPERBOLA
 PHARMACOKINETICS
FIRST ORDER ZERO ORDER
• ALSO CALLED • ALSO CALLED ZERO
LINEAR/EXPONEN ORDER KINETICS
TIAL KINETICS
• HALF LIFE CAN BE • CANNOT
DETERMINED DETERMINE HALF
LIFE
 DRUGS HAVING LOW THERAPEUTIC INDEX (NEED
TDM)
ANTIEPILEPTICS (EXCEPT BENZODIAZEPINES
AMINOGLYCOSIDES
WARFARIN
ANTICANCER DRUGS
THEOPHYLLINE
HEAVY METALS
ANTIARRYTHMICS
PHENOTHIAZINES
 DRUGS HAVING LOW THERAPEUTIC INDEX
(NEED TDM)
CARDIAC GLYCOSIDES
ORAL HYPPOGLYCEMICS
CLINDAMYCIN
CHLORAMPHENICOL
VANCOMYCIN
FLUROQUINOLONES
TRICYCLIC ANTIDEPRESSANTS (TCAD’S)
 COMPARISON BETWEEN SIDE EFFECT, TOXIC EFFECT
AND ADVERSE EFFECT
SIDE EFFECT TOXIC EFFECT ADVERSE EFFECT

Predictable Predictable Unpredictable

Standard dose High dose Standard dose

Wanted/ Unwanted Unwanted

Unwanted
 COMPARISON BETWEEN ADR’S
ADR -A ADR-B
• AUGMENTED • BIZARRE
• PREDICTABLE • UNPREDICTABLE
• SIDE EFFECT • DRUG IDIOSYNCRASY
• TOXIC EFFECT • PHARMACOGENETICS
• ALLERGIC REACTIONS
• NO GENETICS INVOLVED • GENETICS IS INVOLVED
• LOW MORBIDITY • HIGH MORBIDITY
• NO MORTALITY • HIGH MORTALITY
 MECHANISM OF RECEPTOR ACTION
• GPCR (METABOTROPIC/7 TRANSMEMBRANE
SPANNING RECEPTORS)
Gs : Stimulate Adenyl cyclase ---↑cAMP
(β2 agonists, Histamine, Glucagon )

Gi : Inhibits Adenyl cyclase ---- ↓ cAMP

(Opioids, α adrenergic, Muscarinic)

Gq : Stimulates phospholipase C --- IP3 + DAG

( Insulin)
 MECHANISM OF RECEPTOR ACTION CONTINUED

• ENZYME LINKED (TYROSINE KINASE):

Insulin, PDGF, EGF

• INTRACELLULAR RECEPTORS:
NUCLEAR Estrogen, Thyroid hormone, Vit D, VitA
CYTOPLASMIC ACTH, Progestogen, Androgen

• LIGAND GATED ION CHANNEL:

