Pharmacology-1 Lecture 3 (Spring 2024) PDF

# Pharmacology-1 (PCL332/PO315/POC316) ## Spring 2024 - Pharmacokinetics (Part 1) ### Lecture 3 - By Dr/Sarah Baraka Lecturer of pharmacology & Toxicology ## Objectives of the lecture - Know the meaning of pharmacology - Recognize pharmacokinetics - Recognize ADME - Describe Absorption of the dru...

# Pharmacology-1 (PCL332/PO315/POC316) ## Spring 2024 - Pharmacokinetics (Part 1) ### Lecture 3 - By Dr/Sarah Baraka Lecturer of pharmacology & Toxicology ## Objectives of the lecture - Know the meaning of pharmacology - Recognize pharmacokinetics - Recognize ADME - Describe Absorption of the drug - Know factors that affect absorption - Bioavailability and factors affecting it - Routes of administration ## Introduction - What is Pharmacology? - The term "pharma" refers to drugs (which are substances that interact with living systems) - "Ology" refers to the study or knowledge or science > **Pharmacology is the study of drugs and their interaction with living systems through chemical processes.** ## Pharmacology - **Pharmacokinetics** refers to the effect of the body on the drug. - **Pharmacodynamics** refers to the effect of the drug on the body. ### Pharmacokinetics - Absorption - Distribution - Metabolism - Excretion ### Pharmacodynamics - Pharmacological action - Mechanism of Action - Adverse effects (Side effects) ## 1- Pharmacokinetics - Pharmacokinetics is the study of drug disposition in the body (what the body does to the drug; the action of the body on the drug). - Pharmacokinetics is used to determine how rapidly (onset) and for how long the drug will appear at the target organ (duration) (focuses on the changes in drug plasma concentration). - Pharmacokinetic parameters are required to design and optimize an appropriate drug regimen for a patient: - The route of administration - The amount and frequency of each dose - The duration of treatment - Absorption - Distribution - Metabolism - Elimination ## Absorption - Absorption is the movement of drug from the site of administration to the bloodstream. ## Distribution - Distribution is the process of a drug leaving the bloodstream and being distributed throughout the body, into the organs and tissues. ## Metabolism - Metabolism is the process of converting a drug to one or more metabolites, primarily in the liver. - Synonyms include biotransformation. ## Excretion - Excretion is the removal of a drug or its metabolites from the body primarily by the kidneys and urination. - The term Elimination refers to the processes of metabolism and excretion combined. ## 1- Absorption - Absorption is the transfer of a drug from the site of administration to the bloodstream. - Drug absorption requires that drugs cross one or more layers of cells and cell membranes. - The process of drug absorption applies to all routes of administration, except for: - The topical route, in which drugs are applied directly on the target tissue. - Intravenous administration, in which the drug is given directly in the bloodstream. ## Transport of drugs Through Membranes - All human cells are limited by a lipid bilayer membrane. - The membrane lipids consist mainly of phospholipids, sterols (especially cholesterol) and glycolipids. - The amphiphilic nature of the membrane lipids and the aqueous intracellular and extracellular environments cause the membrane to assume a structure with a hydrophobic core and two hydrophilic surfaces (lipid barriers separate aqueous compartments). - **SO** drugs must be hydrophobic with some solubility in aqueous solutions (High the lipid: aqueous partition coefficient). ## Mechanisms of Absorption of Drugs - The drug moves through the phospholipid bilayer by one of these mechanisms: - Passive diffusion - Carrier-mediated transport - Facilitated diffusion - Active transport - Endocytosis and exocytosis ## 1. Passive (Simple) Diffusion - The driving force for passive diffusion of a drug is the concentration gradient across a membrane separating two body compartments (the drug moves from an area of high concentration (GIT) to one of lower concentration (to blood). - Passive diffusion does not involve a carrier. - It is not saturable and does not need a carrier. - It is not specific. - The vast majority of drugs are absorbed by this mechanism. - Water-soluble drugs (small in size and/or high partition coefficient) penetrate the cell membrane through aqueous channels or pores. - Lipid-soluble drugs readily move across most biologic membranes due to solubility in the membrane lipid bilayers. ## 2. Carrier-mediated Transport - Drugs enter the cell through specialized transmembrane carrier proteins that facilitate the passage of large molecules (carrier proteins undergo conformational changes allowing the passage of drugs or endogenous molecules into the interior of cells). - **Facilitated Diffusion:** - It works down a concentration gradient (from high to low). - It does not require energy. - **Active Transport:** - It involves specific carrier proteins that span the membrane. - It is capable of moving drugs against a concentration gradient (from low to high) by the hydrolysis of adenosine triphosphate (ATP). - It requires energy. - The