Pharmacology Review Understand pharmacodynamics and pharmacokinetics and pharmacotherapeutics (Chapter 1) - Pharmacodynamics: the movement of drugs throughout the body; how drugs affect the body (receptors binding) Pharmacokinetic: How the body affects the drugs; Absorption, Distribution, Metabolism, and Excretion. Pharmacotherapeutics: The use of drugs to diagnose, prevent or treat disease, or prevent pregnancy Properties of an ideal drug (Chapter 1) - Effective, Safe, and Selective - Main properties - Reversible, predictable, low cost, no drug-drug interactions, simple generic name, easy administration, chemically stable. - No drug is really ideal 6 rights of drug administration (Chapter 2) - Right patient, right medication, right dose, right route, right time, right documentation. Routes of administration and benefits of each (Chapter 4) - - - Oral - Barrier: Epithelial lining of GI tract, capillary wall Pattern: Slow and variable (solubility, coating, pH, emptying time, food, concurrent medications - Advantages: Easy, convenient, cheap, ideal for self-medication, reversible –> safer than parenteral routes - Disadvantages: Variability, inactivation of some drugs due to gastric acid and enz., possible nausea and vomiting, patient adherence. Intravenous: - Barrier: None - Pattern: Complete and instant - Advantages: Rapid onset → ideal for emergencies, precise control over levels, permits the use of large fluids, ideal for irritant drugs. - Disadvantage: high cost, invasive, irreversible, not ideal for self-administered, risk of fluid overload, infection, and embolism. Intramuscular: - Barrier: Capillary wall - Pattern: Rapid with water-soluble drugs, slow with poorly soluble drugs. Also depends on blood flow. - Advantages: permits use of poorly soluble drugs, permits the use of depot preparations. - Disadvantage: possible discomfort, inconvenience, potential for injury. **Depot preparation: allow the medication to be absorbed slowly over an extended time - reduce the number of injections needed for long-term treatment. Ex: penicillin G. - Subcutaneous: - Same absorption properties, advantages, and disadvantages as IM. Other routes: - Topical, transdermal, inhaled, rectal, vaginal, sublingual, direct injection (joints, heart, nerves, etc) Enteral, parenteral (Chapter 4) - Enteral: Via GI tract (Oral route) Parenteral: Literal meaning is ‘outside of GI tract’ (all the injections) Absorption, metabolism, distribution, and excretion – what happens to a drug if liver or kidney disorders (Chapter 4) - - - - Absorption: the movement of a drug from its site of administration into the blood. - Factors that affect it: Rate of dissolution, Surface area, Blood flow, Lipid solubility, pH partition. Rum Sounds Bad Like Poop Distribution: drug movement from the blood to the interstitial space and into the cells. - Factors: circulation, the ability of the drug to exit the vascular system (membrane permeability, plasma protein binding) Metabolism: AKA biotransformation, the enzymatic alteration of drug structure. - Cytochrome P450 - a key component of the hepatic microsomal enzyme system. - Therapeutic consequences of drug metabolism (AIDAID) - Accelerated renal drug excretion - Depending on the lipid solubility of the drug; metabolizing it can change from lipid-soluble to nonsoluble → increases renal excretion. - Drug inactivation - Can change from pharmaceutically active to inactive forms. - Increased therapeutic action - Metabolism can increase the effect of some drugs. Ex: codeine to morphine. - Activation of prodrugs - Pharmaceutically inactive when administer but comes active with metabolism. Ex: fosphenytoin to phenytoin. - Increased or decrease toxicity - Factors: Age, induction of drug-metabolizing enzyme, first-pass effect, nutritional status, competition among drugs. Excretion: the removal of drugs from the body; mostly through renal excretion. - Renal Excretion has 3 processes: 1. Glomerular Filtration: moves drugs from blood to the tubular urine. If drugs are bound to albumin, they are too large to go into tubular urine → no filtration. 2. Passive Tubular Reabsorption: Moves drugs from the lumen back into the blood via concentration gradient. At this point, drug concentration in blood < drug concentration in the lumen. Works better for lipid-soluble drugs. 