Pharmacokinetics Lecture 2 F24 PDF

Pharmacokinetics Lecture 2 Pharmacology I (PO502) Pharmacology and Toxicology Department Faculty of Pharmacy Yara Abo El Magd, PhD  Learning outcomes  Recall the basic principles of pharmacology, pharmacokinetics and pharmacodynamics. (1-...

Pharmacokinetics Lecture 2 Pharmacology I (PO502) Pharmacology and Toxicology Department Faculty of Pharmacy Yara Abo El Magd, PhD  Learning outcomes  Recall the basic principles of pharmacology, pharmacokinetics and pharmacodynamics. (1- 1-4-1)  Develop scientific thinking, problem solving and decision- making abilities. (4-1-2-2)  Pharmacokinetics Pharmacokinetics: What the body does to the drug. It is the study of the rate and extent of drug:  Absorption  Distribution ADME  Metabolism (biotransformation)  Excretion  Drug Absorption Definition: The process of movement of drug from the site of administration to systemic circulation. General Principle: The faster the absorption, the quicker the onset, but the shorter the duration of pharmacological effect of the drug.  Some principles about drug absorption  Drug absorption is determined by the drug's physicochemical properties, formulation, and route of administration.  Unless given IV, a drug must cross several semi permeable membranes before it reaches the systemic circulation.  Administration of drugs by any other routes rather than IV may result in partial absorption and may decrease drug’s bioavailability  Mechanisms of drug absorption 1) Passive diffusion 2) Facilitated diffusion 3) Active transport 4) Endocytosis & exocytosis  Passive diffusion  Absorption of 90% of drugs is mediated by passive diffusion (the mol. Wt. of the most drugs lie between 100 to 400 Daltons which can be effectively absorbed passively).  The driving force is the concentration gradient.  Passive diffusion process is energy independent but depends more the molecular size of the drugs and lipid solubility.  No carrier is needed  Lipophilic through the lipid bilayer while water soluble through channels or pores.  Facilitated diffusion  Drugs cross the membrane through specialized trans- membrane 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.  It does not require energy, and may be inhibited by compounds that compete for the carrier  Drugs moves through its concentration gradient Active transport  Against the concentration gradient  Energy is required  Limited to drugs structurally similar to endogenous substances (eg, ions, vitamins, sugars, amino acids)  Endocytosis & Exocytosis  Endocytosis involves engulfment of a drug molecule by the cell membrane and transport into the cell, while exocytosis is the opposite.  The cell membrane encloses the fluid or particles, then fuses again, forming a vesicle that later detaches and moves to the cell interior.  Energy is required.  Used in absorption of very large or the highly polar molecules Examples: Peptides and Vit B12 (endocytosis) Norepinephrine (exocytosis)  Factors affecting the rate of drug absorption 1. Degree of drug ionization:  Most of drugs are weak acids or weak bases  Uncharged (unionized) drug passes through membranes readily.  This mean, for weak acids, the protonated form HA can penetrate through membranes, and A– cannot.  For a weak base, the unprotonated form B, penetrates through the cell membrane, but BH+, does not. In other words, the effective concentration of the permeable form of each drug at its absorption site is determined by the ratio between charged and uncharged forms.  The ratio between the two forms is determined by: 1. pH at the site of absorption 2. The strength of the weak acid or base, which is represented by the ionization constant  Acidic drugs (low pKa values) are least ionized in acidic solutions (low pH) and most ionized in alkaline solutions (high pH).  Conversely, basic drugs (high pKa values) are least ionized in alkaline solutions (high pH), and most ionized in acid solutions (low pH).  In either case, the ionized form of the molecule can generally be regarded as the water-soluble form and the non-ionized form as the lipid-soluble form. The ease with which a drug can diffuse across a lipid bilayer is determined by the lipid solubility of its non-ionized form  The acidity of stomach contents means that an acidic drug is present largely in its non-ionized (protonated) form, allowing it to pass into plasma where its ionized form becomes partitioned.  In contrast, basic drugs are highly ionized in the stomach, and absorption is negligible until the stomach empties and the drug can be absorbed from the more alkaline lumen of the duodenum (pH ~8).  Factors affecting the rate of drug absorption 2. Blood flow to the absorption site  Absorption from intestine is favored over that from stomach due to greater blood flow.  Disease involve in blood flow such as heart failure may reduce drug absorption 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.  Surgical removal of part of intestine lowers drug absorption  Factors affecting the rate of drug absorption 4. Contact time at the absorption surface:  In general, ↓ in contact time of a drug at the absorption site, ↓ absorption rate  Severe diarrhea, reduces oral drug absorption.  Anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption.  Presence of food in the stomach, dilutes the drug and slows gastric emptying.  Factors affecting the rate of drug absorption 5. Expression of efflux pumps such as P-glycoprotein:  P-glycoprotein is a multidrug trans-membrane transporter protein responsible for transporting various molecules including drugs across cell membrane.  Its expression leads to: ✔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, thereby reducing fetal exposure to drugs ✔In the intestines: transporting drugs into the intestinal lumen and 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.  Bioavailability Bioavailability can be defined as: the fraction of administered drug that reaches the systemic circulation in a chemically unchanged (as intact drug) form. Determination of bioavailability: Bioavailability is determined by comparing plasma levels of a drug after a particular route of administration (for example, oral administration) with plasma drug levels achieved by IV injection. F = AUCoral/AUCintravenous Which formulation has higher bioavailability? 