Pharmacokinetics

by Dr.Naveen Kumar

1

Drug Metabolism (BioTransformation)

2

Drug Metabolism (Bio-Transformation)
• `Xenobiotics’ • β- slope • Elimination is
(Metabolism  Excretion)

Elimination

• Objective- ↓ lipid solubility
- ↓ Bioactivity

3

End result of all Biotransformation1. Active Inactive Drug (Pentobarbitone) 2. Active Active Drug (Diazepam, Fluoxetine) 3. Inactive Active Drug (Prodrug) (Prodrug) -Enalpril Enalprilat -LevoDopa Dopamine Organs- Liver / Gut / Kidney / Lungs / Skin Cell- EPR (smooth), cytosol, Mitochondria, Nuclear envelope, Plasma membrane

• •

4

Drug Elimination

Excretion

5

Phase-I Biotranformation
(Non-synthetic)

Phase-II Biotranformation
Synthetic/ conjugation) -↓ -↑ ↑ ↑ Conjugation by subgroupsGlucouronate, Acetate, Glutathione, Glycine, Sulfate, Methyl
-UGT- UDP glucuronosyl transferase
-GST- Glutathione-S-transferase -SULT- Sulfotransferase -NAT- N-Acetyl transferase -MT – Methyl transferase -GT- Glycine transferase

Metabolite-Bioactivity- ↑ / ↓ / o -water solubility- ↑ -Functional groupsOH/ NH2/ -SH/ -COOH/ -O

Enzymes-Cyp P450 -Flavin monooxygenases(FMO)
- Hydrolases

6

7

Phase-I Reactions1.Oxidation a) Cyp P450 dependent b) Cyp P450 independent-Amine Oxidation (Adr.) -Dehydrogenation (Ethanol) 2.Reduction a) Cyp P450 dependent-Nitro Reduction (chloroamphanicol)
-Azo Reduction- (Sulfonamides)

Phase-II Reactions(Conjugation Reactions) 1.GlucuronidationParacetamol, Diazepam,Morphine

2.AcetylationINH, Sulfonamides

3.Glutathione ConjugationParacetamol

4.Glycine ConjugationSalicylates

b) Cyp P450 independent-Chloral hydrate 3. HydrolysisPethidine, Lignocaine, procaine

5.Sulfate Conjugationsteroids, methyl-Dopa

6.MethylationDopamine, Adr., NorAdr.
8

Phase-I Cyp450 dependent Oxidation
1. Hydroxylation- Phenytoin, Warfarin 2. Dealkylation-Morphine, Codeine 3. Oxidation- Paracetamol,Cimetidine, Omeperazole 4. Deamination- Diazepam

9

Drug Metabolism

10

Questions
Liver is the main site of metabolism of drugs. The drugs will be changed to following form for rapid excretion. a)Lipid soluble & unionized forms b)Lipid soluble & ionized forms c) water soluble & unionized forms d)water soluble & ionized forms

Ans:

d)
11
11

Q. Select the metabolic reaction: a) Acetylation b) Methylation c) Glutathione conjugation d) Glycine conjugation

Ans:

b)
12

Cytochrome P450

13

Cytochrome P450 Metabolism
• Cytochrome P450 enzymes are hemoproteins & μ-somal • present in liver, kidney, lungs and even brain • Function- Intracellular metabolism of Drugs (mainly Ph-I)
- metabolism of dietary agents - synthesis of endogenous compounds- eg., steroids • catalyse rxns. most Ph-1 & only Glucouronide conjugation in Ph-2

•Cytochrome P450 Polymorphism (2D6, 2C19, 2C9) • Enzyme activity subjected to Induction & Inhibition • 17 families & > 100 isoenzymes
classification: family sub-family CYP 3 A 4 isoenzyme
14

Cytochrome P450 enzymes
Especially CYP 3A4, CYP 2D6, and CYP 2C9 are involved in the metabolism of xenobiotics and drugs.

