Pharmacology - Pharmacokinetics 1 [Autosaved].pptx

Pharmacology - Pharmacokinetics 1 [Autosaved].pptx

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  PHARMACOLOGY Pharmacokinetic(ADME) https://youtu.be/NKV5iaUVBUI?si=MB9XI oQKW7Wmcecr
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  Definition of Pharmacology •Pharmacology is the scientific study of the effects of drugs on living organisms where a drug can be broadly defined as any chemical substance, natural or synthetic substance, which affects a biological system. Pharmacology may involve how organisms handle drugs, identification and validation of new targets for drug action, and the design and development of new drugs to prevent, treat and cure disease.
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  Branches of Pharmacology Pharmacokinetics •‘‘Pharmacodynamics describes what the drug does to the body’’ Pharmacodynamics • ‘‘Pharmacokinetics refers to what the body does to a drug’’
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  Four pharmacokinetic propertiesdetermine the onset, intensity, and the duration of drug action : • Absorption: First, absorption from the site of administration permits entry of the drug (either directly or indirectly) into plasma. • Distribution: Second, the drug may then reversibly leave the blood stream and distribute into the interstitial and intracellular fluids. • Metabolism: Third, the drug may be bio transformed by metabolism by the liver or other tissues. • Elimination: Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces. Using knowledge of pharmacokinetic parameters, clinicians can design optimal drug regimens, including the route of administration, the dose, the frequency, and the duration of treatment.
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  Absorption & Factors ABSORPTIONIS THE TRANSFER OF A DRUG FROM THE SITE OF ADMINISTRATION TO THE BLOODSTREAM. THE RATE AND EXTENT OF ABSORPTION DEPEND ON THE ENVIRONMENT WHERE THE DRUG IS ABSORBED. •HTTPS://YOUTU.BE/MH81Q9DTODC?SI=6N5HIN2-MFEZG9Q J
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  Factors Influencing Drug Absorption Thereare Following Factors That Influence the Drug absorption. • Pharmaceutical • Drug Factors • Biological Factors
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  Pharmaceutical • Formulation • Disintegration •Disolution • Particle Size
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  Drug Factors • LipidSolubility • PH • Ionization
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  Biological Factors • SurfaceArea (Small Intestine ) • Gastric Emptying Time (Stomach) • Presence of Food • Disease • First Pass Metabolism (Mouth to Liver and then Systemic Circulation)
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  Mechanism Of AbsorptionThrough Membrane There are Four Mechanism Through which drug absorb in the body. Passive Diffusion Facilitated Diffusion Active Transport Endocytosis
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  Drug Absorption
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  1. Passive diffusion:The drug moves from a region of high concentration to one of lower concentration. Passive diffusion does not involve a carrier, is not saturable, and shows a low structural specificity. The vast majority of drugs are absorbed by this mechanism. Water-soluble drugs penetrate the cell membrane through aqueous channels or pores, whereas lipid-soluble drugs readily move across most biologic membranes due to their solubility in the membrane lipid bilayers. 2. Facilitated diffusion: Other agents can enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules. These carrier proteins undergo conformational changes, allowing the passage of drugs or endogenous molecules into the interior of cells and moving them from an area of high concentration to an area of low concentration. This process is known as facilitated diffusion. It does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier
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  3. Active transport:This mode of drug entry also involves specific carrier proteins that span the membrane. A few drugs that closely resemble the structure of naturally occurring metabolites are actively transported across cell membranes using specific carrier proteins. Energy-dependent active transport is driven by the hydrolysis of adenosine triphosphate. It is capable of moving drugs against a concentration gradient, from a region of low drug concentration to one of higher drug concentration. The process is saturable. Active transport systems are selective and may be competitively inhibited by other cotransporter substances. 4. Endocytosis and exocytosis: This type of absorption is used to transport drugs of exceptionally large size across the cell membrane. Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug filled vesicle. Exocytosis is the reverse of endocytosis. Many cells use exocytosis to secrete substances out of the cell through a similar process of vesicle formation. Vitamin B12 is transported across the gut wall by endocytosis, whereas certain neurotransmitters (for example, norepinephrine) are stored in intracellular vesicles in the nerve terminal and released by exocytosis.