21 Factors affecting bioavailability  First-pass metabolism: First-pass metabolism occurs when an absorbed drug passes directly through the liver before reaching systemic circulation after oral administration. o 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. Hence, it is primarily administered via the sublingual, transdermal, or intravenous route o Drugs with high first-pass metabolism should be given in doses sufficient to ensure that enough active drug reaches the desired site of action  Solubility of the drug: generally, Lipophilic drugs readily absorbed and has higher bioavailability.  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 GIT by digestive enzymes.  Particle size, salt form, crystal polymorphism, enteric coatings, and excipients.  Distribution Drug distribution is: The process by which a drug reversibly leaves the bloodstream and enters other body compartments (extracellular fluid and the tissues). For drugs administered IV, absorption is not a factor, and the initial phase represents the distribution phase. Factors controlling distribution of a drug 1- Blood flow: The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs  Highly perfused organs such as: Brain, liver, Kidney.  Poorly perfused organs: Adipose tissue, tendons and nail. EX: Propofol IV (general anesthetic) → ↑ lipid solubility + high blood flow (brain) = very rapid distribution to CNS → very rapid effect. 2- Capillary permeability: Capillary permeability 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. A. Organs with higher capillary permeability: Liver & spleen B. Organs with lower capillary permeability : Brain  Lipophilic drugs distribute readily to tissues while hydrophilic ones penetrate through the slit junctions.  Only lipid soluble drugs such as anesthetics can pass BBB through passive diffusion and exsert its action on CNS while no pores to pass water soluble drugs  3- Binding of drugs to plasma proteins and tissues:  Most of foreign compounds are bound to albumin and are not immediately available for distribution to extravascular space.  Albumin is a major carrier for acidic drugs; α1-acid glycoprotein and β- globulin bind to basic drugs.  It is the unbound drug that is pharmacologically active.  Drug (D) + plasma protein (P): DP –(slow dissociation)--> D+P It acts as a drug reservoir: when (D)↓→ (DP) dissociates → free (D) → maintains the free-drug concentration as a constant fraction of the total drug in the plasma. Clinical significance of binding to plasma proteins (PP): - Binding to PP ↓ drug distribution (Vd) -Binding to PP ↓ drug elimination → ↑ drug duration of action (↑ t1/2)  Drugs with higher affinity to plasma proteins displace drugs with lower affinity → ↑ free form and may induce toxicity (drug-drug interaction)  In cases of hypoalbuminemia, the concentration of free drug may increase which may induce toxicity  Many drugs accumulate in tissues as a result of binding to lipids, proteins or nucleic acids, leading to higher concentrations in tissues than in the extracellular fluid and blood.  These tissue reservoirs may prolong drug actions and may cause local drug toxicity.  Volume of distribution  The apparent volume of distribution (Vd): a theoretical volume that represents the total amount of administered drug would have to occupy if it were uniformly distributed.  It relates the total amount of drug in the body to the concentration of drug (C) in the blood. VD= A/C  This volume does not necessarily refer to an identifiable physiological volume but rather to the fluid volume that would be required to contain all the drug in the body at the same concentration measured in the blood. Total body water = 40 liters (L). The Intracellular volume = 25 L. The Extracellular volume = 15 L.  Distribution into the water compartments in the body Plasma Interstitial Total body Intracellular volume volume water 3L 12L 25L 40L Extracellular fluid Low molecular weight lipophilic drug Low molecular weight Large molecular weight OR highly bound to PP hydrophilic drug  Distribution into the water compartments in the body a.Plasma compartment: If a drug has a high molecular weight or is extensively protein bound, it is too large to pass through the slit junctions of the capillaries and, thus, is effectively trapped within the plasma (vascular) compartment. As a result, it has a low Vd ~ 3L. Ex. Heparin b.Extracellular fluid: If a drug has a low molecular weight but is hydrophilic, it can pass through the endothelial slit junctions of the capillaries into the interstitial fluid. However, hydrophilic drugs can't move across the lipid membranes of cells to enter the intracellular fluid. Therefore, these drugs distribute into a volume that is the sum of the plasma volume and the interstitial fluid, which together constitute the extracellular fluid ~ 12 L. Ex. Aminoglycoside. c. Total body water: If a drug has a low molecular weight and is lipophilic, it can move into the interstitium through the slit junctions and also pass through the cell membranes into the intracellular fluid. These drugs distribute into a volume of about 60% of body weight or ~ 40L. EX. Chloroquine. VD is an important parameter that used to calculate the loading dose. VD= A/C  Determination of VD  Factors affecting VD  Lipophilicity increases VD  Tissue binding increases VD  Hydrophilicity decreases VD  Plasma protein binding decreases VD VD is an estimate of tissues uptake of drugs Small VD → tissue uptake is limited (highly bound to plasma proteins) Large VD → extensive tissue uptake (low binding to plasma proteins) Plasma Tissues Plasma Tissues  Half-life (t1/2) The t1/2 is: the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. Effect of a large VD on the half- life of a drug  A large Vd has an important influence on the half-life of a drug.  Delivery of drug to the organs of elimination depends not only on blood flow, but also on the fraction of the drug in the plasma.  If the Vd for a drug is large, most of the drug is in the extra- plasmic space and is unavailable to the excretory organs.  Therefore, any factor that increases the volume of distribution can lead to an increase in the half-life and extend the duration of action of the drug. [email protected]