Download 2.1 absorption

Biopharmaceutics &
Pharmacokinetics-4
Journey of Oral Drugs through GIT
• Drug travels through different region in GI
tract
Mouth
Stomach
Small
Intestine
Large
Intestine
• Tract is almost 4.5 m long
• Each region is different in anatomy, pH,
function
• All these factors affect the drug absorption
Mouth
• Small surface area for drug absorption
• Typical pH = 6.8
• Directly absorbed in to blood circulation
• Drugs absorbed:
• Neutral
• Slightly basic
• lipophilic
Stomach
• Bag like structure, smooth surface
• Typical pH = 1.5- 3 (HCL secretion)
• Acidic drugs:
• Un-ionized so can be absorbed if it dissolves
• Basic drugs:
• Acidic environment helps in dissolution as the
drugs are ionized
• Ionised drug however limits absorption
Why is Stomach NOT a major site for
absorption ??
• Area: Total surface area for absorption is
small
• Nature of Epithelium: Most of the cells
are secretion cells (mucus secreting) & not
absorption
• Gastric Residence Time: Drug stays in
stomach for limited time affecting
absorption
Small Intestine
• Major site of absorption for most of drugs
• Very large surface area
• Folds – Villi – Micro-villi lead to almost
600 times increase in surface area
Why is Small Intestine a major site for drug
absorption
• Large Surface area: Structural arrangement of folds, villi & microvilli
increase the surface area X 600 times
• Long Length: long length results in increased total area compared to
stomach
• Greater Blood flow: almost 6 – 10 times greater than stomach
• Favorable pH: Range is 5 – 7.5, most drugs Un-ionized in this range,
increased absorption
• Slow peristaltic movement & high permeability
Large Intestine
• Length, surface area (No Villi) very small
compared to small intestine
• pH : neutral or slightly alkaline
• Long residence time (6-12 hr) might help in
absorption of poorly soluble
drugs/sustained release
• Major role in absorption of
water/electrolytes
Physiological Factors affecting Drug
Absorption
• Gastric Emptying:
• Passage of drugs from Stomach to Small Intestine
• This movement can be rate limiting as major absorption of drugs
in small intestine
• Different parameters to measure gastric emptying:
• Gastric empting rate
• Gastric emptying time
• Gastric emptying half life
Factors affecting “Gastric Emptying”
1. Volume of Meal
Larger meal , longer emptying time
2. Composition of Meal
Carbohydrates > Proteins > Fats
3. Physical state/Viscosity of Meal
Liquids > Solids
4. Temperature of Meal
High or low temp of food slows gastric emptying
5. Gastrointestinal pH
Slow at low pH, higher at alkaline
Factor affecting “Gastric Emptying”
1. Electrolytes & Osmotic pressure
Isotonic, water show rapid while high electrolyte conc slows gastric emptying
2. Body posture
Standing, lying on right side promotes
3. Emotional state
Stress/anxiety promotes gastric motility while depression slows movement
Factor affecting “Gastric Emptying”
1. Exercise
Vigorous training slows gastric emptying
2. Disease state
Gasteroenteritis, gastric ulcer, pyloric stenosis, diabetes - slows
gastric emptying
Partial/total gastrectomy, duodenal ulcer, hyperthyroidism promotes gastric emptying
Factors affecting “Gastric Emptying”
Drugs
That promote gastric movement: Metoclopramide, domperidone,
cisapride
That inhibit gastric movement: Antacids, anti-cholinergics, narcotic
analgesics, tricyclic antidepressants
Gastric emptying
Rapid emptying advised where
• Rapid onset desired
• Dissolution in intestine (enteric)
• Drugs unstable in stomach
• Drugs best absorbed from distal
small intestine
Delay in gastric emptying advised where
• Food promotes dissolution/absorption
• Disintegration/dissolution promoted
by gastric fluids
• Drugs that dissolve slowly
Time in Intestine (Intestinal Transit)
• Since most absorption in small intestine, longer stay promotes
absorption of drugs
• Peristaltic movement promotes absorption by better membrane
contact, agitation (promotes dissolution)
• Longer stay is preferred for drugs
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Dissolve slowly, release slowly
Dissolve only in intestine
Absorbed from specific sites
Absorption through mucosa is slow
Absorption from colon is minimal
Intestinal
Region
Typical transit
time
Duodenum
5 min
Jejunum
2 hrs
Ileum
3 – 6 hrs
Caecum
0.5 – 1 hrs
Colon
6 – 12 hrs
Gastrointestinal pH
• Wide range on pH, affect absorption through various
effects
• Disintegration
• Enteric coated formulations
• Dissolution
• pH affects dissolution of drugs
• pH affects solubility of weak base/acids
Gastrointestinal pH
• Wide range on pH, affect absorption through various
effects
• Absorption
• Drug pka, surrounding pH determine ionic state of drug
• Non-ionized drug primarily absorbed
• Stability
• Acidic environment can affect stability of drugs
• Ex penicillin, Erythromycin are enteric coated formulations
Disease state affecting drug absorption
• GI diseases & infections
• Celiac disease leads to malabsorption due to
• Increased gastric emptying rate
• Altered intestinal metabolism, permeability
• Impaired secretion of bile
• Crohns disease leads to malabsorption due to
• Altered intestinal metabolism
• Decreased gut surface area
• Decreased intestinal transit time
• Gastric surgeries
Disease state affecting drug absorption
• Cardiovascular diseases
• Cardiac failure affects bioavailability by
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Oedema of intestine
Altering pH
Affecting peristaltic movement
Gastric emptying
Altering blood flow
• Hepatic diseases
• Conditions of hepatic failure (cirrhosis) affects drug bioavailability
• Reduces overall first-pass effect
Shariq
AIKC/FinalYB/2014
Blood flow to GIT
• GIT track extensively perfused by blood/lymphatic system
• Almost 28 % of cardiac output to GIT (Splanchnic circulation)
• High perfusion rate ensures “sink conditions’
• External conditions affect blood flow (drugs, food)
Gastrointestinal Contents
• Food-drug interactions:
• Food can affect absorption
• Can increase OR decrease absorption
• In general drugs absorbed better under fasting conditions
• Delay/Decrease in absorption
• Delay in gastric emptying
• Formation of poorly soluble
complex
• Increased viscosity
• Increase in absorption
• Increased time for dissolution
• Enhanced solubility (bile
secretion)
• Prolonged residence time
Gastrointestinal Contents
• Fluid Volume:
• Large volume facilitates dissolution, absorption
• Drug-Drug interactions:
• Can be either physico-chemical or physiological
• Physico-chemical:
• Adsorption
• Complexation
• pH change
Gastrointestinal Contents
• Drug-Drug interactions:
• Physiological:
• Decreased GI transit : Drugs slow GI movement & promote absorption
• Increased gastric emptying: prokinetic drugs promote emptying improving
absorption
• Altered GI metabolism: Antibiotics affect GI microbial flora affecting
overall bioavailability of drugs
THANK YOU
-PHARMA STREET