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Advanced Pharmacology
Rosenthal, L. D., & Burchum, J. R. (2021). Lehne’s pharmacotherapeutics for advanced practice nurses and physician assistants (2nd^ ed.) St. Louis, MO: Elsevier.
Week 1 (Chapters 1-6)
Ch. 1 Prescriptive Authority
-Prescriptive authority is the legal right to prescribe drugs. MDs and DOs have full authority. Mid-level providers' rights depend on licensure and legislation. -There are two components of prescriptive authority: (1) the right to prescribe independently and (2) the right to prescribe without limitation. *Schedule I drugs have no medical use -All PAs must have a physician relationship -IL NPs have a collaborative relationship with a provider for a certain amount of time -The National Acadamy of Medicine advocated for federal regulation of prescriptive authority so that there is no such difference from state to state ( http://www.nationalacademies.org/hmd/~/media/Files/Report%20Files/2010/The- Future-of-Nursing/Nursing%20Scope%20of%20Practice%202010%20Brief.pdf) Creates gap in care services in more restricted states, especially in underserved or rural areas ACA increases the need for all types of providers
Ch. 2 Rational Drug Selection and Prescription Writing
-Do not prescribe medications for family or friends or yourself. Document a thorough history and physical examination in your records. Include any discussions you have with the patient regarding risk factors, side effects, or therapy options. Have a documented plan regarding drug monitoring or titration, if applicable. If you consult additional providers, note that you did so. What to Consider when Prescribing
- Cost -Can affect whether a pt is compliant. Note the pts financial status. ($4 list)
- Availability in a Pharmacy’s Formulary
- Side Effects (risk vs. benefit)
- Allergies
- Hepatic and Renal Fcn Ex: MSO4 is metabolized by kidneys. In a renal pt, a better choice would be Fentanyl bc it doesn’t require dose reduction.
- Need for monitoring (drug levels, immune suppression) o Does the pt have access to a lab?
- Special Populations (ex: elderly)
Ch. 3 Promoting Positive Outcomes of Drug Therapy
- Ensuring positive outcomes requires establishing a medication education plan, monitoring positive and negative patient responses, identifying and addressing issues of nonadherence, and managing the patient's complete medication regimen. Education- Highly influences pt’s willingness for compliance. Can also dispel rumors r/t the medication Education Components: (1) medication name (Encourage pt to carry med list with generic and brand name) (2) purpose (3) dosing regimen (Should include mg’s, # of tablets, how often to take, what to do if a dose is missed. (4) administration (Taken with food? Shaken? Morning or night?) (5) adverse effects (Ethically obligated to explain this. Teach s/sx to report) (6) any special storage needs (7) associated laboratory testing (teach why, when, where, and how the testing needs done. This determines therapeutic dosing and compliance. Ex: Amiodarone can cause hepatotoxicity, pulmonary toxicity, and thyroid dysfunction. Some rx’s have a narrow therapeutic index (NTI)) pg 10 common reasons for monitoring certain rx’s (8) food or drug interactions (grapefruit juice, alcohol, antacids 2hrs before or after meds) (9) duration of therapy *Provide written instructions based on pts health literacy. Adherence Cost of noncompliance costs the healthcare system billions r/t death, hospitalizations, and exacerbations.
