Pharmacokinetic Absorption PDF

Pharmacokinetic Absorption PharmDr. Davoud Ahmadimoghaddam, Ph.D. Department of Pharmacology & Toxicology School of Pharmacy, Hamadan University of Medical Sciences  Definition Absorption: entry of drug from site of...

Pharmacokinetic Absorption PharmDr. Davoud Ahmadimoghaddam, Ph.D. Department of Pharmacology & Toxicology School of Pharmacy, Hamadan University of Medical Sciences  Definition Absorption: entry of drug from site of administration into plasma. Pharmacokinetics Pharmacodynamics Biological membrane Extravascular administration absorption (first -pass) Plasma Tissue distribution i.v. administration bound fraction Pharmacological effect free fraction elimination Therapeutical effect  Factors influencing absorption Drug dosage form (tablets, injection solutions, with prolonged release etc). Physicochemical properties (lipid solubility, pKa). Physiological and/or pathological parameters of administration site (area size, blood perfusion, local pH, GIT motility).  Bioavailability  The fraction of unchanged drug reaching the systemic circulation following administration by any route.  The area under the blood concentration-time curve (AUC) is proportional to the dose and the extent of bioavailability for a drug if its elimination is first-order.  For an intravenous dose, bioavailability is assumed to be equal to unity.  For a drug administered orally, bioavailability may be less than 100% for two main reasons  incomplete extent of absorption across the gut wall and first-pass elimination by the liver Bioavailability Expresses as a ratio between AUC after extravascular and AUC after intravenous administration. parameter saying how much of administered drug got absorbed into systemic circulation. F (fraction absorbed) 0 < F liver metabolism can decrease the amount of unchanged drug that reaches blood. http://www.icp.org.nz/icp_t6.html  Bioavailability; Rate of Absorption The rate of absorption is determined by the site of administration the drug formulation Blood concentration-time curves, illustrating how changes in the rate of absorption and extent of bioavailability can influence both:  the duration of action &  the effectiveness of the same total dose of a drug administered in three different formulations. The dashed line indicates the target concentration (TC) of the drug in the blood. Dosage form B → 2X dosage form A to attain blood concentrations equivalent.  Bioavailability; Rate of Absorption Differences in rate of absorption → important for drugs given as a single dose  Eg., hypnotic ►induce sleep  dosage form A would reach its target concentration earlier than drug from dosage form C  concentrations from A would also reach a higher level and remain above the target concentration for a longer period.  In a multiple dosing regimen, dosage forms A and C would yield the same average blood level concentrations, although dosage form A would show somewhat greater maximum and lower minimum concentrations.  Bioavailability; Rate of Absorption The mechanism of drug absorption is said to be zero-order when the rate is independent of the amount of drug remaining in the gut, (constant)  eg, when it is determined by the rate of gastric emptying or by a controlled-release drug formulation. In contrast, when the dose is dissolved in gastrointestinal fluids, the rate of absorption is usually proportional to the gastrointestinal concentration and is said to be first- order.  Drug administration Enteral – drug is administered to alimentary tract. Parenteral – drug is administered through other organs than GIT. Alternative Routes of Administration & the First-Pass Effect for convenience (eg, oral) to maximize concentration at the site of action and minimize it elsewhere (eg, topical) to prolong the duration of drug absorption (eg, transdermal) to avoid the first-pass effect (sublingual or rectal & lesser extent rectal suppositories 50%)  direct access to systemic—not portal—veins Although drugs administered by inhalation bypass the hepatic first-pass effect,  the lung may also serve as a site of first-pass loss by excretion  possibly metabolism for drugs administered by nongastrointestinal (“parenteral”) routes.  1) Absorption from oral cavity  absorbed directly to systemic circulation (no first-pass effect)  oral mucosa is highly vascularized  epithelial lining is quite thin  rapid onset of action  drug must stay in contact with the oral mucosa for a sufficient length of time (placed under tongue)  easy interruption of administration (spit/swallow)  nitroglycerin, apomorphine, glucose.  2) Absorption from the stomach  rich blood supply  pH = 1.0 – 2.0 affects the degree of drug ionization  absorption is limited by small area (about 2 m2)  the gastric absorption will vary from patient to patient  ion-trapping - even for i.v. administered basic drugs (morphine)  3) Absorption from the small intestine - large surface area (200m2) - high blood perfusion »» Accordingly, the rate of absorption of a drug from the intestine will be greater than that from the stomach even if the drug is predominantly ionized in the intestine and largely non-ionized in the stomach.  3) Absorption from the small intestine  greater absorption capacity than stomach (even for acidic molecules)  most drugs are absorbed in proximal jejunum  predominant process is diffusion (facilitated diffusion, active transport, endocytosis, filtration may also occur)  Absorption is decreased by: first-pass effect metabolism in the wall of small intestine efflux transporters http://www.icp.org.nz/icp_t6.html  4) Absorption from the large intestine smaller absorptive surface area lower absorption area slower motility solid nature of the intestinal contents impedes diffusion of drugs from the contents to the mucosa absorption site especially for compounds that have not been completely absorbed from the small intestine or for special drug delivery forms.  