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Pharmacology Review

Pharmacology Concepts

  • Pharmacology: study of the interaction between the body and drugs.

  • Pharmacokinetics (PK): movement of drugs through the body — absorption, bioavailability, distribution, metabolism, excretion. See Fig. 3.1 if available.

  • Pharmacodynamics (PD): physiologic/biochemical effects of drugs — what a drug does to the body.

  • Pharmacogenomics: how a person’s genes affect response to medications; long-term goal is personalized drug/dose selection. FDA example: genotyping Asians for HLA- B*1502 before starting carbamazepine due to risk of Stevens–Johnson syndrome in certain alleles.

  • Half-life (t½): time for the drug concentration to decrease by 50%; used to design dosing and withdrawal.

  • Area Under the Curve (AUC): measure of overall drug exposure and bioavailability after a dose.

  • Maximum concentration (Cmax): peak serum concentration after a dose.

  • Minimum inhibitory concentration (MIC): lowest concentration of an antibiotic that inhibits growth after overnight incubation.

  • Trough (Cmin): lowest drug concentration just before the next dose.

Oral Drugs and First Pass Metabolism

  • First-pass metabolism (FPM): most oral drugs (except sublingual) undergo hepatic metabolism before reaching circulation.

  • Pathway: swallowed drug → esophagus → stomach → small intestine → portal circulation → liver (CYP450) → active drug released systemically; some drugs also metabolized by gut bacteria.

  • Some drugs have extensive FPM (e.g., insulin is not orally viable; must be parenteral).

  • Formulations that bypass FPM: IV/other parenteral routes, vaginal gels/creams, transdermal patches, topical ointments/creams/gels.

Drug Metabolism (Biotransformation)

  • Primary organ: liver; CYP450 enzyme system is the most active in metabolism.

  • CYP isozymes responsible for ~90% of metabolism: ext{CYP1A2}, ext{CYP2C9}, ext{CYP2C19}, ext{CYP2D6}, ext{CYP2E1}, ext{CYP3A4}

  • CYP3A4 and CYP2D6 are especially implicated in many interactions.

  • Metabolism can be induced (↑ clearance) or inhibited (↓ clearance), affecting drug levels.

  • Example: carbamazepine is a strong inducer of CYP450 leading to multiple interactions.

  • Other organ systems involved in drug metabolism: kidneys, GI tract (gut bacteria), lungs, plasma, skin.

Drug Excretion

  • Renal filtration is the major excretion pathway; kidneys are the principal elimination organ.

  • Age-related decline in renal function reduces drug excretion; CKD alters metabolism and increases adverse drug reactions risk.

  • Reference Tables (e.g., Drugs Affected by Kidney Disease) exist for CKD adjustments.

Pharmacokinetics: Age-Related Changes

  • Increased fat-to-water ratio

  • Decreased albumin and plasma proteins

  • Decreased liver blood flow and organ size

  • Decreased certain CYP450 pathways (↓ drug clearance)

  • Decreased glomerular filtration rate (GFR)

Potent Inhibitors: CYP450 System

  • Inhibitors slow clearance → higher drug concentrations → overdose risk.

  • Common inhibitors to memorize:

    • Macrolides (e.g., erythromycin, clarithromycin, telithromycin)

    • Antifungals (ketoconazole, fluconazole, itraconazole)

    • Cimetidine (Tagamet)

    • Citalopram (Celexa)

    • Protease inhibitors (e.g., saquinavir, indinavir, nelfinavir)

    • Antipsychotics (clozapine, olanzapine, quetiapine)

    • Grapefruit juice (not a drug, but affects CYP450) — impacts statins, erythromycin, certain CCBs (nifedipine, nisoldipine), antivirals (indinavir, saquinavir), amiodarone, benzodiazepines (diazepam, triazolam), cisapride, carbamazepine, buspirone.

Narrow Therapeutic Index (NTI) Drugs

  • Warfarin (Coumadin): monitor INR.

  • Digoxin (Lanoxin): monitor digoxin level, EKG, electrolytes (K, Mg, Ca).

  • Theophylline: monitor blood levels.

  • Carbamazepine (Tegretol) and Phenytoin (Dilantin): monitor blood levels.

  • Levothyroxine: monitor TSH.

  • Lithium: monitor blood levels and TSH (risk of hypothyroidism).

