Pathopharm Exam 1 PDF Study Guide: Pharmacokinetics & Pharmacodynamics

Pharmacokinetics and Pharmacodynamics ​ Pharmacokinetics: ○​ Understand how and where in the body most drugs are absorbed ○​ Recognize factors that impact drug absorption ○​ Recall how drug distribution occurs (protein-being, free drug, and displacement) ○​...

Pharmacokinetics and Pharmacodynamics ​ Pharmacokinetics: ○​ Understand how and where in the body most drugs are absorbed ○​ Recognize factors that impact drug absorption ○​ Recall how drug distribution occurs (protein-being, free drug, and displacement) ○​ Identify the liver’s role in drug metabolism, which includes the CYP450 system ○​ Understand how the different pathways to drug excretion function (e.g., renal, biliary) and the implications for pharmacotherapy ○​ Explain First Pass Effect ○​ Describe the assessment findings associated with liver and renal dysfunction and implications for drug dosing/scheduling ○​ Define different pharmacotherapy terms including: toxic concentration, therapeutic range, lethal dose, effective dose, onset and duration of action ​ Pharmacodynamics: ○​ Calculate Therapeutic Index and recognize what that number/ratio indicates about drug safety ○​ Recognize factors that impact the body’s responses to drugs ○​ Compare drug efficacy and potency ○​ Distinguish between antagonist and agonist ​ Diphenhydramine (Benadryl): an older antihistamine (called “first generation” antihistamine) ○​ Affects intended target cells- blocks the inflammatory mediator/substance histamine from binding with H1 receptors on mast cells, smooth muscle, and endothelial cells. ○​ This “blocking” prevents many of the signs and symptoms of inflammation related to histamine release… ​ Think of people with hay fever, pollen allergies, allergic reactions to bee venom- ○​ Histamine release causes vessel vasodilation and increased vessel permeability ​ Hence, the runny nose and watery eyes in hay fever. ○​ Histamine is found throughout our body, produced by WBCs on our organs, in our mucosal membranes. ​ Histamine is also an excitatory neurotransmitter in our brain (helps keep us awake). ○​ Know the common side effects for opioids (these happen because morphine binds to NON-targeted cells in the GI tract, in the brain, in the GU system, in certain spinal neurons, in the smooth muscles surrounding our arteries): respiratory depression, confusion, euphoria, decreased blood pressure (hypotension), bradycardia, itching, urinary retention, constipation. Respiratory depression is in red because it is life-threatening. Absorption ​ Transmission of drug from location of administration (GI tract, muscle, skin) to the bloodstream. ○​ Most common routes are enteral (through the GI tract) and parenteral (by injection) ​ Drug absorption is determined by the drug’s physicochemical properties (is it lipid-based, protein-based, or sugar-based? Is it ionized or non-ionized in a given solution?), formulation, and route of administration. ​ Regardless of the route of administration, drugs must be in solution to be absorbed. ○​ Thus, solid forms (e.g., tablets) must be able to disintegrate. ​ Unless given IV, a drug must cross several semipermeable cell membranes before it reaches the systemic circulation. ​ Drugs may cross cell membranes by: ○​ Passive diffusion ○​ Active transport ○​ Pinocytosis (rarely used in drug absorption) ​ Sometimes carious proteins embedded in the cell’s plasma membrane function as receptors and help transport molecules across the membrane. Absorption- Passive Diffusion ​ Drugs diffuse across a cell membrane from a region of high concentration (e.g., GI fluids) to one of low concentration (e.g., blood). ​ Most drugs are absorbed from the stomach and small intestine by passive diffusion. ​ The diffusion rate is directly proportional to the gradient but also depends on the molecule’s lipid solubility, size, degree of ionization, and the area of absorption surface. ○​ Usually small, non-ioinized, or lipid-soluble molecules move via passive diffusion. ​ Drugs exist in 2 forms (in terms of ionization): ○​ Ionized (water-soluble) and non-ionized (lipid-soluble) ​ Most drugs are weak organic acids