pharm lecture 5 quiz

• Absorption is essential for achieving adequate blood drug levels, except in IV administration, and drugs must reach their target site at effective concentrations.

Distribution

• Distribution primarily occurs through systemic circulation, with minor lymphatic contributions.
• Post-circulation, drugs can remain in the vascular space, enter interstitial fluid, or further distribute into intracellular fluid.
• Distribution is affected by physicochemical properties (lipid solubility, size, ionization) and patient anatomy/physiology (tissue perfusion).
• Vessel-rich tissues (liver, kidney, brain, heart) initially receive the most drug, followed by less-perfused tissues (muscle, fat, skin, viscera).
• Tissue drug uptake varies, such as limited water-soluble drug permeability in brain capillaries due to the blood-brain barrier.
• Plasma protein binding influences distribution; drugs bound to plasma proteins cannot diffuse to tissues and this process is saturable.
• Albumin is a major carrier for drugs that act as weak acids, while α1-acid glycoproteins bind drugs that are weak bases.
• Tissue binding involves drug accumulation in tissues, potentially prolonging drug action by binding to non-target cellular components.
• Volume of distribution (Vd) indicates how a drug partitions between blood and tissue compartments.

Elimination

• Drugs are removed from the body unchanged via excretion or converted via biotransformation (metabolism).
• Biotransformation and excretion reduce circulating levels of active drug.
• The rate of drug metabolism and excretion is generally limited by blood flow to the organ.
• The kinetics of elimination for most drugs follow first-order kinetics, with a constant fraction eliminated per unit time.
• Clearance indicates the efficiency of drug elimination from the blood, expressed as the volume of plasma cleared per unit time per unit body weight.
• Total systemic clearance includes elimination via all routes (liver, kidney, others).
• The extent of an organ's contribution to drug clearance can be quantified by the extraction ratio.
• Excretory organs are more efficient at eliminating polar compounds than non-polar compounds.

Excretory Mechanisms

• The kidneys are the most important excretory organ.
• Quantitatively unimportant mechanisms include sweat, saliva, and tears.
• Potential effects on nursing infants can result from excretion in breast milk.
• Lungs excrete gases.
• The intestinal tract allows for direct secretion.
• Biliary excretion of drugs eliminates drugs via feces and reabsorption of excreted drug is possible in the small intestine, causing enterohepatic recirculation.
• The kidneys receive approximately 20% of cardiac output.
• Free (unbound) drugs and metabolites are freely filtered at the glomerular capillaries and is non-saturable and non-selective.
• Plasma protein-bound drugs are not easily filtered.
• Drug secretion in the proximal convoluted tubule adds drug to urine and is saturable, selective, and inhibitable.
• Drug reabsorption from urine back into the blood can be active in the distal convoluted tubule but is mainly passive reabsorption of the nonionized form of the drug.

Metabolism

• Metabolism is the alteration of a drug's chemical structure within a living organism, usually via enzyme-catalyzed reactions.
• The liver is the main metabolizing organ and all orally administered drugs or other substances are first taken to liver via the portal system.
• First-pass effect describes extensive drug metabolism before reaching systemic circulation, reducing bioavailability and preventing oral administration for some drugs.
• Enzymes play a critical role in making drugs more excretable and terminating their action (inactivation).
• Lipid-soluble drugs are metabolized into more water-soluble metabolites for excretion in urine & bile.
• Some drugs are activated by metabolism and are administered as inactive prodrugs to improve bioavailability, decrease GI toxicity, or prolong elimination.
• An example of a prodrug is Ramipril (Altace) which is converted to the active metabolite rampilrilat by hepatic metabolism.
• The liver is the major site of metabolism of xenobiotics (foreign chemical substances).
• Metabolism also occurs in the lungs, GI tract, skin, kidneys, brain, and blood plasma.
• Biotransformation reactions are catalyzed by cellular enzymes in hepatocytes, located in the smooth endoplasmic reticulum, cytoplasm, mitochondria, nuclear/cell membrane, and lysosomes.

Phase I and II Reactions

• Hepatic enzymatic reactions involved in drug metabolism occur in two phases.
• Phase I reactions convert drugs to more polar metabolites that are either excreted or undergo Phase II reactions.
• Phase II reactions attach a substance from the diet to the functional group derived from phase I reactions to create more polar, excretable products.
• Some drugs can undergo Phase II reactions directly.
• Phase I reactions usually involve cytochrome P-450 (CYP) enzymes in the smooth ER.
• CYP450 enzymes are heme-containing proteins that absorb light at 450nm.
• Approximately 12 CYP450s are important for drug metabolism, mainly the CYP2C, CYP2D, and CYP3A subfamilies.
• Oxidation is the most common Phase I reaction, involving the addition of oxygen or removal of hydrogen, often via CYP450 enzymes.
• Less common Phase I reactions are reduction and hydrolysis.
• Phase I reactions introduce or unmask functional groups.
• Phase II reactions couple a drug with substrates from the diet to produce conjugates.
• Conjugates are generally more polar, inactive, and readily excretable.
• Conjugates require the drug (metabolite) to have an oxygen (hydroxyl or epoxide group), nitrogen, or sulfur atoms as acceptors for hydrophilic conjugate moiety.

Conjugation Types

• Glucuronic acid conjugation (UDP glucuronosyl transferase) is a very important pathway for many drugs and endogenous substances such as morphine, acetaminophen, salicylic acid, and chloramphenicol and some phase II metabolites can be excreted into bile for elimination in feces.
• Glucuronidases in gut bacteria can hydrolyze the conjugate, freeing the drug for reabsorption, causing enterohepatic recirculation, which prolongs the drug's elimination half-life.
• Individuals deficient in glucuronide synthesis metabolize certain drugs slowly.
• Sulphate conjugation (sulfotransferases) conjugates phenols and alcohols to sulphate (SO4), an example being acetaminophen morphine.
• Acetylation (N-acetyltransferase) occurs in drugs with an -NH2 group conjugated to COCH3, such as most sulphonamide antimicrobial drugs.
• Glutathione conjugation (glutathione S-transferase) conjugates epoxides and arene oxides to glutathione (GSH), such as some anticancer drugs (alkylating agents).

This section covers drug distribution, essential for achieving adequate blood drug levels. It describes the process of drug distribution through systemic circulation and factors affecting it, such as tissue perfusion and plasma protein binding. Notes physicochemical properties and patient physiology impact distribution.