Pharmacokinetics - Absorption, Distribution, Metabolism, Excretion

1. Annasaheb Dange College Of D.Pharmacy,
Ashta
Presented by-
Miss R. S. Dhole (Assistant Professor)

2.  Pharmacokinetics:
 It is a branch of pharmacology
which deals with-
absorption
distribution
metabolism
and excretion
body
drug
It is an quantitative study of drug movement in, through and out of
the body.

4. Drug absorption
 It is the process of drug movement from site of
administration to systemic circulation.
 Why drugs should be transported?
In order to reach its receptor and produces biological
functions.

5. Drug absorption
 If oral……from Stomach & Intestine to portal circulation
 If rectal……from Rectum to systemic circulation
 If Intramuscular…..from muscles to systemic circulation…
If Intravenously-----
 So, for absorption, drug needs crossing of the cell
membrane.

6. Drug absorption
Cell membrane consists of
Lipid bilayer
Protein channels

7. Drug absorption
• Lipid layers are mostly “tight junction”
 Only lipid soluble substances can diffuse through it…..
 Water soluble substances can’t cross through tight lipid
layer…..

8. Drug transport processes
 Passive Diffusion
Simple diffusion (99%)
 Specialized transport
• Active transport
• Facilitated diffusion
• Endocytosis
• Exocytosis

9. DIFFUSION

10. Passive Diffusion
• Most common
• Occurs along concentration gradient.
• Requires no energy
• No carrier is needed
• No active role of the membrane
• No saturation of system
• Depends on lipid solubility.
• Depends on pKa of drug
 Almost all drug follow this Process

11. Carrier Mediated Transport
• Involve- membrane transport proteins - drug transporters or
carriers
• Specific for the substrate
• Saturable and inhibitable
• Depending on Energy requirement
a. Facilitated diffusion
b. Active transport
Drug
molecules bind
to the
transporter
Translocated
across the
membrane
Released on the
on other side of
the membrane.

12. Facilitated diffusion
• Transporter- Solute carrier (SLC) transporter
• Occurs along the concentration gradient
• Saturable
• Structure specific
• No requirement of energy
• Eg- Glucose , amino acids, vitamins

13. Active transport
• Energy dependent
• Transports solutes- against its concentration gradient
• Specific
• Saturable.
• Eg- Sodium, Potassium, Chloride, Calcium
• Types-
1. Primary active transport
2. Secondary active transport

14. • Primary active transport-
1. Energy is obtained by-ATP
2. Transporter- ATP binding cassettee (ABC)
3. Uniport
 Secondary active transport-
1. Affected by another SLC transporter
2. The energy required in transporting an ion---- transport of another ion
or molecule either in the same direction or opposite direction.
3. Mediate both- uptake and efflux of drugs and metabolites

15. • Endocytosis is a form of active transport in which
a cell transports molecules into the cell (endo- + cytosis) by
engulfing them in an energy-using process.
• Eg- Fats , starch , oil soluble vitamins, Insulin
• Exocytosis is a form of active transport in which
a cell transports molecules out of the cell (exo- + cytosis) by
expelling them in an energy-using process.
• Eg- Neurotransmitter from nerve cell, Pancreas releases insulin

17. • Information about drug absorption is necessary-
1. To determine frequency of drug administration
2. To define duration of effect
3. To predict onset of desired and undesired effect

18. Bioavailability
 Bio: Blood
 (Systemic circulation)
 Availability : How much available?

19. Bioavailability
• Simply….
 Percentage or amount of drug that is absorbed from
given dosage from that reaches systemic circulation
• If 100 mg of drug A is administered orally & 60 mg
reaches in systemic circulation-
• Then the oral bioavailability of drug A is 60%
• What about i.v.???

20. • Depends on various routes,
i.v> i.m.> s.c. >oral> topical
• Determined by
1. Concentration-time curve in blood (AUC)
2. Rate of excretion in urine

21. Factors affecting absorption & bioavailability
 Physiological Factors
1. Ionization
2. pH
3. GI transit time
4. Area of absorbing surface
5. Presence of other agents
6. Presence of disease
 Dosage Forms
1. Particle size
2. Disintegration and dissolution rate
3. Formulation
 Physical Properties of Drug
1. Physical State
2. Solubility

22. Dosage forms
 Particle size-
1. Smaller particle size shows greater absorption
2. Large aggregates of active drug--- Do not disintegrate rapidly
3. Eg- Chloramphenicol, Steroids
 Disintegration and dissolution rate
 Formulation-
1. Use of inert diluents can affect absorption as well as stability of
medicament
2. Eg- Calcium and magnesium ions- reduce absorption of tetracycline
3. Useful in formulating in sustained release dosage forms

23. Physiological Factors
 Ionization-
1. Unionized drugs and ionized drugs
 pH-
1. pH of GIT and blood interfere with absorption of drug
2. Acidic drugs are absorbed from stomach (Eg- Salicylates,
barbiturates)
3. Basic drugs are absorbed from small intestine (Eg- Pethidine,
ephedrine)

24. Drug distribution
• Reversible transfer of a drug between the blood and
the extra vascular fluids and tissues of the body
• After drug absorption,
1. Free form
2. Bound to plasma proteins

