aASAS

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Factors Affecting Rate and Extent of Absorption
of A Drug

• Dr. Hidayat H. Khan

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Absorption

• Passage of Drugs from site of Administration to
  the Systemic Circulation
• One of the Pharmacokinetic Processes

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Rate of drug absorption- passage of the drug from
its site of
administration into the circulation
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Factors Affecting Rate and Extent of Absorption

• Drug Related Factors
• Physicochemical Properties of the Drug
• Patient Related Factors

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Drug Related Factors

• Lipid Solubility
• Degree of Ionization
• Concentration of Drug
• Physical State
• Molecular Size

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• Dosage Form
• Particle Size
• Disintegration Time (Rate of breakup)
• Dissolution Rate (Rate at which it goes into
  solution
• Formulation

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Patient Based Factors

• Route of Administration
• pH of the Absorbing Surface
• Surface Area of Absorption
• Thickness of Diffusing Path
• Vascularity of Absorbing Surface

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Absorption from GIT

• Presence of Food
• Presence of Other Drugs
• GIT Motility
• Metabolism
• GIT Disease
• P-Glycoproteins

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Lipid Solubility or Lipid Aqueous Partition
Coefficient

• Measure of how readily a drug enters the lipid
  medium from an aqueous medium.
• Flux (C1-C2) x
• Area x Permeability Co-efficient
• Thickness

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Degree of Ionization

• The extent to which a drug becomes ionized
  depends on the pH of the Medium and the pKa of
  the drug
• Acidic drugs remain mostly unionized in the
  acidic medium (stomach)

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• Basic drugs remain mostly unionized in the
  alkaline medium (intestine)
• Some drugs remain highly ionized
• a) Negatively charged Heparin
• b) Positively charged Tubocurarine
  Suxamethonium

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• Some drugs do not ionize remain in unionized
  form-for example digoxin and chloramphenicol

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Effect of pH on the absorption of weak acids and
weak bases -many drugs are weak acids or weak
bases
HA H A- for weak acids
the protonated form is
nonionized HB H B
for weak bases the
unprotonated form is nonionized i.e.
the red form goes across biomembranes
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• Thus
• HA and B are unionized
• HB and A- are ionized

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Dissociation Constant and pKa

• The Ka is the dissociation constant and pKa is
  the negative logarithm of the dissociation
  constant of the weak electrolyte.

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• pKa is a measure of the strength of interaction
  of a compound with a proton
• The less the interaction the lower the pKa
• Since acids have tendency to donate proton and
  thus have less interaction, they have lower pKa
• Thus lower the pKa the stronger the acid

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Henderson Hasselbalch Equation

• pH pKa log unprotonated
• Protonated
• For Acid
• pH pKa log A- (Ionized)
• HA (Non-ionized)
• For Base
• pH pKa log B (Non-ionized)
• BH (Ionized)

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Example

• If pH pKa
• pH pKa log ionized
• un- ionized
• pH pKa log ionized
• un- ionized
• thus 0 log ionized
• un- ionized

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• Log ( ?) 0
• Log (1) 0
• Thus Ionized 1
• Unionized
• Thus 50 of drug is ionized and 50 is unionized

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• Thus pKa is numerically equal to the pH at which
  the drug is 50 ionized AND 50 unionized
• If an acidic drug of pKa 3.5 (aspirin) is put in
  the medium of pH 3.5, 50 of the drug would be in
  the ionized form.

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• If the pH is increased by 1 unit then,
• 4.5 3.5 log A-
• HA
• OR 4.5-3.5 log A-/HA
• OR log A- 1
• HA
• OR A- 10
• HA

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• If the pH is decreased by 1 unit then,
• 2.5 3.5 log A-/HA
• OR 2.5-3.5 log A-
• HA
• OR log A- -1
• HA
• OR A- 1/10
• HA

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• It means that 1 unit change in pH causes a 10
  fold change in ionization
• If an acidic drug such as Aspirin is put in a
  medium of 2.5 , then 90 of the drug will be in
  the protonated or unionized form

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• From the Henderson Hasselbalch equation
• When pH is less than pKa,
• the Protonated forms HA (unionized form) and BH
  (ionized form) dominate
• And when pH is greater than pKa, deprotonated
  forms A- (ionized) and B (un-ionized) dominate