(2) passage with the aid of a transport system- carriers that can move drugs from one side of the cell membrane to the other side. All transport systems are selective. P-glycoprotein (PGP) or multidrug transporter protein is a transmembrane protein that transports a wide variety of drugs out of cells. (3) direct penetration of the membrane- Most drugs are too large for channels and pores and lack a transport system. “like dissolves like.” Membranes are composed primarily of lipids; therefore, to directly penetrate membranes, a drug must be lipid soluble (lipophilic). **Of the three, direct penetration of the membrane is the most common. Polar Molecules and Ions -Some molecules are NOT lipid soluble Can not transport across a lipid membrane Called polar ions and molecules Polar molecules have no net charge; however, they have an uneven distribution of electrical charge. Positive and negative charges within the molecule tend to congregate separately from one another. POLAR SOLVENT Polar Ions : DO have a net charge (either pos or neg). Unable to cross membranes so must become non-ionized. -most rx’s are either weak acids or bases. Weak acids become ionized in base and vice versa. Want the drug to be nonionized to work so don’t ionize it. i.e. aspirin is a weak acid so it absorbs in the stomach because of the acidic environment. When it passes into the alkaline small intestine, it becomes ionized and can not be absorbed. pH partitioning (Ion Trapping): Drugs Want to be ionized, despite their medical purpose, therefore, given the choice, they will accumulate in an area with their opposite pH. Absorption -The rate of absorption determines how soon effects will begin. The amount of absorption helps determine how intense the effects will be -Drug preparations are considered chemically equivalent if they contain the same amount of the identical chemical compound
- Preparations are considered equal in bioavailability if the drug they contain is absorbed at the same rate and to the same extent The BBB has PGP that pumps drugs out of cells and helps protect the CNS WATER!!!!
*Can be chemically equivalent and vary in bioavailability -The rate of dissolution is the amount of time it takes for a drug to dissolve and determines the rate of absorption
- Surface Area: The small intestine has a LARGE # of microvilli and is therefore a greater source for drug absorption than the stomach -Lipid Solubility- highly lipid-soluble drugs are absorbed more rapidly than drugs whose lipid solubility is low. This occurs because lipid-soluble drugs can readily cross the membranes that separate them from the blood, whereas drugs of low lipid solubility cannot. Distribution -determined by 3 major factors:
- blood flow to tissues- Abscesses and tumors( particularly solid tumors) affect blood flow, i.e. the ability of a drug to reach the site.
- the ability of a drug to exit the vascular system- through capillary beds or the BBB. The BBB has super tight junctions, therefore it is very hard for drugs to pass through. ONLY lipid soluble or drugs with transport systems can get through the BBB. **Newborns do not have a fully developed BBB and have an increased sensitivity to meds
- Most drugs cross the placenta via simple diffusion. Lipid-soluble, nonionized compounds readily pass from the maternal bloodstream into the blood of the fetus. Protein Binding: Plasma Albumin is a large protein molecule that is too large to exit the bloodstream, making it a good source for drug binding. But albumin MUST be attracted to that drug. Bad news: the drug can not leave the system until the bond with albumin is broken. Because the number of binding sites is limited, drugs with the ability to bind albumin will compete with one another for those sites. As a result, one drug can displace another from albumin, causing the free concentration of the displaced drug to rise, thus increasing the intensity of drug responses
- the ability of a drug to enter cells- Many drugs produce their effects by binding with receptors located on the external surface of the cell membrane; however, some drugs must enter cells to reach their sites of action, and practically all drugs must enter cells to undergo metabolism and excretion Metabolism (Biotransformation)
- Most drug metabolism that takes place in the liver is performed by the hepatic microsomal enzyme system, also known as the P450 system
- Therapeutic Consequences of Drug Metabolism: - Accelerated renal excretion of drugs most important. Can not excrete highly lipid- soluble forms of medications. Transforms them into water-soluble. - Drug inactivation- most common end result of drug metabolism - Increased therapeutic action- metabolism can increase the effect of some drugs. Ex: codeine to morphine. - Activation of prodrugs A prodrug is a compound that is pharmacologically inactive as administered and then undergoes conversion to its active form through metabolism. Example, a drug that cannot cross the BBB may be able to do so as a lipid-soluble prodrug that is converted to the active form in the CNS. - Increased toxicity- Increased toxicity is illustrated by the conversion of acetaminophen into a hepatotoxic metabolite. It is this product of metabolism, and not acetaminophen itself, that causes injury when acetaminophen is taken in an overdose - Decreased toxicity Factors that Effect Drug Metabolism Age Induction and Inhibition of Drug-Metabolizing Enzymes- Drugs may be P substrates, P450 enzyme inducers, and P450 enzyme inhibitors First-Pass Effect- rapid hepatic inactivation of certain oral drugs To circumvent the first-pass effect, a drug that undergoes rapid hepatic metabolism is often administered parenterally Nutritional Status- in malnutrition, certain cofactors may be depleted Competition Between Drugs- Can cause suppression of one or both drugs. If metabolism is depressed enough, a drug can accumulate to dangerous levels. Enterohepatic Recirculation- a repeating cycle in which a drug is transported from the liver into the duodenum (through the bile duct) and then back to the liver (through the portal blood. The process is limited to drugs that have undergone glucuronidation, a process that converts lipid-soluble drugs to water-soluble drugs by binding them to glucuronic acid. Because of enterohepatic recycling, drugs can remain in the body much longer than they otherwise would. Excretion
- Drugs and their metabolites can exit the body in urine, bile, sweat, saliva, breast milk, and expired air. The most important organ for drug excretion is the kidney.