or bases, existing in both non-ionized and ionized forms in an aqueous environment. ○​ The non-ionized form is usually lipid soluble (lipophilic) and diffuses readily across cell membranes. ○​ The ionized form has low lipid solubility (but high water solubility- i.e., hydrophilic) and high electrical resistance and thus cannot penetrate cell membranes easily. ​ Using the Henderson-Hasselbalch equation, it is possible to calculate the percentage of a drug that is ionized and non-ionized in the stomach. Factors Affecting Drug Absorption ​ Drug formulation and dose: liquid formulations ○​ Absorbed faster than tablets or capsules ​ Dose: high dose → fast absorption → rapid onset of action ​ Route of administration: IV drugs → very rapid absorption and onset of action ​ Size of drug molecule: large molecule → low aborption ​ Surface area of absorption site: large surface → fast absorption ​ Digestive motility: may speed up or slow down the absorption; depends on the drug and where it is absorbed. ​ Blood flow: great blood flow → fast absorption ​ Lipid solubility of drug: lipid soluble absorbed faster than water-soluble ​ Degree of ionization of drug: charge of a molecule/drug depends on the pH of the environment and whether or not that drug is a weak acid or a weak base. ○​ Non-ionized form is usually lipid soluble (lipophilic) and diffuses readily across cell membranes. ​ pH of local environment and whether or not the drug is weak acid or a weak base: ○​ Whether a drug is acidic or basic, most absorption occurs in the small intestine because the surface area is larger and membranes are more permeable. ​ Drug-drug/food-drug interactions: ○​ Ex: foods or drugs containing calcium, iron, and magnesium delay absorption of Tetracyclines (a class of antibiotics). ​ High-dietary supplement/herbal product-drug interactions: ○​ Fatty foods → slow stomach motility → delay absorption DO know which route of administration allows drugs to start working fastest in the body (think about absorption and distribution…which route of administration is immediately in bloodstream and doesn’t have to cross any membranes?). ​ Know that greater blood flow, greater lipid solubility, higher dose, larger surface areas = means faster absorption; larger molecules have a harder time (slower) being absorbed. Distribution of Medications ​ Transport of drugs throughout the body\ ○​ Main factor determining distribution is the amount of blood flow to body tissues. ○​ Kidneys, brain, GI tract, and skeletal muscles receive the largest supply of blood. ​ After administration and absorption, drugs are initially present in plasma and may be partly bound to plasma proteins. ○​ May subsequently gain access to interstitial fluid and intracellular water. ​ Blood-brain barrier: consists of cerebral capillaries, and endothelial cells that have overlapping “tight” junctions restricting passive diffusion.  ○​ The capillaries also have a basement membrane with astrocytes. ​ All of these “layers” serve as blockages to drug entry into the CNS ​ However, low molecule weight, lipid-soluble drugs (e.g., general anesthetics, local anesthetics, opioid analgesics) can cross the barrier and enter the CNS (but where they go in the brain is restricted by CNS proteins). Given which organ gets the most blood (see above) what are s/s of patient who experiencing hypoperfusion (discussed in class). ​ Think of the patient hemorrhaging blood, what organs starts to shutdown? (remember, no blood means no oxygen or nutrients getting to cells and no/minimal waste removal – ATP production goes way down so how is that cell going to continuing performing its functions? Not very well). ​ What is blood made of? Distribution- Protein-Binding of Drugs ​ Most drugs are bound to plasma proteins after being absorbed into the bloodstream. ​ As a general rules, agents that are minimally protein bound penetrates tissue better than those that are highly bound, but the unbound drugs is excreted much faster. ​ Plasma proteins include albumin, lipoproteins, and alpha 1-glycoprotein. ​ It is the unbound fraction of the drug that produces pharmacologic effects. ○​ It is also the fraction that may be metabolized and/or excreted. ​ Ex: “the fraction bound” of the anticoagulant warfarin is 97%. ​ This means that of the amount of warfarin in the blood, 97% is bound to plasma proteins. The remaining 3% (the fraction unbound) is the fraction that is free to reach tissues, be metabolized, and eventually excreted. Therapeutic effects, absorption, distribution of drugs, metabolism, excretion, what do liver and renal failure look like?  ​ Hepatic microsomal enzyme system (P450/CYP450 system) ○​ A family of enzymes usually present in the endoplasmic reticulum of hepatocytes that inactivate drugs and accelerate drug excretion. ○​ CYP450 enzymes can be induced or inhibited by many drugs resulting in drug interactions in which one drug enhances the drug’s actions in the body or reduces the therapeutic effect of another drug. Cases of increased and decreased metabolism in the liver ​ Changes in the function of the hepatic microsomal enzymes can significantly affect drug metabolism ​ Some drugs increase metabolic activity in the liver – a process called enzyme induction ​ Phenobarbital → increases liver synthesis of enzymes and by doing so, phenobarbital increases its own rate of metabolism → higher doses are required ​ Certain patients have reduced hepatic enzyme activity, including infants and the elderly. These populations are more sensitive to drug therapy ​ Patients with severe liver damage → decreased liver enzyme production → decreased drug metabolism and increased risk of drug accumulation to toxic levels in the body FIRST PASS EFFECT → Excretion of Medication ​ Kidneys: primary site of excretion. ​ Free drugs, water-soluble agents, electrolytes, and small molecules- easily filtered in the glomerulus (a cluster of capillaries around the end of a kidney tubule, where waste products are filtered from the blood). ​ pH of filtrate can increase excretion ○​ Weak acids (aspirin) are excreted faster when the filtrate is alkaline, and weak basic drugs (diazepam) are excreted faster when the filtrate is slightly acidic. Organ dysfunction- impaired excretion or metabolism of drugs ​ Drug dosages and schedules may need to be altered in these patients (reduced doses; less frequent administration) ○​ Ex: people with liver or kidney disease ​ Excretion concerns: check laboratory values to see how bad their organ disease is (for kidney, these labs are serum Blood Urea Nitrogen (BUN) and creatinine. ​ Metabolism concerns: checking serum liver enzymes to assess liver function. ○​ Consider alternative routes of delivery that bypass the first-pass effect (e.g., sublingual, rectal, parenteral). Creatinine ​ A chemical waste molecule that is generated from muscle metabolism. ​ Is produced from creatine, a molecule of major importance for energy production in muscles. ​ Approximately 2% of the body’s creatine is converted to creatinine every day (this happens at a steady rate). ​ Damages kidneys result in lower creatinine levels in the urine and higher levels in the blood. ○​ know normal creatinine is < 1.3 and normal BUN is 5-20 ​ Biliary excretion: ○​ Drugs secreted into the bile and leave the body in feces ​ However, most bile is recycled by the body (circulates back to the liver via enterohepatic recirculation). ○​ Drugs that undergo biliary excretion end up “going along for the ride” and are recirculated numerous times with the bile. ​ This ends up prolonging the effects of the drug in the body. ​ Eventually, drugs recirculated in the bile are metabolized by the liver and excreted by the kidneys. Renal Damage from Drugs or Diseases ​ Nephrotoxicity and kidney damage or inflammation ​ Fluid volume overload: edema, hypertension, crackles in the lungs, jugular vein distention ​ Electrolyte build-up: mostly a build-up issue because most excess electrolytes in the body are excreted via urine. ○​ Build-up of potassium (hyperkalemia), build-up of phosphorus (hyperphosphatemia), and magnesium (hypermagnesemia).  ​ Hypocalcemia & osteoporosis (long term)- kidneys make active forms of Vitamin D that allows us to absorb calcium from diet. ​ Uremia/Azotemia: build-up of waste products in blood ○​ Creatinine and blood urea nitrogen (BUN) ​ Urine output down: ○​ Obliguria: