Pharmacokinetics Lecture Notes PDF

1. Pharmacokinetics Dr. Esraa M Elnahas Lecturer of Clinical Pharmacology Faculty of Medicine Ain Shams University  Intended Learning Outcomes (ILOs): 1. Define drug absorption & factors affecting it 2. Relation between pH of the surrounding medium and drug pKa 3. Ho...

1. Pharmacokinetics Dr. Esraa M Elnahas Lecturer of Clinical Pharmacology Faculty of Medicine Ain Shams University  Intended Learning Outcomes (ILOs): 1. Define drug absorption & factors affecting it 2. Relation between pH of the surrounding medium and drug pKa 3. How changes in pH can affect Ionization/non-ionization of drug and its clinical significance 4. Hepatic 1st pass metabolism and factors affecting it 5. Bioavailability  Pharmacology Pharmakon  (meaning ‘drug’) logia  (meaning ’knowledge of’) Pharmacokinetics Pharmacodynamics  Pharmacokinetics What the body does to the drug ? Pharmacodynamics What the drug does to the body ?  Pharmacokinetics -Effect of body on the drug. -It includes (ADME) : Absorption Distribution Metabolism Excretion 1. Absorption  1. Absorption The transport of a drug from site of administration (Drug crosses cell membranes) to the systemic circulation.  Site of administration Ingestion (GIT) Inhalation (Lungs) Dermal (Skin) Systemic circulation  Factors affecting drug absorption from GIT 1. Dosage form, Molecular weight & solubility can affect drug dissolution. 2. Stability in Gut: GIT secretions; food& other co-administered drugs. 4. Gut pH & drug's pKa affect ionization & absorption of drug (Lipid Solubility). 5. Absorptive system: gastric emptying, surface area, GIT disease, Blood flow to absorption area.  Different dosage forms have different pharmaceutical properties. ❖Drug absorption of various preparations 1. Liquids (Fastest) 3. Tablets 4. Enteric-coated tablets (Slowest) 2. Powders ❑ Lipid Diffusion It is the most important means by which drugs enter the body and are distributed within it. It is dependent on Drug being lipid-soluble (lipophilic) i.e. exists mainly in the non-ionized form.  Drug being lipid-soluble (lipophilic) i.e. exists mainly in the non-ionized form ➔ Absorbed ✓ ± ± ± Drug being Water-soluble (Hydrophilic) are Ionized ± ± form i.e.: Non-diffusible ➔ not Absorbed  Ionization of the drug depends on the relation between pH of the surrounding medium and drug pka  Gut pH & drug's pKa pH: how acidic or basic a substance or solution is  pKa “The acid-base dissociation constant” The pKa of a drug is the pH of the medium at which: 50% of the drug is ionized and 50% is Non-ionized (When the pH of the medium = pKa of the drug). ± ± ± = ± Most drugs are either weak acids or weak bases  A real live, actual clinical question... Aspirin is an acidic drug. In the stomach will it exist mostly in ionized or non-ionized form? NON-IONIZED  Ionization of weak acids decreases at pH < pKa Acidic Drug e.g. Aspirin pKa= 3.5 put into gastric pH = 2 Acidic pH of stomach pH 2 Pka 3.5 0 7 ± ± >50% ± pKa Basic Drug e.g. Theophylline pKa= 8.8 put into intestinal pH = 10 Alkaline pH Pka 8.8 pH 10 of Intestine 7 14 ± ± ± 50% Ionized Non-Ionized  Moral of the story... Acidic drugs are best absorbed from acidic environments To  absorption of an acidic drug… acidify the environment To  absorption of an acidic drug… alkalanize the environment... Basic drugs are best absorbed from basic environments Interactions at Site of Excretion (Clinical Significance of pKa) Acidic drug Acidic pH Non-Ionized ✓✓ Basic drug Alkaline pH Non-Ionized Absorption Acidic drug Alkaline pH Ionized  Absorption Basic drug Acidic pH Ionized 2. Kidney Drug poisoning (useful in treatment of toxicity) ❑ Alkalization of urine used in Acidic drug poisoning → ↑ ionization of acidic drugs (aspirin) →↓tubular reabsorption → ↑ renal excretion. ❑ Acidification of urine used in Basic drug poisoning → ↑ ionization of basic drugs (amphetamines) →↓tubular reabsorption → ↑ renal excretion.  1st pass metabolism “Presystemic Elimination” ▪ Mostly occurs with orally administered drugs. ▪ Part of the drug metabolized in the liver, gut wall or the lungs before reaching systemic circulation  Hepatic 1st pass metabolism ▪ After oral administration, Drugs are first absorbed into portal circulation to the liver before reaching systemic circulation. Bioavailability Some drugs are extensively metabolized in their first-pass e.g. nitroglycerin & propranolol.  Bioavailability It is the percentage % of drug that reaches the systemic circulation unchanged and becomes available for biological effect.  Bioavailability Factors Affecting Bioavailability I. Factors affecting GI absorption (pH & pKa). II. Factors affecting First-pass metabolism.  Factors affecting 1st pass metabolism 1.Route of administration: can be avoided in Parenteral route (completely) Sublingual route (completely) Rectal route (to a lesser extent): Upper 2/3 Portal, Lower 1/3 Systemic.  Factors ↓Hepatic 1st pass metabolism -↓portal blood flow: portal hypertension, propranolol (βB). -↓hepatic metabolism: liver failure - enzyme inhibitors e.g. erythromycin. Thank you