Renal Drug Excretion:
- (1) glomerular filtration, (2) passive tubular reabsorption, and (3) active tubular secretion.
- Factors That Modify Renal Drug Excretion: Chronic renal dz, pH-dependent ionization, competition for active tubular transport, and patient age. -pH-dependent ionization can be used to accelerate renal excretion of drugs. By manipulating urinary pH in such a way as to promote the ionization of a drug, we can decrease passive reabsorption back into the blood and can thereby hasten the drug's elimination. This principle has been used to promote the excretion of poisons and medications that have been taken in toxic doses. -Competition for active tubular transport: Competition between drugs for active tubular transport can delay renal excretion, thereby prolonging effects. Tubules can carry so many molecules at a time. Time Course of Drug Responses
- It is possible to regulate the time at which drug responses start, the time they are most intense, and the time they cease. Plasma Drug Levels
- the time course of drug action bears a direct relationship to the concentration of a drug in the blood. Need a balanced plasma drug level that is neither subtherapeutic nor toxic. Half-Life -How rapidly the decline of a drug level occurs. The time required for the amount of drug in the body to decrease by 50%. Ex: The half-life of morphine is approximately 3 hours. By definition, this means that body stores of morphine will decrease by 50% every 3 hours—regardless of how much morphine is in the body. Plateau Drug Levels
- When the amount of drug eliminated between doses equals the dose administered, average drug levels will remain constant and a plateau will have been reached.
- When a drug is administered repeatedly in the same dose, a plateau will be reached in approximately four half-lives.
- When plateau must be achieved more quickly, a large initial dose can be administered. This large initial dose is called a loading dose. After high drug levels have been established with a loading dose, the plateau can be maintained by giving smaller doses.
- When drug administration is discontinued, most (94%) of the drug in the body will be eliminated over an interval equal to approximately four half-lives.
-Two major classes: (1) noncompetitive antagonists and (2) competitive antagonists -Noncompetitive antagonists bind irreversibly to receptors the more noncompetitive antagonist present, the less effect an agonist will be able to produce -Competitive antagonists are reversible. Compete with agonists for receptor binding. Whichever is present in higher concentration will bind to receptor.
- Partial Agonists- the maximal effect that a partial agonist can produce is lower than that of a full agonist. Can act as antagonists as well as agonists *when the receptors of a cell are continually exposed to an agonist, the cell usually becomes less responsive. When this occurs, the cell is said to be desensitized or refractory or to have undergone downregulation *Continuous exposure to antagonists has the OPPOSITE effect, causing the cell to become hypersensitive (also referred to as supersensitive). One mechanism that can cause hypersensitivity is synthesis of more receptors. Drug Responses That Do NOT Involve Receptors- act through physical or chemical interactions. Ex: Antacids, antiseptics, saline laxatives, and chelating agents Interpatient Variability. -ED50: the dose that is required to produce a defined therapeutic response in 50% of the population. Can be considered a standard dose and is usually the starting dose. Therapeutic Index: measurement of a drug’s safety. Defined as the ratio of the Lethal dose for 50% of a population (LD50) and the ED50. A LARGE therapeutic index means the drug is relatively safe Drug-Drug Interactions -When two drugs interact, there are three possible outcomes: (1) one drug may intensify the effects of the other ( potentiative ) (2) one drug may reduce the effects of the other ( inhibitory ) (3) the combination may produce a new response not seen with either drug alone (rare) Ex: ETOH and disulfiram (Antabuse) Most common
-Drugs can interact through four basic mechanisms: (1) direct chemical or physical interaction- usually renders both drugs inactive. Most common when drugs are combined in IV solutions. Frequently, produces a precipitate (2) pharmacokinetic interaction- Can alter absorption, distribution, metabolism, and excretion. Ex: altered absorption can occur when gastric pH is increased. This can inhibit the absorption of other meds.
