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GENERAL PHARMACOLOGY LEC 1 ‫ أسماء نجم‬.‫د‬ OBJECTIVES - Define pharmacokinetics - list routes of adminstration - What is mechanism of absorption? - Enumerate factors affecting absorption - What is bioavailability? - What is half life? Pharmacokinetics denotes the effects of biologic syste...

GENERAL PHARMACOLOGY LEC 1 ‫ أسماء نجم‬.‫د‬ OBJECTIVES - Define pharmacokinetics - list routes of adminstration - What is mechanism of absorption? - Enumerate factors affecting absorption - What is bioavailability? - What is half life? Pharmacokinetics denotes the effects of biologic systems on drugs. The major processes involved in pharmacokinetics are absorption, distribution, metabolism, and elimination. 1 August 2024  ROUTES OF DRUG ADMINISTRATION The route of administration is determined by: 1-the properties of the drug (for example, water or lipid solubility, ionization) 2- by the therapeutic objectives (for example, the desirability of a rapid onset, the need for long-term treatment, or restriction of delivery to a local site). Major routes of drug administration include enteral, parenteral, and topical 1 August 2024 4  ABSORPTION OF DRUGS Absorption is the transfer of a drug from the site of administration to the bloodstream. The rate and extent of absorption depend on 1- the environment where the drug is absorbed. 2- chemical characteristics of the drug. 3- the route of administration (which influences bioavailability). Routes of administration other than intravenous may result in partial absorption and lower bioavailability. 1 August 2024 5 For IV administration, absorption is complete, or the total dose of administered drug reaches the systemic circulation (100% bioavailability). Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability. 1 August 2024 6  A. Mechanisms of absorption of drugs from the GI tract 1. Passive diffusion: (the drug moves from a region of high concentration to one of lower concentration). not involve a carrier is not saturable shows a low structural specificity. The vast majority of drugs are absorbed by this mechanism. 1 August 2024 7 1 August 2024 8 2. Facilitated diffusion: Other agents can enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules. not require energy can be saturated may be inhibited by compounds that compete for the carrier. 1 August 2024 9 3. Active transport: Energy-dependent is driven by the hydrolysis of adenosine triphosphate. It is capable of moving drugs against a concentration gradient. The process is saturable. Active transport systems are selective may be competitively inhibited by other cotransported substances. 1 August 2024 10 4. Endocytosis and exocytosis: Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug filled vesicle. e.g. Vitamin B12 Exocytosis is the reverse of endocytosis. e.g.norepinephrine released by exocytosis. 1 August 2024 11  B. Factors influencing absorption Most drugs are either weak acids or weak bases. Acidic drugs (HA) release a proton (H+), causing a charged (ionized) anion (A – ) to form: HA ←→ H + + A – Weak bases (BH +) can also release an H +. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged (non-ionized) base (B): BH + ←→ B + H + A drug passes through membranes more readily if it is uncharged (non-ionized). Thus, for a weak acid, the uncharged, protonated HA can permeate through membranes, and A – cannot. For a weak base, the uncharged form ,B , penetrates through the cell membrane, but BH + , the protonated form, does not. 1 August 2024 12 The effective concentration of the permeable form is determined by the relative concentrations of the charged and uncharged forms. The ratio between the two forms is determined by 1- the pH at the site of absorption and 2- by the strength of the weak acid or base, which is represented by the ionization constant, pKa 1 August 2024 13  The pKa is a measure of the strength of the interaction of a compound with a proton [The lower the pKa of a drug, the more acidic it is. Conversely, the higher the pKa, the more basic is the drug]. In acidic media (low PH, e.g. stomach), acidic drugs will be non- ionized (HA) or lipid soluble, while basic drugs will be ionized (BH + ) or water soluble. In basic media (high PH, e.g. small intestine), acidic drugs will be ionized (A – ) or water soluble, while basic drugs will be non-ionized (B) or lipid soluble. 1 August 2024 14  B. Factors influencing absorption 2. Blood flow to the absorption site: The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach. 3. Total surface area available for absorption: the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient. 1 August 2024 15  4- Contact time at the absorption surface If a drug moves through the GIT very quickly, as can happen with severe diarrhea, it is not well absorbed. The presence of food in the stomach both dilutes the drug and slows gastric emptying. Therefore, a drug taken with a meal is generally absorbed more slowly. 