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  2. Drug Factors A.Effect of pH on drug absorption: Most drugs are either weak acids or weak bases. Acidic drugs (HA) release a proton (H+), causing a charged 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 base (B): (BH=B H+.) A drug passes through membranes more readily if it is uncharged. Thus, for a weak acid, the uncharged, protonated HA can permeate through membranes, and A− cannot.
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  For a weakbase, the uncharged form B penetrates through the cell membrane, but the protonated form BH+ does not. Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms. The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pKa.
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  Ionization /Dissociation Constant 1.PKa stands For (acid dissociation/Ionization constant). 2. 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.]
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  B. Blood flowto the absorption site: The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach. [Note: Shocks severely reduces blood flow to cutaneous tissues, thereby minimizing absorption.] C. Total surface area available for absorption: With a surface rich in brush borders containing microvilli, the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient. [Note: Intestinal diseases like Celiac, gastroenteritis can reduce the surface area]
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  3. Contact timeat the absorption surface: If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. [Note: 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.] 4. Expression of P-glycoprotein: P-glycoprotein is a transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell. - It “pumps” drugs out of the cells. - P-glycoprotein reduces drug absorption. - In addition to transporting many drugs out of cells, it is also associated with multidrug resistance.
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  Bioavailability “Bioavailability is therate and extent to which an administered drug reaches the systemic circulation”
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  Determination of bioavailability Determinationof 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. https://youtu.be/BQQns7RAUzA?si=o0JKjhP_YI5TJ1 T4
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  2. Factors thatinfluence bioavailability a. First-pass hepatic metabolism: First-pass metabolism by the intestine or liver limits the efficacy of many oral medications. For example, more than 90% of nitroglycerin is cleared during first-pass metabolism. b. Solubility of the drug: For a drug to be readily absorbed, it must be largely lipophilic, yet have some solubility in aqueous solutions. This is one reason why many drugs are either weak acids or weak bases. 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.
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  D-Nature of thedrug formulation: Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption
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  DRUG DISTRIBUTION Drug distributionis the process by which a drug reversibly leaves the bloodstream and enters the interstitial (extracellular fluid) and the tissues. Factors that influence Distribution A. Blood flow The rate of blood flow to the tissue capillaries varies widely. For instance, blood flow to the “vessel- rich organs” (brain, liver, and kidney) is greater than that to the skeletal muscles. Adipose tissue, skin, and viscera have still lower rates of blood flow.
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  B. Capillary Permeability Capillarypermeability is determined by capillary structure and by the chemical nature of the drug. Capillary structure varies in terms of the fraction of the basement membrane exposed by slit junctions between endothelial cells. For Example :- In the liver and spleen, a significant portion of the basement membrane is exposed due to large, discontinuous capillaries or slit-junctions through which large plasma proteins can pass (Diagram A). In the brain, the capillary structure is continuous, and there are no slit junctions (Diagram B).
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  Binding of drugsto plasma proteins and tissues Binding to plasma proteins: Reversible binding to plasma proteins drugs in a no diffusible form and slows their transfer out of the vascular compartment. Albumin is the major drug-binding protein and may act as a drug reservoir (as the concentration of free drug decreases due to elimination, the bound drug dissociates from the protein). This maintains the free drug concentration as a constant fraction of the total drug in the plasma.
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  Binding to tissueproteins: Many drugs accumulate in tissues, leading to higher concentrations in tissues than in the extracellular fluid and blood. Drugs may accumulate as a result of bind into lipids, proteins, or nucleic acids. Drugs may also be actively transported into tissues. Tissue reservoirs may serve as a major source of the drug and prolong its actions or cause local drug toxicity. (For example, acrolein, the metabolite of cyclophosphamide, can cause hemorrhagic cystitis because it accumulates in the bladder.
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  Lipophilicity • Lipophilicity Thechemical nature of a drug strongly influences its ability to cross cell membranes. Lipophilic drugs readily move across most biologic membranes. These drugs dissolve in the lipid membranes and penetrate the entire cell surface. The major factor influencing the distribution of lipophilic drugs is blood flow to the area. In contrast, hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions.
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  Total body clearance Thetotal body (systemic) clearance, CL total, is the sum of all clearances from the drug- metabolizing and drug-eliminating organs. The kidney is often the major organ of elimination. The liver also contributes to drug clearance through metabolism and/or excretion into the bile. Total clearance is calculated using the following equation: CL total = + CL hepatic CL renal + + CL pulmonary CL other where CL hepatic + CL renal are typically the most important