Metabolic Contribution
hepatic only CYP 2C9 10% CYP 1A2 other 2% 3% CYP 3A4 CYP 2D6 CYP 2C9 CYP 1A2 other

CYP 2D6 30% also small intestine

CYP 3A4 55%

15

P 450 - ?

16

Cytochrome P450 Metabolism
Drug-R + O2 CYP Drug-OR + H2O

NADPH

NADP

1. Microsomal enzymes- Cytochrome P450 & NADPH Cytochrome P450 reductase 2. NADPH (energy transferring unit) 3. Molecular O2

17

Cytochrome P450 enzyme Inhibitors
• Ketoconazole, Cimetidine, Ciprofloxacin, Erythromycin, Chloramphenicol, Fluoxetine, Grapefruit juice • Fast time course (within hours) • Drug interactions- Ketoconazole + Terfenadine - Ciprofloxacin + Theophylline

18

Cytochrome P450 enzyme Inducers
• Anti-Epileptic drugs- Carbamazepine, Phenytoin, Phenobarbitone • Rifampin, Griseofulvin, • Glucocorticoids • Smoking tobacco, aromatic H-C, Charbroiled meat • Drug Interactions- Rifampin + Oral contraceptives - Phenobarbitone + Warfarin

19

Clinical Implications of drug Metabolism
(Factors influencing drug Metabolism)

1. Drug interactions 2. Genetic Factors– Polymorphisms & inter-individual variations 3. Tolerance by Auto-induction- eg., Carbamazepine 4. First pass Metabolism 5. Age 6. Sex 7. Disease 8. Diet and Environment
20

Genetic Polymorphisms in drug Metabolism
Defect N-Acetylation (Acetylator polymorph. Oxidation (cyp2C19 poly.) Drug INH Adverse effect Peripheral neuropathy in slow actylators Ataxia / sedation

Phenytoin

21

Genetic Polymorphisms in drug Metabolism
Defect Oxidation (Cyp2C9 Poly.) Drug Warfarin Adverse effect Bleeding

Ester Hydrolysis Succinylcholine

Prolonged Apnea

22

Age & maturation of Liver Function
Glucuronidation & other Conjugation

Acetylation

23

Cytochrome P450
Drug-Disease metabolic Interactions
• • • • Liver disease Phenobarbitone in congenital jaundice Acute Paracetamol toxicity by Rifampicin Anti-Epileptics resulting in Osteomalacia

24

Drug-Food metabolic Interactions

• Grapefruit- Cyp inhibitor
25

Drug-Food metabolic Interactions

• Brussels sprout - Cyp inducer
26

Drug-Food metabolic Interactions

• Charbroiled meat- Cytochrome P450 1A2 inducer
27

Factors influencing drug MetabolismEnvironmental factors

Smoking induces Cyp1A2 & decreases the effects of Dextropropoxyphene, BZDs, Theophylline & insulin.

Alcohol

Smoking Tobacco
28

Q. Which disease states significantly effect drug metabolism?: a) b) c) d) Alcoholic cirrhosis Chronic active hepatitis Glomerulonephritis Paracetamol hepatotoxicity

Ans:

a), b) & d)
29

Q.A decrease in the rate of drug metabolism is observed in all except: a) b) c) d) New borns Elderly patients Patient’s with damaged liver Pateint’s receiving prior phenobarbitone treatment

Ans:

d)
30

Drug Excretion

31

32

Excretion of Drugs

M A J O R M I N O R
33

Excretion by the Kidney

34

Excretion by the Kidney

1) Glomerular filtration -Molecular size constraints (MW < 5000)
-Plasma protein binding -Renal blood flow

2) Tubular secretion - PCT
- Non-selective carrier systems for organic acids/bases - Transporter proteins- OAT / OCT / P-gp - active transport / competitive/ saturable.
35