5) Absorption from the rectum not large absorptive area but extensive vascularity local and systemic administration drugs escape the first-pass effect and enzymes of the stomach and intestine absorption is rather variable site of administration: - when drug may cause gastric irritation - after gastrointestinal surgery - during protracted vomiting - in uncooperative or unconscious patients - inducing anesthesia in children Factors influencing drug absorption from the GIT 1)Gastric Emptying Time 2)Intestinal Motility 3)Food 4)Formulation Factors 5)Presystemic elimination 6)Drug interactions  1) Gastric Emptying Time Bcz of large surface (∼200 m2) the rate of absorption of a drug from the intestine will be greater than that from the stomach even if the drug is predominantly ionized in the intestine and largely non-ionized in the stomach. Thus, factor that accelerates gastric emptying will increase the rate of drug absorption whereas factor that delays gastric emptying is expected to have the opposite effect. Increased GET Decreased GET Physiological liquids, gastric distention solids, acids, fat duodenal ulcers, acute abdomen trauma and pain, labor of childbirth, gastric Pathological chronic pancreatitis, juices, intestinal obstruction, pneumonia, diabetes mellitus gastroenterostomy reserpine, guanethidine, anticholinergic drugs, Pharmacological anticholinesterases, ganglionic blocking drugs, cholinergic agents narcotic analgesics  2) Intestinal Motility ↓Decreased motility  ↑ absorption of poorly soluble drugs  ↓ absorption of drugs metabolized in the small intestine ↑ Increased motility  ↑ contact with mucosa > ↑absorption  diarrhea > ↓ absorption of drugs  3) Food Absorption of most drugs from the GIT is reduced or delayed by the presence of food in the gut. Highly ionized drugs (decamethonium, tetracyclines) can complex with Ca2+ ions in membranes, food or milk » leading to a reduced absorption. Increased splanchnic blood flow during eating » increase the rate of drug absorption Food can change the pH of the stomach from 1.5 to more than 3. Competition for active transport (levodopa).  4) Formulation factors Drugs administered in aqueous solution are absorbed faster and more completely than are tablet or suspension forms. The ability of solid dosage form to dissolve, as well as the solubility characteristics of the individual drug in the highly acidic gastric juice must be considered (acido-labile drugs-PNC).  5) Presystemic elimination Acid hydrolysis (acid gastric juice, gastric enzymes - PncG, erythromycin, oxytocin) P-glycoprotein (Cyclosporine) Metabolism in the gut wall (morphine) Liver metabolism (first pass effect (P450), nitroglycerin)  6) Drug interactions TTC + polyvalent ions of metal (antacids, food) → chelate complexes cholestyramine (resin) + acidic drugs → sequestration of ionized drugs (warfarin, penicillin G, propranolol) Inhibition of efflux transporters > increased absorption of substrate (cyclosporine)  Parenteral drug administration 1) Inhalation: absorption of drugs from the lung 2) Transdermal: absorption of drugs through the skin 3) Injections  1) Absorption of drugs from the lungs Drugs given for both local and systemic effects Drugs are inhaled as gases (volatile anesthetics) as aerosols (liquid droplets, solid particles e.g. antiasthmatics) Absorption is facilitated by: - large surface area of the pulmonary alveolar membrane (50-100 m2) - limited thickness of these membranes (ca. 0.2 μ) - high blood flow to the alveolar region  1) Absorption of drugs from the lungs  Very rapid onset of action (as after i.v.)  Many drugs are absorbed by diffusion. The driving force: combination of the blood-air partition coefficient and the difference in partial pressures. Solid particles in aerosol may be removed from the lung by: - direct absorption into the blood - endocytosis - by absorption through the lymphatic system  The fate of drug in the lung depends on the size of the particles.  2) Absorption of Drugs Through The Skin Mostly for their local effect (creams or ointments). The barrier against the rapid penetration is formed by the stratum corneum, or outer layer of the epidermis. This is due to the close-packed cellular arrangement, decreased amount of lipid in these cells.  2) Absorption of Drugs Through The Skin Even highly lipid soluble compounds will be absorbed much more slowly than from other sites. If penetration does occur, it is probably accomplished by diffusion through the hair follicles, sweat glands, or sebaceous glands. Accidental absorption of toxic drugs through the skin may produce harmful systemic effects, examples: organic phosphates (parathion) insecticides (DDT, chlordane). In clinical practice: transdermal systems for administration of nicotine, nitroglycerin, scopolamine or estrogens.  3) Intramuscular and Subcutaneous Administration  Most common means of parenteral drug administration. The absorption after i.m. injection is more rapid than after s.c. because of: - the high tissue blood flow - the ability of injected solution to diffuse laterally Drug absorption after i.m. or s.c. administration depends on: - the quantity and composition of connective tissue - the capillary density - the rate of vascular perfusion of the area  3) Intramuscular and Subcutaneous Administration Can be modified by: - co-injection of agents that alter local blood flow (e.g., vasoconstrictors) - by substances that decrease tissue resistance to lateral diffusion (e.g. hyaluronidase) - by massaging Absorption can be delayed to prolong systemic drugs effects. This is accomplished by slowly dissolving forms of the drug:  i.m. injection of aqueous drug suspensions  s.c. implantation of compressed pellets  injection of drug in oil (A single i.m. injection of an aqueous suspension of medroxyprogesteron acetate - a hormonal cytostatics PROVERA - in humans elicit progestational effects for 30 days or more) 3) Intramuscular and Subcutaneous Administration Advantages: 1. increased reliability and precision in the drug blood level 2. rapid absorption and onset of drug action 3. ability to give large volumes of solution Disadvantages: - pain (rich sensory innervation of the skin) - Tenderness - local tissue necrosis (with highly alkaline injections) - microbial contaminations - nerve damage  i.v. injections No absorption! For compounds that: have narrow therapeutic index are poorly or erratically absorbed are extremely irritating to tissues are rapidly metabolized  Used in emergency situations. Disadvantages:  the drug can neither be removed nor its absorption retarded  embolism  introduction of bacteria or virus (HIV) Thank You For Your Attention