Beers Criteria

  • Guidance on medications to avoid in adults >65; developed 1991 by Mark Beers; adopted by American Geriatrics Society.

  • 2015 update: guidelines list by organ system, therapeutic category, and drug name with rationale and evidence.

  • 2020 updates emphasize avoidance of

    • Antipsychotics: quetiapine, clozapine, pimavanserin (use with caution)

    • DOACs rivaroxaban and dabigatran: higher bleeding risk than warfarin/DOACs

    • Tramadol: risk of hyponatremia (SIADH)

    • Opioids: avoid combining with benzodiazepines or gabapentinoids due to severe respiratory depression risk

Drugs Affected by Kidney Disease

  • NSAIDs: reduce renal blood flow; risk to kidneys.

  • ACE inhibitors (ACEIs): risk of hyperkalemia with CKD; caution with potassium supplements or potassium-sparing diuretics.

  • Warfarin: increased bleeding risk with CKD; higher risk of over-coagulation when INR elevated.

  • Severe CKD/ESRD: higher risk of hemorrhagic complications; require more frequent monitoring.

  • Lithium: risk of kidney injury; monitor renal function closely.

  • IV contrast dyes: risk of AKI with CT/MR/angiography.

  • Potassium-sparing diuretics: ↑ hyperkalemia risk with CKD.

  • Oral sodium phosphate: FDA warning (2019) for CKD patients due to potential AKI and electrolyte disturbances.

Safety Issues Associated with Common Prescription Drugs

  • H2 antagonists (famotidine, cimetidine, nizatidine): can cause mental status changes with CKD; avoid if creatinine clearance < 50 ext{ mL/min}.

  • Proton Pump Inhibitors (PPIs): omeprazole — risks include fractures, pneumonia, C. diff infection, hypomagnesemia, B12/iron malabsorption, atrophic gastritis; interact with warfarin, diazepam, carbamazepine, phenytoin, ketoconazole; monitor.

  • Vitamin K antagonists (Warfarin): interacts with many herbs (garlic, gingko, ginseng) and others (feverfew, green tea, fish oil); avoid before surgery (discontinue 7 days prior).

  • Thiazolidinediones (Pioglitazone): boxed warning for heart failure; contraindications include history of MI, stroke, bladder cancer, type I diabetes, liver or eye problems; monitor dyspnea, weight gain, cough.

  • Atypical antipsychotics (risperidone, olanzapine, quetiapine): high risk of weight gain, metabolic syndrome, diabetes; boxed warning for higher mortality in elderly; monitor TSH, lipids, glucose/A1C; monitor weight; caution.

  • Bisphosphonates (alendronate, risedronate): esophagitis risk if not taken with water; take upon awakening with 8 oz water; sit upright for 30 minutes; contraindications include active GI disease, CKD, esophageal stricture/varices.

  • Statins: need avoid grapefruit juice; risk of drug-induced hepatitis or rhabdomyolysis with azoles; high-dose simvastatin (80 mg) carries high rhabdomyolysis risk; Chinese descent at higher risk with simvastatin and niacin; monitor CK.

  • Lincosamides (clindamycin): higher risk of C. difficile colitis.

  • Inhaled corticosteroids: potential adrenal insufficiency in children with long-term high-dose use; test for adrenal insufficiency if hypoglycemia, hypotension, altered mental status, weakness, Cushingoid features, growth deceleration.

  • Systemic glucocorticoids: cataracts, osteoporosis, skin changes, mood changes, weight gain, HTN.

  • Anticonvulsants (phenytoin): gingival hyperplasia; toxicity signs include horizontal nystagmus, ataxia, etc.

Drugs Used to Treat Heart Disease

  • Cardiac glycosides: Digoxin

    • Use has declined due to newer therapies; now 2nd–3rd line for HFrEF.

    • Narrow therapeutic range: 0.5 ext{ to } 2.0 ext{ ng/mL}.

    • Toxicity risk: GI symptoms, hyperkalemia, bradycardia, AV blocks, VT/VF, confusion, visual changes (yellow-green tint).

    • Digoxin-specific antibodies available (Digibind/DigiFab) for toxicity.

    • If plant sources with glycosides suspected, ED referral.

  • Anticoagulants: overview below.