Excretion by the Kidney
2. Tubular secretion Acidic Drugs- (Organic Anion Transporter(OAT)) Penicillin, Probenacid, Methotrexate, Sulfonamides, Aspirin (salicylates) Endogenous- (Uric acid, Oxalates, Prostaglandins)

Basic Drugs- (Organic Cation Transporter(OCT)) Quinidine, Digoxin, Morphine, atropine.
36

Excretion by the Kidney 3. Tubular Reabsorption • Passive diffusion • Lipid solubility • Urine pH & pKa of the drug
-Weakly basic drugs (Morphine/ Amphetamine)- ↑ Excreted in acidic Urine - Weakly Acidic drugs (Barbiturates / Aspirin)- ↑ Excreted in Basic Urine - Strong acids & strong bases are ionized - Polar & ionized- Quarternary NH4 compounds, Aminoglycocides, Penicillins
37

Drug Excretion in urine

Nature of the Drug- ?

Weak Basic drug
38

Age & maturation of Kidney function

7

Glomeruler Filtration

Tubular secretion
39

Excretion by the Liver
Biliary Secretion – -active transport for organic acids, bases & neutral compounds - Molecular size constraints (MW > 300) - Tranporter proteins-P-gp Eg.,-Ampicillin, Erythromycin, Corticosteroids -Enterohepatic Circulation

40

Enterohepatic circulation

Eg., Digitoxin,

Morphine, Ethinyl Estradiol (OCP), Rifampicin, Benzodiazepines
41

Excretion through Breast Milk
Highly toxic drugs excreted via milkCNS drugs-Ethanol, Benzodiazepines,
Phenobarbitone, Phenytoin, Opiates, Lithium, Plasma (pH=7.4) Weak Base- Unionized

Endocrine Drugs-Corticosteroids, Anti-thyroids

Chemotherapeutics-Tetracycline, Chloroampanicol, Sulfonamides, Anticancer drugs

Breast Milk
(pH=6.6)

Weak bases-Ionized (Ion-Trapping)
42

EXCRETION BY OTHER ROUTES
• LUNG – - For gases and volatile liquids by diffusion.eg.,General Anaesthetic agents & Ethyl Alcohol • Faeces- Neomycin, Purgatives, Mebendazole • Excretion through -sweat, saliva,Skin, Hair Griseofulvin Skin KI / Li / Phenytoin / Iodine - Saliva Amines / Urea drv. - Sweat As / Hg / Iodides - Hair follicles

43

Clearance (CL)
• Quantifies elimination • Clearance: volume of plasma cleared of drug per unit time. Clearance = Rate of elimination (mL / min) plasma conc • Total Body Clearance = CLliver + CLkidney + CLlungs + CL others • Fundamental Pk Parameter • Plasma clearance Cl = Ke .Vd
High CL ( 1000mL/ min)Hydralazine, Morphine, Verapamil

Low CL ((< 10mL / min)Digitoxin,
Phenobarbitone, Valproate, warfarin
44

t ½- Half-life of elimination

Conc. (Cp)

2

4

6

8

10
45

Time (hrs)

t ½- Half-life of elimination
• • • • time for plasma conc. to decrease by half. Elimination t ½ Vs Biological effect t ½ . Derived Pk parameter Useful in estimating: -time to reach steady state concentration. -time for plasma conc. to fall after dosing is stopped.

t1/2 = 0.693 x Vd/CL
46

t ½- Half-life of elimination
t ½ < 1 hrs
Adenosine Dopamine Succinylcholine

t ½ ( 1 - 12 hrs)
Paracetamol Aspirin Atenolol Tetracycline

t ½ > 24 hrs
Digoxin Diazepam

Phenobarbitone
Warfarin Chloroquine
47

Pharmacokinetic parameters
• Fundamental Pk Parameters -Vol of distribution Vd = DOSE / Co
-Plasma clearance CL = Ke .Vd -Bioavailability F = (AUC)o / (AUC)iv