carrier can be saturated, selective, and can be inhibited by compounds that compete for that carrier. - Example: For transfer of TOO LARGE or TOO lipid insoluble molecules - **Facilitated diffusion:** (Peptides/glucose/amino acids) - **Active transport:** (ion transfer) e.g., Na+/K+ ATPase Pump which transfer ions against Conc. gradient ## 3. Endocytosis and Exocytosis - This type of absorption is used to transport drugs of exceptionally large size across the cell membrane. - **Endocytosis:** (engulfment of a drug) - It is the reverse of endocytosis. - It is the release of neurotransmitters from stored vesicles. - **Exocytosis:** - It is the engulfment of a drug by the cell membrane and transport into the cell. - It is a process where drug binds to cell surface receptor, the drug is engulfed and carried into the cell forming a new vesicle inside the cells. - Once inside, the membrane is disassembled and the contents are released into the cytosol. - **Vitamin B12 is transported across the gut wall by endocytosis.** - **(Norepinephrine) is stored in intracellular vesicles in the nerve terminal and released by exocytosis.** ## Factors Influencing Absorption - **Factors Related to the Absorbing Surface:** - Effect of pH on drug absorption - Blood flow to the absorption site - Total surface area available for absorption - Contact time at the absorption surface - Expression of P-glycoprotein ## 1. Effect of pH on Drug Absorption - Most drugs are either weak acids or weak bases that exist in both ionized and nonionized forms in the body. - Only the nonionized form of these drugs is sufficiently soluble in membrane lipids to cross cell membranes. - **For Acidic Drugs:** - Acidic drugs (HA) release a proton (H⁺), causing a charged anion (A^-) to form (On dissociation give anion and Proton). - HA - H⁺ + A^- - The protonated form of a weak acid is nonionized. - In acidic medium→ Lots of Proton are present→ a greater amount of acidic drug will be in the unionized form (shift towards left) →↑Absorption. - In basic medium→ less protons→ a greater amount of acidic drug will be ionized (shift towards right)→↓ Absorption. - **For Basic Drugs:** - The uncharged base (B) gain a proton (H⁺), to form a weak bases (BH⁺) = ionized = charged. - BH⁺ B + H⁺. - The protonated form of a weak base is ionized. - In acidic medium Lots of Proton are present→weak basic drugs will be in protonated form (BH⁺) = ionized→↓ Absorption. - In basic medium→ less protons→ the uncharged base (B) will predominates→↑ Absorption. > **Conclusion:** > - Weak acidic drugs (HA) are preferentially absorbed at low pH. > - Weak basic drugs (B) are preferentially absorbed at higher pH. > - Weak acids or weak bases will be absorbed in similar media. - The effective concentration of the permeable form of each drug is determined by the relative concentrations of the charged and uncharged forms. - This is determined by the pH at the site of absorption and by the ionization constant, pKa of the weak acid or base. - pKa is a measure of the strength of the interaction of a compound with a proton. - **For basic drugs:** (BH⁺) = ionized → not absorbed, B → absorbed (for this drug to be absorbed pKa << PII) - **For acidic drugs:** (HA) = nonionized → absorbed, A^- → non absorbed (for this drug to be absorbed pKa >> PH). ## 2. Blood Flow to the Absorption Site - ↑BF → ↑absorption. - High vascularity = High blood flow = high absorption (e.g., small intestine). - The intestines receive much more blood flow than does the stomach → so absorption from the intestine >>>> the stomach. ## 3. Total Surface Area Available for Absorption - ↑SA → ↑absorption. - Absorption of the drug is directly proportional to the surface area available. - The intestine has a surface area about 1000-fold that of the stomach as its surface is rich in brush borders containing microvilli (making absorption of the drug across the intestine more efficient). ## 4. Contact Time at the Absorption Surface: - ↑contact time → ↑absorption. - Increase motility (with severe diarrhea) → Decrease absorption (as the drug moves very quickly through the GIT). - The gastric emptying rate is a measure of the speed of delivery of gastric contents into the intestine. - ↑↑ the rate of gastric emptying (prokinetic agents) → ↑↑ the rate of absorption of a drug. - Anything that delays the transport of the drug from the stomach to the intestine → delays the rate of absorption. > **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. ## 5. Expression of P-glycoprotein - ↑Expression of p-glycoprotein → ↓absorption. - P-glycoprotein is a transmembrane transporter protein responsible for transporting various molecules from tissues (EFFLUX TRANSPORTERS - pumps drugs out of cells). - It is expressed in tissues throughout the body (the liver, kidneys, placenta, intestines, brain capillaries). - However, in the luminal membrane of the intestinal cells (enterocytes) → P-glycoprotein reduces drug absorption by transporting it back into the intestinal lumen → which may limit the absorption of a drug. ## Bioavailability - Bioavailability (BAV) is defined as the fraction (F) of the administered dose of a drug that reaches the systemic circulation in an