Pharmacokinetics, Laboratory Monitoring, and Drug Interactions

  • INR monitoring and targets:

    • Atrial fibrillation without prosthetic valve: INR ext{ target} = [2.0, 3.0]

    • Prosthetic heart valves: INR ext{ target} = [2.5, 3.5]

  • Direct Oral Anticoagulants (DOACs) vs Warfarin:

    • DOACs: direct thrombin inhibitors (dabigatran) and direct Xa inhibitors (apixaban, rivaroxaban, edoxaban, betrixaban).

    • DOACs: fixed dosing, fewer drug interactions, no routine INR monitoring; used for VTE prophylaxis and AF, among other indications.

    • Warfarin (Coumadin): vitamin K antagonist; requires INR monitoring; interacts with many foods and drugs; pregnancy category varies (see PLLR notes below).

    • Reversal: dabigatran (idarucizumab, Praxbind), FXa inhibitors (andexanet alfa, Andexxa); also FFP or PCC can be used in some settings.

  • Warfarin specifics:

    • Pregnancy: category-specific; mechanical valve in pregnancy may have different considerations; many pregnancy categories exist due to fetal risks.

    • Onset of action: typically 24–72 hours; full anticoagulation effect can take 5–7 days after initiation.

    • Dosing and stabilization: may require referral to anticoagulation clinic.

    • INR management: routine monitoring; single out-of-range INR adjustments guided by clinical context.

    • Dietary vitamin K foods (kale, spinach, collards, mustard greens, broccoli) can decrease anticoagulation effect; educate on daily intake.

    • Major interactions: grapefruit juice, antibiotics, NSAIDs, herbal products, etc.

    • Vitamin K reversal: available if needed.

    • Purple toes syndrome is a rare adverse effect; bleeding risks exist.

  • Other anticoagulants and bleeding risk modifiers:

    • Drugs that increase bleeding risk: Warfarin, DOACs, heparins, antiplatelets (clopidogrel), aspirin; reversal agents vary by agent.

    • Boxed warnings and monitoring recommendations exist for high-risk populations.

Antimicrobials: Classes, Key Points, and Safety

  • Macrolides:

    • Generally bacteriostatic; can be bactericidal at high concentrations.

    • Major drug interactions: strong CYP3A4 inhibitors; erythromycin and clarithromycin are potent inhibitors; azithromycin has fewer interactions.

    • QT prolongation risk; caution in patients with myasthenia gravis; avoid in pregnancy with some macrolides (telithromycin has higher risk).

    • Common agents: erythromycin, azithromycin, clarithromycin.

    • Adverse effects: GI distress; hepatotoxicity (especially erythromycin estolate); QT prolongation; potential MG exacerbation.

    • Practical tips: use one pharmacy database to monitor interactions; monitor warfarin if co-administered.

  • Tetracyclines:

    • Broad-spectrum; bacteriostatic; active against numerous gram-positive/negative and atypicals.

    • Pregnancy/lactation contraindicated; teeth discoloration risk in last half of pregnancy and in children until age 8; doxycycline permissible for RMSF in all ages per 2018 CDC stance.

    • Drug interactions: binds minerals (calcium, iron, zinc, magnesium, aluminum); avoid with antacids, dairy, iron products; reduces OCP effectiveness.

    • Common agents: doxycycline, tetracycline, minocycline, tigecycline (IV only with boxed warning), eravacycline, sarecycline, omadacycline.

    • Adverse effects: photosensitivity, esophageal irritation if capsule/ tablet lodges in esophagus, rare pseudotumor cerebri; avoid in pregnancy, infancy, or children ≤8 years.

    • Dosing/storage tips: take on an empty stomach; avoid with minerals; discard expired tetracyclines.

    • Indications by agent (examples): doxycycline for RMSF/STIs/respiratory infections; minocycline for acne and CA-MRSA; doxycycline dosing and specific uses vary by condition.

  • Fluoroquinolones (Quinolones):

    • Broad-spectrum; effective against gram-negatives and atypicals; newer agents also cover many Gram-positives.

    • High oral bioavailability; FDA warnings to reserve for severe infections when alternatives exist.

    • Major risks: Achilles tendon rupture (higher risk with steroids, age >60, organ transplant); QT prolongation; CNS effects; phototoxicity; hepatotoxicity; risk of aortic dissection; avoid in children and pregnant/breastfeeding due to cartilage/soft tissue toxicity.

    • Common agents: ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, gemifloxacin. Ophthalmic forms exist.

    • Interactions: avoid concomitant QT-prolonging drugs; minerals/antacids reduce absorption; risk of tendon pathology with steroids.