- altered distribution can occur by (1) competition for protein binding and (2) alteration of extracellular pH. If there is competition for albumin binding it leaves one or both drugs free in the plasma which can produce a toxic effect. -altered distribution. Ex: if a drug were to increase extracellular pH, that drug would increase the ionization of acidic drugs in extracellular fluids, causing acidic drugs to be drawn out of cells into extracellular space. -Altered Metabolism- Drugs that increase the metabolism of other drugs do so by inducing synthesis of hepatic drug-metabolizing enzymes. CYP enzymes. (p.30) -For example, if a woman taking oral contraceptives were to begin taking phenobarbital, induction of drug metabolism by phenobarbital would accelerate metabolism of the contraceptive, thereby lowering its level. If drug metabolism were increased enough, protection against pregnancy would be lost. To maintain contraceptive efficacy, dosage of the contraceptive should be increased. (3) pharmacodynamic interaction- interactions in which the interacting drugs act at the same site (ALWAYS INHIBITORY) or interactions in which the interacting drugs act at separate sites (drugs influence the same physiologic process). Ex: MSO4 and Valium both act as CNS depressants. Ex 2: HCTZ and Spironolactone. One is K+ wasting and one is K+ sparing. Together they balance K+ to baseline normal excretion. (4) combined toxicity- administering 2 meds that have the potential for liver toxicity -Minimizing Adverse Drug–Drug Interxns: reducing the # of meds a pt is on and take a drug hx. Food-Drug Interactions -Can increase or decrease absorption -Grapefruit juice: Inhibits the metabolism of certain meds inside the intestine, resulting in increased absorption and toxic build up of med in blood. Due to involving intestinal metabolism, grapefruit juice does not affect IV medications.
Medication Guides
- MedGuides, are FDA-approved documents created to educate patients about how to minimize harm from potentially dangerous drugs. Required when the FDA has determined that (1) patient adherence to directions for drug use is essential for efficacy or (2) patients need to know about potentially serious effects when deciding to use a drug. Boxed Warnings
- strongest safety warning a drug can carry and still remain on the market. Provides a concise summary of the adverse effects of concern. Ex: Phenergan. Risk Evaluation and Mitigation Strategies -Some drugs can cause such serious adverse effects that they require an iPledge by the patient. Ex: Accutane. Must be careful to ensure women don’t get pregnant. Medication Errors -Defined by the National Coordinating Council for Medication Error Reporting and Prevention as “any preventable event that may cause or lead to inappropriate medication use or patient harm, while the medication is in the control of the healthcare professional, patient, or consumer.”
- Many medication errors result from using error-prone abbreviations, symbols, and dose designations (List on p.40).
- you can report a medication error through the Medication Error Reporting (MER) Program, a nationwide system run by the ISMP
Ch. 6 Individual Variation in Drug Responses
- body size can be a significant determinant of drug effects. Smaller people need smaller doses.
- Drug sensitivity varies with age. Infants and older adults especially (older adults = presence of multiple comorbidities and treatment with multiple drugs.). Pathophysiology (1) kidney disease- can reduce drug excretion, causing drugs to accumulate in the body. (2) liver disease- can cause drugs to accumulate. Liver = major site of drug metabolism (3) acid-base imbalance- pH partitioning (4) altered electrolyte status- rare to affect drug response. Exception = digoxin in the presence of hypokalemia.