Nicotinic, Apartate, Glutamate, Glycine
• WARFARIN
ACIDIC DRUGS
• HEPARIN
• PROBENECID
• DIURETICS
• BARBITURATES
• SULPHONAMIDES
• ANTITUBERCULAR DRUGS
• NSAID’s
• Β LACTAMS
• DIGOXIN
• QUINOLONES
 BASIC DRUGS
• PHENYTOIN BENZODIAZEPINES
• β LOCKERS ANTIMALARIALS
• LIGNOCAINE
• NITRATES
• OPIOIDS
• TCAD’s
• PHENOTHIAZINES
• MACROLIDES
• AMPHETAMINE
• EPHEDRINE
 DEFINITIONS
• CHRONOPHARMACOLOGY: STUDY OF DRUGS IN RELATION
TO TIME
• POSOLOGY: STUDY OF DRUG DOSES
• ORPHAN DRUG:FOR RARE DISEASE, NOT MARKETED,
COST WILL NOT BE RECOVERED
• SERENDIPITOUS DRUG: CHANCE DISCOVERY
• SEQUESTRATION: DRUG BOUND TO TISSUE PROTEINS
 DEFINITIONS
• PHARMACOGNOSY: STUDY OF SIOURCES AND
IDENTIFICATION OF DRUGS FROM PLANTS
• LIGAND: SUBSTANCE BINDING TO RECEPTOR
• XENOBIOTIC: ANY FOREIGN SUBSTANCE
• INUNCTION: RUBBING OF A DRUG MIXED WITH
OIL/FATTY SUBSTANCE INTO THE SKIN , WITH
ABSORPTION OF THE ACTIVE INGREDIENT
 ORPHAN DRUGS
• ATOVAQUONE
• DIGIBIND TACROLIMUS
• N-ACETYLCYSTEINE DASATINIB
• MONOCLONAL ANTIBODIES DECITABINE
• ALFA-GLUCOSIDASE THALIDOMIDE/
• ERYTHROPOETIN LENALIDOMIDE
• ANAGRELIDE
• AMINOSIDINE
• INFLIXIMAB
 SERENDIPITOUS DRUGS
• MINOXIDIL IN ALOPECIA
• HEPARIN
• PHENOLPTHALEIN AS LAXATIVE
• PENICILLIN-G
• HAMYCIN
• AMANTADINE IN PARKINSONISM
• ARTIFICIAL SWEETENERS (ASPARTAME, SACCHARIN,
CYCLAMATE)
• SILDENAFIL
 SERENDIPITOUS DRUGS CONTINUED
• PRONTOSIL
• ANAESTHETIC (ETHER, NITROUS OXIDE)
• RETIN- A ANTIWRINKLE ACTION
• LSD
• CHLORPROMAZINE
• CHLORDIAZEPOXIDE
• CISPLATIN
 TRANSDERMAL PATCH
DRUG USE
• SCOPOLAMINE • MOTION SICKNESS
• ESTRADERM TTS • HRT
(ESTROGEN)
• NICOTINE • SMOKING WITHDRAWAL
• POSTMENOPAUSAL HOT
• CLONIDINE FLUSHES
 TRANSDERMAL PATCH CONTINUED
DRUG PATCH
• NTG • NOCTURNAL ATTACKS
OF ANGINA PECTORIS
• FENTANYL • TERMINAL CANCER
PAIN
• TESTOSTERONE • MALE HYPOGONADISM
• NSAID • SPORTS MEDICINE
 DRUG RESERVOIRS
DRUG STORAGE SITE
• THIOPENTONE, DDT, • ADIPOSE TISSUE
PHENOXYBENZAMINE
• TETRACYCLINE, ARSENIC, LEAD, • BONE
FLUORIDES, CISPLATIN
• ACIDIC DRUGS • PLASMA PROTEIN (ALBUMIN)

• CHLOROQUINE, I2, CPZ • CELLULAR

 DRUG RESERVOIRS CONTINUED
DRUG STORAGE SITE
TRANSCELLULAR • CHLORAMPHENICOL,
• AQUEOUS HUMOUR PREDNISOLONE

• CSF • AMINO SUGARS,

SUCROSE
• JOINT FLUID • AMPICILLIN
• PLEURAL FLUID • MTX, IMIPRAMINE
 ENZYME INDUCERS
• RIFAMPICIN NNRTI’s
• PHENYTOIN RIFABUTIN
• BARBITURATES 20% INH
• CARBAMAZEPINE CLOFIBRATE
• CHRONIC ALCOHOL INTAKE DDT
• ST. JOHN’s WORT TROGLITAZONE
• GRISEOFULVIN GLUTETHIMIDE
• PYRIDOXINE
• AMINOGLUTETHIMIDE
 ENZYME INHIBITORS
• CIMETIDINE DISULFIRAM
• VERAPAMIL ERYTHROMYCIN
• SODIUM VALPROATE PROTEASE INHIBITORS
• 80% INH KETOCONAZOLE
• ALLOPURINOL CARBIDOPA
• ACUTE ALCOHOL INTAKE MAOI’s
• CHLORAMPHENICOL
• FLUROQUINOLONES
• CAPTOPRIL