3. Active Tubular Reabsorption: Active pumps that pump drugs from blood to the tubular urine. P-glycoprotein can pump a variety of drugs into the urine. Factors that affect excretion: pH-dependent ionization, competition for active pumps, age. First-pass effect (Chapter 4) - - Refers to the rapid hepatic inactivation of certain oral drugs; can be inactivated/completely metabolized on its first pass through the liver → NO therapeutic effect. These drugs are best to give parenterally instead to bypass the liver. Pharmacodynamic interactions (Chapter 5) - Dose-Response relationships - Relationship between the size of an administered dose and the intensity of the response produced. ↑Dose = ↑Response. - - Three phases: (1) dose too low for effect (2) bigger dose corresponding to bigger response. (3) Bigger doses are unable to elicit a bigger response. Efficacy vs Potency - - Efficacy compares the level of therapeutic effect between two drugs at the same dose. - Potency compares which drug gets to therapeutic level at the smaller dose. Drug-Receptor interactions - Drugs - chemicals that produce effects by interacting with other chemicals - Receptors - special chemicals in the body that most drugs interact to produce effects - Receptors mimic or block the action of endogenous regulatory molecules and increase or decrease the rate of physiological activity normally controlled by that receptor - EXAMPLE: norepinephrine in the heart = ups cardiac output (CO) - Simple occupancy theory - (1) response level is proportional to the number of occupied receptors - (2) reaches the max level when ALL receptors are occupied. - Cannot explain why two drugs have different potency and maximal efficacy. - Modified occupancy theory - Look at the affinity and intrinsic factor Potency (Chapter 5) - Higher potency means that the drug can be given in smaller doses; does not mean that the drug with higher potency is more effective. Does not associated with maximal efficacy. ED50 and LD 50 (Chapter 5) - ED50: The dose that gives a predefined therapeutic effect in 50% of the population. This dose is usually considered a standard dose and is used for the initial treatment dose. - LD50: The dose that is lethal in 50% of the population. Receptor binding (Chapter 5) - Usually is reversible When binding to a receptor, it MIMICS or BLOCKS the action of endogenous regulatory molecules. Cannot give cells new functions. Drugs produce their therapeutic effects by helping the body use its preexisting capabilities. 4 main receptor families - Cell membrane-embedded enzymes (ex insulin; binding active enz, response in seconds) - Ligand-gated ion channels (in milliseconds ex: ACTH or GABA which keeps body systems in check) - G protein-coupled receptor systems (cascade reactions) - Transcription factors (found in cells-usually affect DNA, delay responses; hours to days) *** Fastest to slowest: Ligand-gated ion channels, cell membrane embedded enzymes, G protein cascade, transcription factors.** Agonist, antagonist, partials (Chapter 5) - - - Agonist: Activate the receptors; have high affinity and intrinsic activity. Can make the processes faster OR slower. - Ex: Dobutamine mimics norepinephrine at cardiac receptors. - Continuous exposure to agonist can cause down-regulation (desensitized) Antagonist (competitive): Block the endogenous from binding to the receptors. Have the same affinity as the endogenous molecules but no intrinsic activity. - Ex: beta-blockers used for patients with high BP. - Noncompetitive: irreversibly bind to the receptor → fewer available receptors → decrease effects of endogenous regulators. The impact is not permanent since receptors get replaced. - Continuous exposure to antagonist can cause hypersensitivity. Partial agonist: agonists that have moderate intrinsic activity, so it doesn’t activate the receptor as much. Can act as either agonists or antagonists. Pharmacologic classification - Based on the medication's chemical structure or therapeutic use. Therapeutic range – narrow; therapeutic index (Chapter 4) - The therapeutic range is the dose between MEC and toxic levels. The ratio of drugs’s LD50 to its ED50 A narrow therapeutic index indicates the drug is not as safe and would require monitoring of concentration in plasma. The effect of albumin levels (Chapter 5) - The normal albumin level is 3.5 mg/L Reversible binding with the drugs Drugs bound to albumin cannot leave the vascular system since they are too large to fit through the pores → may increase drug concentration in plasma. Albumin also carry the drug to the destination → affects distribution Generic names vs brand names (Chapter 3) - Generic names: Also know as nonproprietary name; assigned by US council. Each drug only have one generic name. - Brand names: Assigned by manufacturers; can be confusing with similar OTC medications. **Both generic and brand name should have the exact same active ingredients** MEC (Minimum Effective Concentration) - The minimum dose for the drug to have a therapeutic effect. Half-life (Chapter 4) - The time required for the amount of drug in the body to decrease by 50%; determines the dosing interval. Food-Drug interactions ○ Drug absorption ● Decreased rate, the extent of absorption (occasionally) – milk and tetracycline, fiber and digoxin ○ Increased absorption -High-calorie meal and saquinavir (HIV and AIDs med), without food, not enough is absorbed. ○ Drug metabolism ● The grapefruit juice effect (not occurring with other citrus fruits or juices) – statins!! ● Inhibits the metabolism of certain drugs (inhibiting CYP3A4) ● Raises the drugs blood levels (increases in felodipine…lovastatin (chol), cyclosporine, midazolam, and so on) ○ Food can affect drug toxicity ● Monoamine oxidase inhibitors (MAOIs) and