Tolerance: decreased responsiveness to a drug as a result of repeated drug administration. -3 types of drug tolerance: (1) pharmacodynamic tolerance- minimum effective concentration (MEC) of a drug becomes abnormally high. Result of adaptive processes that occur in response to chronic receptor occupation. Minimum effective concentration (MEC) of a drug becomes abnormally high. (2) metabolic tolerance- tolerance resulting from accelerated drug metabolism. Ability of certain drugs (e.g., barbiturates) to induce the synthesis of hepatic drug- metabolizing enzymes. Rates of drug metabolism to increase. Does not affect the MEC. (3) tachyphylaxis- reduction in drug responsiveness brought on by repeated dosing over a short time. Depletion of a cofactor is required for med to act. Ex: transdermal Nitro Individual Variability in Absorption
- Bioavailability- amount of an active drug that reaches the systemic circulation from its site of administration. Different formulations of the same drug can vary in bioavailability. Factors such as tablet disintegration time, enteric coatings, and sustained-release formulations can alter bioavailability and can thereby make drug responses variable.
- occur primarily with oral preparations
- greatest concern = drugs with a narrow therapeutic range (small level change can = significant change in response).
- Diarrhea can reduce absorption by accelerating the transport of drugs through the intestine. Conversely, constipation may enhance the absorption of some drugs by prolonging the time available for absorption. Gender- and Race-Related Variations Ex:
- When used to treat heart failure, digoxin may increase mortality in women while having no effect on mortality in men.
- Alcohol is metabolized more slowly by women than by men. As a result, a woman who drinks the same amount as a man (on a weight-adjusted basis) will become more intoxicated.
- Certain opioid analgesics (e.g., pentazocine, nalbuphine) are much more effective in women than in men. As a result, pain relief can be achieved at lower doses in women.
WEEK 2 – CARDIOVASCULAR
Chapter 36- Review of Hemodynamics
The circulatory system is composed of the heart and blood vessels. The heart is the pump that moves blood through the arterial tree. The blood vessels have several functions:
- Arteries transport blood under high pressure to tissues.
- Arterioles are control vessels that regulate local blood flow.
- Capillaries are the sites for exchange of fluid, oxygen, carbon dioxide, nutrients, hormones, and wastes.
- Venules collect blood from the capillaries.
- Veins transport blood back to the heart. In addition, veins serve as a major reservoir for blood. -distribution of blood is uneven: most (64%) of the blood is in veins, venules, and venous sinuses; the remaining 20% is in arteries (13%) and arterioles or capillaries (7%). The large volume of blood in the venous system serves as a reservoir.
- Blood moves within vessels because the force that drives flow is greater than the resistance to flow. -Resistance to flow is determined by the diameter and length of the vessel and by blood viscosity. Cardiac Output: the average person, heart rate is about 70 beats/min and stroke volume is about 70 mL. Multiplying these, we get 4.9 L/min—the average value for CO.
- rate: Rate is increased by the sympathetic branch acting through β1-adrenergic receptors in the sinoatrial (SA) node -Rate is decreased by the parasympathetic branch acting through muscarinic receptors in the SA node. Parasympathetic impulses reach the heart through the vagus nerve. -Stroke Volume: determined by 3 factors: (1) myocardial contractility – determined by the amount of venous return to the heart (2) cardiac preload (End diastolic volume): Force of venous return. More return = more stretch = more force (3) cardiac afterload: arterial pressure that the left ventricle must overcome to eject blood. Primary determinant in CO
Starlings Law: The Starling law states that the force of ventricular contraction is proportional to muscle fiber length
- In the failing heart, the Starling law breaks down. That is, the force of contraction no longer increases in proportion to increased ventricular filling. As a result, blood backs up behind the failing ventricle. Regulation of Arterial Pressure: AP= PR (peripheral resistance) x CO Peripheral resistance is regulated primarily through constriction and dilation of arterioles
- AP is regulated primarily by three systems: the ANS (acts quickly r/t changes in BP), the renin- angiotensin-aldosterone system (RAAS) (Acts more slowly), and the kidneys (Long-term control) The Baroreceptor Reflex: -The reflex works as follows: Baroreceptors (pressure sensors) in the aortic arch and carotid sinus sense AP and relay this information to the vasoconstrictor center of the medulla
- rapid action but not sustained action -Drugs that lower AP will trigger the baroreceptor reflex. For example, if we administer a drug that dilates arterioles, the resultant drop in PR will reduce AP, causing the baroreceptor reflex to activate. The most noticeable response is reflex tachycardia. The baroreceptor reflex can temporarily negate efforts to lower AP with drugs. -The RAAS supports AP by causing (1) constriction of arterioles and veins and (2) retention of water by the kidneys. Vasoconstriction is mediated by a hormone named angiotensin II. Water retention is mediated in part by aldosterone through the retention of sodium Renal Retention of Water -Sustained low AP = renal H2O retention = rise in AP sustained low AP results in kidneys retaining water because of low RBF = reduced GFR = decreased urine output Low AP also activates RAAS which further decreases RBF Natriuretic Peptides : protect the cardiovascular system in the event of volume overload Natriuretic peptides work primarily by (1) reducing blood volume and (2) promoting dilation of arterioles and veins. Both actions lower AP.
Distal nephron : late distal convoluted tubule and collecting duct- Na+ and K+ exchange via Aldosterone. Determines the final concentration of the urine and is regulated by antidiuretic hormone (ADH) Sodium–potassium exchange ALDOSTERONE: principal mineralocorticoid of the adrenal cortex stimulates reabsorption of sodium from the distal nephron causes potassium to be secreted Introduction to Diuretics How Diuretics Work -Prevent reabsorption of H2O Na+ retention K+ excretion
*Amt of excretion of urine depends on how much sodium and chloride are retained (water follows) More solute retention = more water = more urine production
- drugs that act early in the nephron have the opportunity to block the greatest amount of solute reabsorption **proximal convoluted tubule drugs are more effective Ex: a diuretic will increase daily urine output by 1.8 L for each 1% of solute reabsorption that is blocked. A 3% blockade of solute reabsorption will produce 5.4 L of urine a day—a rate of fluid loss that would reduce body weight by 12 pounds in 24 hours 4 Classes of Diuretics
- Loop: Most effective because it acts on the ASCENDING LOOP OF HENLE a. MOA: substantial amount (20%) of filtered NaCl is normally reabsorbed in the loop of Henle b. Pharmacokinetics: oral acts in 1hr and lasts 8 hrs. Metabolized by liver and excreted by kidney c. Therapeutic uses: Pulmonary edema r/t CHF, edema of hepatic, cardiac, or renal origin on which less strong diuretics did not help, HTN of other diuretics did not work. Works well in RF pts because works even in presence of low RBF d. Adverse Effects: Hyponatremia, hypochloremia, and dehydration. HYPOKALEMIA. OTOTOXICITY With furosemide, deafness is transient. With ethacrynic acid (another loop diuretic), irreversible hearing loss may occur. Other A/E’s hyperglycemia, hyperuricemia, increased LDL and lowered HDL. Carry a Black Box Warning r/t severe dehydration e. Not safe in pregnancy f. Drug-drug interactions: DIGOXIN!!! Digoxin toxicity increased in hypokalemia so patients in both need close monitoring i. Ototoxic drugs like gentamycin should be avoided in combo with Loops ii. Lithium iii. K+ sparing diuretics iv. NSAIDS g. Other loops: ethacrynic acid (Edecrin), torsemide (Demadex), and bumetanide. All work the same way on the thick ascending loop of Henle
- Thiazides: Lesser water loss than Loops. HCTZ. a. MOA: early segment of the distal convoluted tubule. Only 10% of water reabsorption happens here so the effects are less than Loops. i. Need adequate renal function to work b. Pharmacokinetics: 2 hr onset. Peak in 4-6hrs. Last up to 12hrs. c. Therapeutic Uses: HTN and edema d. Adverse Effects and Drug Interactions: SAME AS LOOP BUT NOT OTOTOXIC. Use with caution in patients with cardiovascular disease, renal impairment, diabetes mellitus, or a history of gout and in patients taking digoxin, lithium, or antihypertensive drugs.