active form. - For example, if 100 mg of a drug is administered orally and 70 mg is absorbed unchanged = reaches the systemic circulation in an active form → the bioavailability is 0.7 or 70%. - Determining bioavailability is important for calculating drug dosages for non-intravenous routes of administration. ## Determination of Bioavailability - Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (oral administration) with levels achieved by IV administration. - By plotting plasma concentrations of the drug versus time; the area under the curve (AUC) can be measured. - After IV administration → 100% of the drug rapidly enters the circulation. - When the drug is given orally only part of the administered dose appears in the plasma. ## Factors that influence bioavailability - **IV administration** confers 100% bioavailability. - **Orally administered drugs** - only part of the administered dose appears in the plasma. - **First-pass hepatic metabolism:** It means that a drug absorbed from the GI tract reaches the liver via the hepatic portal vein before entering the systemic circulation, extensively converted to inactive metabolites during their first pass through the gut wall and liver → low bioavailability. > **First-pass metabolism by liver limits the efficacy of many oral medications should be given in doses sufficient to ensure that enough active drug reaches the desired site of action.** ## Drug Distribution - Is the reversible transfer of drug from the bloodstream to the rest of extracellular fluid (interstitial fluid/ Transcellular fluid) and tissues (Drug reaches their site of action). - For drugs administered IV → absorption is not a factor, and the initial phase immediately following administration represents the distribution phase. - **Drug moves out of the plasma to:** - Transcellular fluid (within the epithelial-lined spaces) - Intracellular fluid (inside the cell) - Interstitial fluid (between the cells) ## The Distribution of a Drug from the Plasma to Other Compartments depends on: - Capillary permeability - Binding to plasma proteins and tissues - Volume of distribution ## 1. Capillary Permeability - Capillary permeability is determined by - Capillary structure (dependent on the fraction of the basement membrane exposed by slit junctions between endothelial cells) - The chemical nature of the drug (size and lipophilicity) - **In the liver and spleen:** - A large portion of the basement membrane is exposed due to large, discontinuous capillary structure (slit junction). - **In the brain:** - The capillary structure is continuous (tight junctions). - Drugs must pass through the endothelial cells of the CNS capillaries or undergo active transport. ### Tight Junctions - Very tight spaces between endothelial cells. - Only lipid-soluble drugs can pass through the endothelial cell membrane/or actively transported. - Prevents a lot of drugs from entering the brain. ### Slit Junctions - Large space between endothelial cells. - Large drugs and large plasma proteins can pass through. - Drug penetration to tissue is easy. ## 2. The Chemical Nature of the Drug (size and lipophilicity) - The chemical nature of a drug strongly influences its ability to cross cell membranes. - **Molecular size:** - Extremely large molecules (e.g., anticoagulant heparin). - It is largely confined to the plasma compartment and not distributed into tissues. - **Lipid Solubility:** - Lipophilic drugs readily move across most biologic membranes. - These drugs dissolve in the lipid membranes and penetrate the entire cell surface. - Hydrophilic drugs do not readily penetrate cell membranes and must pass through slit junctions (contain aqueous pores). ## 2. Binding of Drugs to Plasma Proteins and Tissues Proteins ### 1. Binding to Plasma Proteins - **Free (D) + (PP) ↔ (D-PP))** - **Unbounded drug:** - Free drugs - Active form of drug → give the pharmacological action of drug. - Diffuse into interstitial fluid and cells. - Metabolized and excreted. - REVERSIBLE BINDING to plasma proteins sequesters drugs in a non-diffusible form and slows transfer out of the vascular compartment. - **Bounded drug:** - Inactive form of drug. - Non-diffusible form - Non-metabolized - Non-excreted ### 2. Binding to Tissue proteins - Many drugs accumulate in tissues → leading to higher concentrations in tissues >>> interstitial fluid and blood. - Drugs may accumulate because of binding to lipids, proteins, or nucleic acids. - These act as tissue reservoirs which may serve as a major source of the drug and prolong its actions or cause local drug toxicity. ## 3. Volume of Distribution ### Vd: - It is defined as the volume of fluid in which a dose of a drug would need to be dissolved in to give the desired plasma drug conc. - It is a proportionality constant that relates the total amount of drug in the body to the plasma concentration of the drug at a given time. - **Vd= (amount of drug in the body) / (plasma drug concentration)** - **Volume of Distribution (L) = (amount of drug in the body) / (plasma concentration of drug)** - The Vd does not necessarily represent the volume in a particular body fluid compartment. - The Vd is an (APPARENT VOLUME/ NOT A REAL VOLUME) that represents