• Derived Pk Parameter -plasma half-life (t1/2) t1/2 = 0.693 / Ke

-

48

Plasma conc. of a drug at time-0 is 80μg/ml.If it’s t1/2 is 2 hours, concentration in plasma at 8 hours , in μg/ml will bea) 20 b) 40 c) 5 d) 0
____________________________________________________________________________________________________

c) 5

Q.If there is 32 mg/ml of drug X at 8 AM, what is the conc. of drug at 1PM? (Given Ke=0.693/hr) : a) b) c) d) 1 mg/ml 4 mg/ml 8 mg/ml 16 mg/ml

t1/2 = 0.693 / Ke

Ans:

a)
50

First Order Elimination (Linear Kinetics)
• Constant Fraction of drug eliminated per unit time. • Rate of elimination proportional to plasma conc.

Conc

t 1/2

Time

Plasma conc.

51

First Order Elimination
C0

Log C (Plasma conc.)

Slope=m

y

=

b + ( m).x

Time

52

Zero Order Elimination
• Constant amount of the drug is eliminated per unit time • constant rate of elimination irrespective of plasma concentration
Log conc. Conc.

t 1/2

Time

Time

Dose
53

Kinetics of Elimination
First Order Kinetics (Exponential kinetics) (Linear kinetics) Zero Order Kinetics (saturation kinetics / Non-Linear netics)

.

Zero
Log conc.

1st

Time
54

Linear kinetics 1st order Kinetics (most drugs)
Rate of elimination

Non-linear Kinetics Zero-order Kinetics Eg., alcohol
Rate of elimination

Blood drug conc

Blood drug conc
55

Mixed order Kinetics Eg., Phenytoin, Aspirin

Rate of elimination Blood drug conc
56

Types of Kinetics
First Order Kinetics•Constant fraction of the drug is eliminated per unit time • rate of elimination proportional to plasma concentration (CL is constant) • t 1/2 is constant regardless of drug conc. (t1/2 = 0.693/k ) • Most Drugs

Zero order Kinetics•Constant amount of the drug is eliminated per unit time • rate of elimination is constant ( CL is ↓ with ↑ in dose) • No true t ½

• eg.,-Alcohol
-Mixed order-Theophylline, Aspirin, Warfarin,Phenytoin, 57

Q. Graphically the change in Log drug conc. Vs time yields a straight line :
a) b) c) d) Zero order kinetics First order kinetics Both Neither

Ans:

b)
58

Time (Hrs)

Plasma conc(C)

Elimination (%)

0

200
100 50 25 12.5 6.25

0
50 75 87.5 94 97

200

2 4 6 8 10

Conc (mg/dL)

100
50 25
12.5
6.25

Concentration after a single IV dose

2

4

6

8

10
59

Time (Hrs)

Questions
The half life of drug is 4 hrs. 95% of the drug will be completely eliminated from body after how many half lives? a)Two half lives b)three half lives c) four half lives d)five half lives

Ans:

c)
60
60

Multiple dosing
200

Steady State Plasma Conc. (Cpp)

The time to reach steady state is ~4-5 t1/2’s
Conc (mg/dL)

Concentration due to repeated doses

100
50 25
12.5
6.25

Concentration after a single IV dose

2

4

6

8

10
61

Time (Hrs)

Multiple dosing
At Steady State Amount administered = Amount eliminated between doses
300 250 200

Css

Cp
100 50

Css usually attained at ~4-5 x t1/2

2

4

6

8

10

Time (Hrs)

62

The Plateau Principle
• Time to the Steady State is a function of t ½.
(Css is reached at 4-5 t 1/2)

• Steady state reached is a function of dose & dose interval • Only for 1st order Kinetics • At Steady State plasma levelRate of Elimination = Rate of Administration
(CL X Css) (Dosing Rate)  Css = (Dose) x 1 T CL
63

