Biopharmaceutics & Pharmacokinetics-4

Journey of Oral Drugs through GIT Large Intestine Small Intestine Stomach Mouth Drug travels through different region in GI tract Tract is almost 4.5 m long Each region is different in anatomy, pH, function All these factors affect the drug absorption DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

Mouth Small surface area for drug absorption Typical pH = 6.8 Directly absorbed in to blood circulation Drugs absorbed: Neutral Slightly basic lipophilic DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

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 DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

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 DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

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 DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

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 DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

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 Typical gastric time: 1-2 hours Pyrolic sphincter, opens up, only allows well emulsified food (<2 mm), intestine food control, contracts to have food pushed inside Dissolution/absorption, gastric emptying promoted on empty stomach, so lots of oral studies require empty stomach

Factors affecting “Gastric Emptying” Volume of Meal Larger meal , longer emptying time Composition of Meal Carbohydrates > Proteins > Fats Physical state/Viscosity of Meal Liquids > Solids Temperature of Meal High or low temp of food slows gastric emptying Gastrointestinal pH Slow at low pH, higher at alkaline

Factor affecting “Gastric Emptying” Electrolytes & Osmotic pressure Isotonic, water show rapid while high electrolyte conc slows gastric emptying Body posture Standing, lying on right side promotes Emotional state Stress/anxiety promotes gastric motility while depression slows movement DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

Factor affecting “Gastric Emptying” Exercise Vigorous training slows gastric emptying Disease state Gasteroenteritis, gastric ulcer, pyloric stenosis, diabetes - slows gastric emptying Partial/total gastrectomy, duodenal ulcer, hyperthyroidism - promotes gastric emptying DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

Factors affecting “Gastric Emptying” Drugs That promote gastric movement: Metoclopramide, domperidone, cisapride That inhibit gastric movement: Antacids, anti-cholinergics, narcotic analgesics, tricyclic antidepressants DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

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 DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

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 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 Peristaltic movement promotes solbilization in intestine

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 DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

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 DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

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 Celiac disease is a condition that damages the lining of the small intestine and prevents it from absorbing parts of food that are important for staying healthy Crohn's disease is a form of inflammatory bowel disease (IBD). It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus)

Disease state affecting drug absorption Cardiovascular diseases Cardiac failure affects bioavailability by 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 Propranolol undergoes high 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) DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

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 DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

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 DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

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 DCT: only 10 % reabsorbed, impermeable to water, leads to further dilution of filtrate

THANK YOU -PHARMA STREET