5- Expression of P-glycoprotein: P-glycoprotein is a multidrug transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes. It is expressed throughout the body, and its functions include: In the liver: transporting drugs into bile (for elimination) In kidneys: pumping drugs into urine (for excretion) In the placenta: transporting drugs back into maternal blood In the intestines: transporting drugs into the intestinal lumen (reducing drug absorption into the blood) In the brain capillaries: pumping drugs back into blood (limiting drug access to the brain) Thus, in areas of high expression, P-glycoprotein reduces drug absorption. 1 August 2024 16  C. Bioavailability The fraction (or percentage) of the administered dose of drug that reaches the systemic circulation. 1. Determination of bioavailability: Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with levels achieved by IV administration. After IV administration, 100% of the drug rapidly enters the circulation. 1 August 2024 17 1 August 2024 18 2. Factors that influence bioavailability: a. First-pass hepatic metabolism: If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug entering the systemic circulation is decreased. b. Solubility of the drug: For a drug to be readily absorbed, it must be largely lipophilic, yet have some solubility in aqueous solutions. hydrophilic drugs are poorly absorbed because of their inability to cross the lipid-rich Cell Membrane 1 August 2024 19  2. Factors that influence bioavailability: c. Chemical instability: Some drugs, such as penicillin G, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes. d. Nature of the drug formulation: Particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients 1 August 2024 20  Bioequivalence: Two related drug preparations are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. 1 August 2024 21  D- DRUG DISTRIBUTION ❑Drug distribution is the process by which a drug reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and the tissues. ❑Depends on: Blood flow; Capillary permeability; Binding of drugs to plasma proteins and tissues; Lipophilicity ; and Volume of distribution Vd. 1 August 2024 22  A. Blood flow B-Capillary permeability It determined by capillary structure and by the chemical The rate of blood f low to tissues varies nature of the drug. widely, as a result, unequal distribution To enter the brain, drugs must pass occurs. through the Blood f low to the brain, liver, and kidney is endothelial cells of the capillaries of the greater than that to the skeletal muscles, CNS or be most viscera, skin, and fat. actively transported like levodopa. Lipid- e.g. The high blood f low, together with the soluble drugs high lipid solubility of thiopental, permit it to readily penetrate into the CNS because rapidly move into the CNS and produce they can dissolve anesthesia. in the membrane of the endothelial cells. Ionized or polar drugs generally fail to enter the CNS because they are unable to pass through the endothelial cells of the CNS. 1 August 2024 23  The degree of binding of the drug to plasma and tissue proteins: Reversible binding to plasma proteins sequesters drugs in a non-diffusible form and slows their transfer out of the vascular compartment. Plasma albumin is the major drug-binding protein and may act as a drug reservoir. Bound drugs are pharmacologically inactive; only the free, unbound drug can act on target sites in the tissues. Albumin has the strongest af finities for hydrophobic drugs, while hydrophilic drugs do not bind to albumin. The relative hydrophobicity of the drug: Hydrophobic drugs readily move across 1 August 2024 most biologic membranes. 24  VOLUME OF DISTRIBUTION The volume of distribution (Vd) relates the amount of drug in the body to the plasma concentration 1 August 2024 25 A. First-Order Elimination The rate of elimination is proportional to the concentration (i.e., the higher the concentration, the greater the amount of drug eliminated per unit time). Drugs with first-order elimination have a characteristic half-life of elimination that is constant regardless of the amount of drug in the body 1 August 2024 26 B. Zero-Order Elimination The rate of elimination is constant regardless of concentration This occurs with drugs that saturate their elimination mechanisms This is typical of ethanol and of phenytoin and aspirin at high therapeutic or toxic concentrations. 1 August 2024 27 1 August 2024 28  HALF-LIFE The time required for the amount of drug in the body or blood to fall by 50%. For drugs eliminated by first-order kinetics, this number is a constant regardless of the concentration 1 August 2024 29  HALF-LIFE 4–5 half-lives of dosing at a constant rate are considered adequate to produce the effect to be expected at steady state 1 August 2024 30  Thank you 1 August 2024 31