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Pharmacology
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Bioavailability
The fraction of unchanged drug reaching the systemic circulation in following administration by any route
Measure of both rate and extent of drug that reaches the general circulation from an administered dosage form.
Drug in dosage form A successful TherapyDesired Effect
Attain and maintain an adequatedrug concentration at active site
Excretion
Metabolism
Distribution
Absorption
Drug dissolved in GIT fluid
Ability of drug dosage form to release drug after administered to patient
MTC
MEC
time
Blood conc.
Solid Dosage Form Granules Fine particles
Disintegration Deaggregation
Very limited Limited Optimum dissolution dissolution dissolution
Drug is dissolved in
GIT fluid
Membrane
Absorption
Drug in blood
Sequence of event involved in the dissolution and absorption of a drug from tablet dosage form
Drug in Dosage Form
AUC oralBioavailability = X 100 %
AUC Injected
Drug injected
AUC injected
AUC Oral
Drug given orally
Drug administered
Blood Conc.
Time (hours)
Determination of the Bioavailability
Comparing plasma concentration of drug after particular route of administration with plasma drug level by injection
Blood Conc.
Time (hours)
Two 250 mg. Erythromycin Tablet No Film or Enteric Coating
Two 250 mg. Erythromycin Tablet Film Coated
Two 250 mg. Erythromycin Tablet Enteric Coated
Factor affecting Bioavailability :
I. Patient variableII. Pharmaceutical variableIII. Route of administration IV. Time of administration
I. Patient variable Anatomy and Physiology patient factors : 1. Anatomical factor : Stomach :
* Primary function is not absorbing membrane * Stomach content contact with epithelial cell 30’ – 2 hr provides weakly acidic drug absorption Small Intestine : Villi and microvilli optimum absorption
Large intestine : Absorption is not completely
2. Physiological factor : a. Membrane area of absorptive site :
* Stomach abs. of weakly acidic drug * Intestine optimum absorption
b. pH of GIT fluid : * Various pH of GIT fluid
# pH fraction of un/dissociated drug if the fraction of undiss. Absorption
* With meal pH , and will be slowly c. Gastric emptying time :
* Optimal absorption is in small intestine The rate of gastric emptying time influences
drug absorption * Acid/enzyme-labile drugdegradation Intact drug
d. Intestinal transit : * Longer the period time in small intestine absorption
bioavailability
* Motility contact availability
e. Degradation and metabolism in GIT / Gut wall metabolism- Susceptible to Acid/enzymatic degradation bioavailability
ex.: Pro-drug ; Clindamycin palmitate degraded
become Clindamycin bioavailability
f. Hepatic metabolism ; First pass effect bioavailability
Transport mechanism of drug across GI membrane
Water Water
Protein
Lipid
Membrane is phospholipid bilayer : • Protein – lipid lipoidal layer permeable to hydrophobic molecule• Pore 0,4 nm molecule size < 0,4 nm pore
molecule size >>>> passive diffusion
GIT Fluid GIT membrane Blood
Drug in solution Drug bring into systemic circulations
Partition Diffusion Partition
Drug absorption • Generally passive diffusion• Active transport ; Levodopa, Thiamin etc.• Ion paring ; Tetracycline
II. Pharmaceutical Variable
A. Physicochemical properties of drug
B. Manufacturing technique of drug
C. Drug dosage form
A. Physicochemical properties of drug :
* Particle size : Smaller greater surface area dissolution rate
* Solubility of drug : too hydrophilic
too lypophylic* Solvate formation ; hydrated, unhydrate form Ex.: Amoxcicillin unhydrate is easily dissolved in
water* Polymorphism ; amorphous, crystalline Crystalline form is easily dissolved in water* Complexation ; - excipient in dosage form
- natural component in GIT
* Salt form
* Wettability
Absorption
B. Manufacturing process : 1. The composition of the dosage form
For ex.: other material in formulation (adjuvant) - Lubricating agents;
* hydrophilic* hydrophobic agents diss.rate
- Disintegrating agents diss.rate
2. Manufacturing techniqueCompression force
C. Dosage form1. Solution :
- Disperse system- Absorption (rate and/or extend) fastest and complete- OOA rapid
2. Suspension / Emulsion* Aqueous solubility Require the dissolution of drug* Absorption < solution* OOA < solution
3. Powder- Dissolution process
- Particle size, solubility etc - Possibility absorption of drug onto inert material
- Absorption < solution
4. Capsule:
- Capsule shell- Hard gelatin caps. dissolve readily than soft capsule - Require dissolution process
- Particle size, solubility, absorpt. Onto inert material- Absorption < powder
5. Tablet :- The rate of absorption < powder disintegration, deaggregation and dissolution process
6. Coated tablet :- Sugar coated more easily soluble than film coated- Factor influencing rate of absorption = factor in tablet- Enteric coated tablet disintegrates in intestine alkaline media - Sublingual tablet placed under the tongue and will readily
absorbed by mucose membrane
7. Suppositories :- Vaginal Supp. : local effect- Rectal supp. : - local
- systemic
The dissolution rate of drugs (that resists to gastric acid ) is decline according to following sequence : Solution – suspension – powder – capsule – tablet – sugar coated – film coated – enteric coated – prolong action (sustained released tablet)
III. ROUTE OF ADMINISTRATION :
1. Oral : With or without first pass effect With a first-pass effect:
1. Metabolism in GI fluid and membrane : Various pH solution, enzymes, mucous etc.
2. Hepatic metabolism3. Excreted into the bile
drug plasma level Bioavailability
Without a first-pass effect : drug plasma level drug absorbed
2. Rectal :- first-pass effect partially avoided- local effect- absorption unpredictable
3. Parenteral1. Intravenous :
- No absorption process- Complete drug availability- Bioavailability 100%
2. Intramuscular- Drug from aqueous sol.absorbed > suspension- OOA will vary- Absorption into blood site of injection
4. Topical : Local effect5. Inhalation :
- Very large surface for absorption- Alveolar and vascular epithelial membrane are quite permeable rapidly absorption- Gaseous or volatile substances
RODA Bioavailability (%)
OralRectalParenteral I.V. I.M. S.C.TopicalInhalationTransdermal
5 to < 10030 to < 100
10075 to < 10075 to < 100-5 to < 10080 to < 100
time
Blood concentration
V
IVIIIII
I
TheophyllinI. Intravenous 0.5 grII. Rectum (enema) 0.5 grIII. Oral 0.5 grIV. Oral 0.3 grV. Rectal suppositoria 0.5 gr
IV. Time of administration :
Food can modify drug absorption through :
- Altering gastric emptying time
- Altering GIT secretion
- Competition on drug absorption
- Drug complexation
- GIT content viscosity
How to calculate Bioavailability of drug :
Comparing :
Drug blood concentration or
urinary drug excretion
From Any dosage form
With Intravenously administration
Bioavailaability is expressed on scala 1 – 100 %
Parameter determining Bioavailability :
- Area Under Curve ( AUC )
- Height of Peak ( b max )
- Time of Peak ( t max )
AUC = The amount of drug absorbed following administration at single dose of
drugb.max = Height of peak : the highest drug achieved after administrationt.max= Time of peak : the length of time necessary to achieved the highest drug blood concentration after administration