the relationship between the dose of a drug, and the resulting plasma concentration of the drug. - The dose of a drug depends on its volume of distribution (not vice versa). > **Volume of Distribution** > 1- Characteristic of a particular drug. > 2- Independent of dose. ## Based on the above equation: - A drug with a high Vd leaves the plasma and enters the extravascular compartments of the body → meaning that a higher dose of a drug is required to achieve a given plasma concentration. - **(High Vd → More distribution to other tissues)** - Conversely, a drug with a low Vd remains in the plasma → meaning that a lower dose of a drug is required to achieve a given plasma concentration. - **(Low Vd → Less distribution to other tissues)** ## Factors affecting Vd - **Factors related to the drug:** - Size - Lipid solubility - Plasma protein binding - **Factors related to the body:** - Total body fluid volume - Plasma protein availability ## 1. Factors related to the drug (size, lipid solubility, plasma protein binding) - Once a drug enters the body, it can distribute into any one of these three compartments of body water (which depend on the drug characters): - **Plasma compartment** (single compartment): - High molecular weight (too large to pass through the slit junctions of the capillaries). - Highly protein bound. - Vd= plasma volume (intravascular). - Low vd. - **Extracellular fluid** (two compartments): - Low molecular weight (pass to interstitial through slit junctions). - Hydrophilic (can't cross lipid bilayer). - Vd = the sum of the plasma volume + the interstitial fluid (extracellular fluid). - Medium Vd. - **Total body water** (multi-compartment): - Low molecular weight (pass to interstitial). - Lipophilicity (cross lipid bilayer). - High binding to tissue proteins. - Vd = the sum of the plasma volume + the interstitial fluid + intracellular fluid. - High vd ## 2. Factors related to the body - **Total Body fluid volume:** - ↑Volume → ↑distribution. - Renal failure (fluid retention → ↑Vd). - Dehydration (decreased body fluids → ↓Vd). - **Plasma protein availability:** - ↓plasma proteins → ↑distribution. - The Vd of drugs that are normally bound to plasma proteins such as albumin can be altered by: - **Liver disease:** (↓ PP synthesis) → ↑ free form of drug → ↑Vd. - **Kidney disease:** (glomerulonephritis) (urinary protein loss) →↑ free form of drug → ↑Vd. ## Clinical Significance of Vd - Determination of the drug half-life - Determination of the drug loading dose ## 1. Effect of Vd on Drug Half-life - **Half-life (t1/2):** ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­The time required for plasma concentration of a drug to decrease by 50%. - **The elimination half-life (t1/2):** ­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­­The time required for the plasma concentration of a drug to decline by 50% during the elimination phase. - Vd has an important influence on the half-life of a drug because drug elimination depends on the amount of drug delivered to the execratory organs (liver or kidney). - **If a drug has a large Vd**, most of the drug is out of the plasma → delivery to elimination organs → increase the half-life and extend the duration of action of the drug. - **Large Vd:** - **↓ Elimination:** - **↑T 1/2** - **Low Vd:** - **↑ Elimination:** - **↓T 1/2** - **Elimination ∝ (1/Vd)** ## Elimination α CL - **k = (CL/Vd)** - **k = (0.693/t1/2)** - **t1/2 = (0.693 * Vd) / CL** - where 0.693 is the natural logarithm of 2, and k is the elimination rate constant. ## Clearance (CL): - It estimates the volume of blood from which the drug is cleared per unit of time (L/hr) / (ml/min). ## Factors Affecting Half-Life - Most Common Effect on Half-Life - **Effects on Volume of Distribution:** - **Aging** (decreased muscle mass → decreased distribution) - **Decreased** - **Obesity** (increased adipose mass → increased distribution). - **Increased** - **Pathologic fluid** (increased distribution). - **Increased** ## 2- Determination of the Drug Loading Dose - **Vd is used to:** determine the amount of drug that must be administered to achieve the desired plasma drug concentration. - **Loading dose = priming dose:** It is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose. - After administration of a loading dose; additional maintenance doses can be administered to maintain the desired plasma concentration of the drug. - **For example, for theophylline, estimated Vd for an adult weighing 70 kg is 35 L, and the desired C is 15 mg/L. The calculation is as follows:** - Loading dose = Vd (L) x Cp (mg/L) = 35 x 15 = 525 mg. > **Loading dose (mg) = [Cp (mg/L) x Vd (L)] / F** > - Where Cp represents the desired plasma concentration of drug. > - Vd represents the volume of distribution. > - F represents the bioavailability of drug (IV administration = 1). ## Unlike, the loading dose, which is dependent on the drug's Vd, the maintenance dose is dependent on clearance (Cl). - **Maintenance dose rate (mg/hr) = [Cp (mg/L) x Cl (L/hr)] /F** - Cp represents the desired plasma concentration of drug. - Cl represents the clearance rate of drug. - F represents the bioavailability of drug (IV administration = 1). > **Thank You**