    • Indications (selected): pseudomonal pneumonia, cystic fibrosis-related infections, traveller’s diarrhea (severe), anthrax postexposure prophylaxis (ciprofloxacin), minor infections alternatives preferred.

    • Patient counseling: limit activity during therapy to reduce tendon rupture risk; avoid in high-risk patients.

  • Cephalosporins and Penicillins (Beta-lactams)

    • Cephalosporins: five generations; for NPExams cover first–third generations; all are beta-lactams that inhibit cell-wall synthesis; resistance via beta-lactamases.

    • First generation: active against gram-positive cocci; limited anaerobic coverage; MRSA coverage lacking; cross-reactivity with penicillin allergy possible.

    • Second generation: broader spectrum; active against some gram-negatives; still good for ENT/RTI.

    • Third generation: better gram-negative coverage; CNS penetration for meningitis; cross-check for penicillin allergies due to anaphylaxis risk.

    • Common penicillins: penicillin VK, amoxicillin, amoxicillin-clavulanate, dicloxacillin; indications include strep throat, otitis media, rhinosinusitis, syphilis, cellulitis (non-MRSA).

    • Adverse effects: hypersensitivity; CDAD risk; leukopenia/thrombocytopenia (rare).

    • Important notes: ceftriaxone (Rocephin) used for gonorrhea; avoid in hyperbilirubinemia and preterm infants due to kernicterus; penicillin allergy increases risk for cephalosporin allergy; empiric CNS indications for third-gen cephalosporins.

  • Other antibiotics (summary concepts):

    • TMP-SMX (Bactrim DS): teratogenic in first trimester; warfarin interactions; G6PD deficiency considerations; UTI use; potential SJS risk.

    • Lincosamides (Clindamycin): bacteriostatic/bactericidal depending on organism; higher risk for C. difficile colitis; indicated for penicillin-allergic patients with gram-positive infections.

    • Macrolides vs tetracyclines: drug interaction profiles differ; tetracyclines avoid with antacids/Calcium products; macrolides strong CYP inhibitors except azithromycin.

    • Penicillins: broad-spectrum uses; resistance via penicillinases; adverse events include diarrhea, CDAD, candidal vaginitis; caution with mononucleosis when using amoxicillin (rash).

  • Common drugs of abuse (overview):

    • Cannabis: euphoria, increased appetite, conjunctival injection; tachycardia; psychomotor effects 12–24 hours; variable legality.

    • Prescription opioids: euphoria, respiratory depression; risk with alcohol; naltrexone reversal.

    • Dextromethorphan: euphoria, tachycardia, seizures in overdose; interactions with MAOIs/SSRIs/SNRIs.

    • Cocaine: euphoria, paranoia, tachycardia; nasal damage with chronic use.

    • Methamphetamine: bruxism, weight loss, dental caries; stimulant effects.

Common Drug Safety Themes and Monitoring

  • Eye examinations are required with several drugs due to potential vision-related adverse effects:

    • Digoxin (yellow-green vision, halos if levels high)

    • Ethambutol and linezolid (optic neuropathy)

    • Corticosteroids (cataracts, glaucoma, optic neuritis)

    • Fluoroquinolones (retinal detachment)

    • PDE5 inhibitors (cataracts, ischemic optic neuropathy)

    • Isotretinoin (cataracts, reduced night vision)

    • Topiramate (angle-closure glaucoma, increased ICP)

    • Hydroxychloroquine (optic neuropathy, vision loss)

  • Boxed warnings apply to several drug classes; many require pregnancy risk assessment under PLLR.

FDA Labeling and Regulation

  • FDA Pregnancy and Lactation Labeling Rule (PLLR) updated June 30, 2015; replaced traditional letter categories (A, B, C, D, X) with:

    • Pregnancy

    • Lactation

    • Females and Males of Reproductive Potential

  • Drugs to avoid in pregnancy include finasteride, isotretinoin, warfarin, misoprostol, certain antipsychotics, ACEIs/ARBs, thalidomide, DES, etc.

Controlled Substances and Prescribing

  • US Controlled Substances Act schedules:

    • Schedule I: no accepted medical use; high abuse potential (e.g., heroin, MDMA, PCP).

    • Schedule II: high potential for abuse with severe dependence; prescriptions require original signed paper or specific arrangements for electronic prescriptions; no refills for Schedule II; 30-day supply majority.