tyramine-containing foods (aged products) ● Theophylline and caffeine ● Potassium-sparing diuretics and salt beverages (water retention) ● Aluminum containing antacids and citrus beverages ○ Drug action ● Warfarin and foods rich in vitamin k (works against) ● Timing of drug administration - some drugs are better tolerated on an empty stomach, others should be taken with food, esp for nausea ● Drug supplement interactions → conventional drugs can interact with herbal preparations ○ Just as likely as prescription meds ● Reliable info about drug-herb interactions is lacking ● Ex ST john's wort inducing drug-metabolizing enz and reducing the blood levels of many drugs Plateau levels (Chapter 4) - Occurs when the drug concentration in plasma reaches its peak level, occurs after 4 half-life. Nonrenal routes of elimination (Chapter 4) - Breast milk: lipid-soluble drugs have more access to breast milk. Bile: drugs that are in bile can either be reabsorbed back to portal blood (via enterohepatic recirculation) or go to the small intestine and be excreted in feces. Lungs: Drugs like volatile anesthetics can be excreted through the lungs, some are also excreted through sweats and saliva. Potentiation (Chapter 6) - One drug may increase the therapeutic effect of the other drug when taken together. - Considered as ‘potentiative’ effect - May be beneficial or detrimental - These two have the same therapeutic effect but different mechanisms - Acts on the same receptors?** Interpatient variability (Chapter 5) - The dose required top produce a therapeutic response varies between patient; usually start with ED50 dose (approximation) If initial dose does not work, can adjust based on patient’s need. Patient education - Make sure they know: drug name and therapeutic category, dosage size, dosing schedule, route and technique of administration, expected thera response & when it will develop, and nondrug measures to enhance thera responses, duration of treatment, method of storage, symptoms of major adverse effects and how to help, drug-drug and food-drug interactions (ex phenelzine and amphetamines and figs!), and whom to contact in an emergency. Drugs and the blood-brain barrier - - Blood brain barrier refers to the presence of tight junction between the cells that compose capillary walls in CNS → Drugs then have to pass through the CNS capillary instead of staying between them. P-glycoprotein increase drug expose from cells of brain capillaries into the blood → decrease drug exposure to brain. Angioedema (Chapter 7) - One of the allergic/hypersensitive reactions to a drug. Fluid build-up in blood vessels. ***Additional things to know from the slides Chapter 4 - Enterohepatic Recirculation - Repeating cycle in which drug is transported from the liver into the duodenum (via bile duct) then back to the liver via portal blood. - For drugs that underwent glucuronidation. - Glucuronidation - a process that converts lipophilic to hydrophilic. - Induction of drug-metabolizing enzymes - Increases its own metabolize rate or other drugs that are used concurrently - Result: have to increase dosage for therapeutic effect. - pH-dependent ionization - Acidic drugs accumulate/ionize on the alkaline side - Basic drugs accumulate/ionize on the acidic side **Ionized drugs can no longer cross the plasma membrane. - Loading dose: the initial large dose to get it to a therapeutic level. Chapter 5 - Affinity - the strength of thee attractions - Intrinsic - Ability of the drug to activate a receptor upon binding it Chapter 6 - Drug-Drug interactions: - May significantly affect the outcome of therapy - Four mechanisms: - Direct chemical/physical interaction - Cannot combine drugs in the same container prior to establishing compatibility - Pharmacokinetic interaction - Whichever causes alterations to the ADME process. Ex: altered the P45enzymes in the metabolism step (inhibition or induction) - Alterations of P-glycoproteins (acts in intestinal epithelium, placenta, blood-brain barrier, liver, kidney tubules) - Pharmacodynamic interaction - Same receptor: almost always inhibitory - At separate sites: potentiative or inhibitory - Combined toxicity - Drug with overlapping toxicities should not be used concurrently - Ex: isoniazid and rifampin - P-glycoproteins - Enzymes that pumps drugs out of cell - Acts at sites of intestinal epithelium, placenta, blood-brain barrier, liver, and kidney tubules. Chapter 7 - Adverse Drug Reactions - Any noxious, unintended, and undesired effect that occurs at normal drug dose. - Side effects - A nearly unavoiable secondary drug effect produced at therapeutic dose - Idiosyncrasy effect - An uncommon drug response resulting from a genetic predisposition. - Iatrogenic disease - Disease produced by drugs; drug-induced disease. - Signs of live rinjury: jaundice, dark urine, light-colored stools, nauseea, vomiting, malaise, abdominal discoomfort, and loss of appetite. - REMS and iPLEDGE - plans to make surre that women who are pregnant or plan to be pregnant do not have access to isotretinoin drugs.