On Monday a patient begins taking a daily dose of a drug with a half-life of 1 day. If he takes the same dose every day, on what day will his plasma drug levels reach plateau? A) Wednesday B) Thursday C) Sunday D) Saturday
____________________________________________________________________________________________________

B) Thursday

Dosing Schedule
• Drugs with very short t ½ (Secs to Mins) e.g., Dopamine (IV infusion) • Drugs with short t ½ (30 Mins – 2 hrs) e.g., Penicillins • Drugs with t ½ (6 – 24 hrs) – administer the drug at each t 1/2 . (Most drugs) • Single dose treatment e.g., Hypnotics, Analgesics, Laxatives • Drugs with long t ½
65

Loading dose(s)
Loading dose = Cpeak . Volume of distribution

Cp

time

66

Dosing Schedule
Drugs with long t ½ Eg., Digoxin (t ½ = 40 hrs) Loading Dose = Vd x Css  Maintainance Dose rate = CL x Css Loading dose• Drugs with long t ½ • Drugs to be used in critically ill patients- e.g., Lignocaine
67

Therapeutic window
Peak Levels

Minimum Toxic level Target Css Cp Minimum therapeutic level time
68

Trough levels Theophylline (5- 20 / ml) Phenytoin (10-20 / ml) Lithium (0.5-1.5 Meq/ L)

Therapeutic Drug monitoring (TDM)
Indications• Drugs

with low therapeutic index eg., Li, Digoxin, Antiepileptics, Antiarrythmics, Theophylline etc. • Inter-individual Pk variations & drug polymorphisms eg., antidepressants, Li • Toxic drug use in Renal failure pateints & elderly eg., Eg., Gentamicin •Drug Poisonings • Failure of response or toxicity eg., Digoxin, antibiotics, antivirals • To check compliance
69

Prolongation of Drug Action
• Delay in absorption -Oral administration- SR tabs
-Parenteral adm.-Oily soln.,Depot-(Fluphenazine, penicillins,) s.c implants / pellets, LA + vasoconstrictors -Trandermal drug delivery system - Insulin Zinc suspension / Protamine Insulin - Ocuserts- Pilocarpine Delayed Metabolism- L-DOPA + Carbidopa, CholineEstrase Inhibitors-physostigmine Altered Vd (Alteration in PPB)- Sulfonamides Delayed Excretion- Probenacid + Penicillins Altered Molecular Structure- Benzodiazepines
70

• • • •

Pharmacodynamics (Pd)
• `Pharmacon’- drug / dynamics – action • The action of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic action. • how drugs work on the body • Effects are quantitative • Pilocarpine  +Muscarinic Receptors MIOSIS Morphine  3rd cranial
71

Pharmacodynamics (Pd)
• Site of drug action- Extracellular- Antacids, Chelating agents - Cell membranes- Adrenaline, dopamine - Intracellular- Sulfonamides, 5-FU • Mechanism of drug action- Non-Biomolecule mediated - Biomolecule mediated

72

(Pd)- Non-Biomolecule mediated drug action

1. Physical Action
• • • • • • • Osmosis- MgSo4, Mannitol Adsorbtion- Charcoal, Kaolin Astringents- Tannic acid, Calamine lotion Demulscents- Pectin, cough linctus Radioactivity- I 131, I 123 Radioopacity- BaSo4 Mass- Bulk Laxatives

2. Chemical action
• • • Alteration of pH- antacids, NH3Cl, NaHCo3 Chelation- EDTA, Desferrioxamine, BAL Oxidizing agents- KMno4, I2
73

(Pd)- Biomolecule

mediated drug action

1. 2. 3. 4.

Enzymes mediated Intrinsic Ion channels mediated Transporter proteins mediated ReceptorsType-I- Ligand Gated Ion Channels Type-II- G-Protein Coupled Receptors (GPCR) Type-III- Enzyme linked Receptors Type-IV- Nuclear Receptors
74

Sign up to vote on this title
UsefulNot useful