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• We can also conclude that an acidic drug will be
  MORE unionized in an ACIDIC medium and thus
  better absorbed
• And basic drug will be ionized in an acidic
  medium and will be less absorbed
• Because When pH is less than pKa, the
  Protonated forms HA (unionized form) and HB
  (ionized) dominate

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Ion Trapping

• The unionized form of acidic drugs that cross the
  surface membrane of gastric mucosal cell reverts
  to ionized form within the cell (pH 7) and thus
  slowly passes on to the ECF
• Thus it become trapped in the cell.
• A weak electrolyte crossing a membrane to
  encounter a pH from which it cannot escape
  easily
• Other sites Breast milk, aqueous humor,
  prostatic and vaginal secretions

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Application

• Acidic drugs are ionized more in alkaline urine,
• Therefore do not diffuse back into the kidney
  tubules and are excreted faster
• So if some person has taken excess acidic drug,
  we can make the urine alkaline to INCREASE the
  excretion of the acid

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Other Drug Related Factors

• Physical State
• Concentration of Drug
• Molecular Size
• Dosage Form
• Particle Size
• Disintegration Time (Rate of breakup)
• Dissolution Rate (Rate at which it goes in
  sol.)
• Formulation- Use of diluents

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Patient Based Factors

• Route of Administration
• pH of the Absorbing Surface
• Surface Area of Absorption
• Thickness of Diffusing Path
• Vascularity of Absorbing Surface

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Question

• Aspirin is weak organic acid with a pKa of 3.5.
  What of a given dose will be in the lipid
  soluble form at a stomach pH of 2.5?
• About 1
• About 10
• About 50
• About 90

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Question

• For Which of the following drugs will excretion
  be most significantly accelerated by
  acidification of the urine? Suppose Urine pH can
  be modified over range 5.5-7.5
• A) Weak acid with pKa of 5.5
• B) Weak acid with pKa of 3.5
• C) Weak base with pKa of 7.5
• D) Weak base with pKa of 6.5

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Absorption from GIT

• Presence of Food
• GIT Motility
• Presence of Other Drugs
• Metabolism
• GIT Disease
• P-Glycoproteins

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Presence of Food

• Generally most drugs are absorbed better on an
  empty stomach
• Presence of food dilutes the drug and retards
  absorption
• Food delays gastric emptying
• Certain drugs form poorly absorbed complexes with
  food constituents e.g. tetracyclines with calcium
  in milk

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GIT Motility (GIT Transit time)

• Increased GIT motility as seen in diarrhea and by
  certain drugs decreases GIT transit time and thus
  decreases absorption
• Delayed gastric emptying decreases absorption and
  vice versa

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Presence of Other Drugs

• Formation of insoluble complexes e.g.
  Tetracyclines with Iron preparations and
  antacids,
• Vitamin C and iron
• Some drugs may alter GIT motility
• Some drugs may cause mucosal damage
• Alteration of gut flora by antibiotics may
  disrupt the enterohepatic recycling of oral
  contraceptives and digoxin

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Enterohepatic Recycling

• A number of drugs form conjugates with glucoronic
  acid in the liver and are excreted in the bile
• These glucoronides are too polar (ionised) to be
  reabsorbed
• They remain in the GIT where they are hydrolysed
  by enzymes and GIT bacteria to release the parent
  drug which is then reabsorbed

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Entrohepatic cycling-
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Metabolism/Destruction

• Rapid degradation (metabolism) of the drug in the
  GIT decreases absorption
• Penicillin G is destroyed by acid
• Insulin by peptidases and thus ineffective orally
• Enteric coating of some drugs can prevent this

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GIT disease

• Malabsorption Tropical sprue, Ulcerative
  Colitis
• Diarrhea
• Obstruction in GIT tract including Intestinal
  Obstruction

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P Glycoproteins

• P-glycoproteins are type of special carriers
  present in the membrane of many cells. They are
  less selective and are specialized for expelling
  foreign molecules,
• P-glycoprotein modulates the intestinal drug
  transport and functions to expel drugs from the
  intestinal mucosa into the lumen.

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Methods To Delay Absorption

• Decreasing Blood Flow Addition of Adrenaline to
  a local anaesthetic
• Use of relatively insoluble slow release form
  e.g. procaine penicillin
• Subcutaneous Implants
• absorption prop. to surface area of
  implant e.g. steroids estrogens

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Importance of Study

• Bioavailability
• Frequency of Administration
• Clinical Efficacy
• Toxicity
• Drug Interactions