25. Body Compartments Types of drug
Total body water Small, water soluble molecules
Extracellular space Large water soluble molecules
Intravascular space
Very large, strongly protein bound
molecules
Body fat Highly lipid soluble molecules
Bones Fluoride and lead

26. Factors affecting distribution
• Tissue permeability
• Ionization
• Regional blood flow
• Tissue storage
• Plasma protein binding
• Membrane barriers

27. Blood Flow
• Drugs distributed quickly and completely in well perfused
tissue
• High perfusion rate- Brain, Heart, Kidney
• Less – Skeletal muscle, fat

28. Plasma Protein Binding
• Fraction of drug molecule binds reversibly with plasma
protein
• Rate of binding depends on the individual compound.
• Eg- Albumin, α1 acid-glycoprotein, lipoprotein, globulins
• Bound drug- P’kinetically and P’dynamically - Inert
• Always an equilibrium between bound & free drug
concentration

29. Significance
• Acts as temporary store for drug
• Makes drug longer acting
• Drugs having higher affinity displace drugs having weaker
affinity
Eg- 1. Aspirin displaces methotrexate
2. Phenytoin displaces warfarin
3. aspirin displaces sulfonylureas

30. Blood Brain Barrier
 Includes capillary endothelial cells
1. Which have tight junction
2. Lack large intracellular space
 Together with Neural Tissue (Glial cell)
1. Lipoidal in nature and limits entry of non-lipid soluble drugs
(Streptomycin, neostigmine)
2. Only lipid soluble, unionized drug can penetrate and have action on
CNS
3. Efflux carrier like P-gp present in brain extrude drugs that enter
brain by other processes.
4. Presence of enzyme- MAO, cholinesterase

32. Tissue Storage
• Drugs accumulate into specific organs or bound to specific tissue
constituents
Organ Drug
Skeletal Muscle,
Heart
Digoxin (muscle protein)
Liver Chloroquine, Digoxin, Tetracycline
Kidney Chloroquine, Digoxin
Thyroid Iodine
Brain Chlorpromazine, acetazolamide, isoniazid
Retina Chloroquine (nucleoproteins)
Bones and teeth Tetracyclines, heavy metals (to
mucopolysaccharide of connective tissue)
Adipose tissue Thiopentone, ether, phenoxybenzene

33. Biotransformation
• Chemical alteration of drug within body
• which converts nonpolar compound to polar compound
• Primary site- LIVER
• Others- Kidney, Intestine, Lungs, Plasma, Skin

34.  Conversion of active drug to inactive metabolite
Eg- Ibuprofen, Paracetamol, Lidocaine, Chloramphenicol,
Propranolol
 Active drug to active metabolite
Eg- Diazepam--- Oxazepam,
Digitoxin--- Digoxin
Morphine-- Morphine-6-glucuronide
 Inactive drug to active drug (Prodrug)
Eg- Levodopa- Dopamine
Prednisone- Prednisolone
Primidone- Phenobarbitone

35. Reactions
 Phase I reaction
1. Nonsynthetic reaction / Functionalization reaction
2. Functional group is generated
3. Metabolite- Active / inactive
4. Oxidation, Reduction, Hydrolysis
 Phase II reaction
1. Synthetic reaction / conjugation reaction
2. Conjugation with endogenous molecule
3. Metabolites- Inactive
4. Glucuronide conjugation, Acetylation, Sulfate conjugation, Glycine
conjugation,

36. Excretion
• Process where drug and/or their metabolites are irreversibly
transferred from internal to external environment.
• Process of removal of drug from body
• Channels - Kidney, Lungs, Intestine, Skin, Saliva, Milk, Bile

37. • Kidney-
 Most important channel
 Majority of drugs
 Process involved in elimination of drug in urine are-
1. Glomerular filtration
2. Tubular reabsorption
3. Tubular secretion
 Excretion of acidic and basic drugs- depends on pH of urine
 Eg- Phenobarbitone, Aspirin, Propranolol, Salbutamol, Morphine,
Quinidine, Penicillin

38. • Intestine-
 Through the faeces
 Liver: P-gp- which transports drug or their metabolites- from systemic
circulation to intestinal lumen
 Larger mol.wt. molecules are eliminated
 Eg- Laxative- Cascara sagrada, Senna
Heavy metals
• Lungs-
 Exhaled air
 Gases and volatile liquids are eliminated by this route
 Eg- General anaesthetics, alcohol

39.  Skin-
 Through sweat
 Minor drug excretion process
 Reason for skin rashes
 Eg- Heavy metals
 Saliva-
 Iodides
 Excessive salivation- chronic and heavy metal poisoning

40. • Milk-
 Antibiotics are entered – breast milk--- passive diffusion
 Lipid soluble, basic drugs
 Harm the infant
Eg- Sulphonamides, anticancer drugs, anthraquinones, Chloramphenicol,
morphine, ciprofloxacin, metformin
 Why most of drugs are contraindicated to lactating
mothers?

41. • Bile-
 Drugs- excreted through bile---- reabsorbed again intestine
 By hepatic portal circulation- prolonging action of drug
 Eg- erythromycin, tetracycline, phenolphthalein