    • Schedule III–V: less potential for abuse; can be prescribed via paper, phone verbal orders, or electronic systems with some state variations.

  • DEA number required on prescriptions for controlled substances; state boards may require collaborative agreements with physicians in NP practice.

Prescribing Process and Safety Practices

  • The Five Rights of safe prescribing:
    1) Right patient, 2) Right drug, 3) Right dose, 4) Right time, 5) Right route.

  • E-prescribing is preferred for many payers and improves formulary adherence.

  • Drug formularies and generics: most prescriptions are filled with generics; patients may request brand names; non-formulary meds may incur higher costs.

  • Tamper-resistant prescription pads are required by many jurisdictions; some prescriptions can be electronic.

Complementary and Alternative Medicine (CAM) & Integrative Medicine

  • CAM includes herbal supplements, probiotics, acupuncture, homeopathy, Ayurveda, yoga, meditation, etc.; integrative medicine combines CAM with standard care when shown to be safe and effective.

  • Herbal supplements (examples): Echinacea, feverfew, cinnamon, glucosamine, ginkgo, saw palmetto, kava, valerian, St. John’s wort, turmeric, fish/krill oil.

  • Homeopathy: Law of Similars; highly diluted substances; official lists (Homeopathic Pharmacopoeia of the United States).

  • Ayurveda: ancient Indian system balancing diet, spices, herbs, yoga.

  • CAM interactions: herbals can interact with conventional medicines (e.g., Ginkgo with NSAIDs, St. John’s wort with many drugs); caution in major illnesses.

Practical Dosing, Monitoring, and Counseling Tips

  • Do not rely on memorizing drug doses as heavily as disease management concepts; understand mechanisms, safety, interactions, and monitoring requirements.

  • For many older adults, Beers Criteria-guided choices help reduce adverse events.

  • In older adults, consider lower starting doses, slower tapering, and closer monitoring for adverse effects.

  • Always assess dietary intake of vitamin K if a patient is on warfarin; high vitamin K foods can decrease INR.

  • When prescribing antibiotics, consider resistance patterns, pregnancy status, and potential drug interactions; avoid fluoroquinolones when not necessary due to safety concerns.

Quick Reference: Common Mechanisms and Practical Rules

  • CYP inhibition vs induction:

    • Inhibition: ↑ levels of co-administered drugs; watch for toxicity.

    • Induction: ↓ levels of co-administered drugs; possible loss of efficacy.

  • QT prolongation risk is a recurring concern with macrolides, fluoroquinolones, some antiarrhythmics, and other drugs; monitor electrolytes (K, Mg) and avoid coadministration with other QT-prolonging agents when possible.

  • NSAIDs: avoid in HF, severe renal disease, or active GI bleeding; COX-2 inhibitors offer lower GI risk but have their own considerations; avoid long-term NSAID use with aspirin for cardioprotection unless clinically justified.

  • Acetaminophen (paracetamol): max daily dose generally 3{,}000 ext{ mg} ext{ (3 g)} to 4{,}000 ext{ mg} ext{ (4 g)} depending on guidelines; acetylcysteine is antidote for overdose; chronic alcohol use increases hepatotoxicity risk.

  • Capillary-based monitoring for certain drugs (e.g., digoxin levels, INR for warfarin) is critical; labs and EKGs guide adjustments.

  • Avoid abrupt discontinuation of certain medications (e.g., benzodiazepines, SSRIs, SNRIs, steroids) due to withdrawal risks; taper as advised.

Summary: Key Takeaways for Exam Readiness

  • Know core PK/PD concepts, definitions, and how to apply them to drug selection, monitoring, and safety.

  • Memorize major drug classes and representative drugs, with their key safety issues, monitoring requirements, and special populations (elderly, CKD, pregnancy, pediatrics).

  • Understand the RAAS system, why ACEIs/ARBs are used, and contraindications (angioedema, pregnancy, CKD considerations).

  • Be able to categorize antihypertensive agents by class, mechanism, and common adverse effects; know when to prefer diuretics, RAAS blockers, CCBs, or ARNIs.

  • Recognize major drug interactions (CYP inhibitors/inducers, grapefruit juice effects) and high-risk combinations (bleeding risk with anticoagulants and antiplatelets, QT prolongation risks).

  • Know common infections pharmacology: macrolides, tetracyclines, cephalosporins, penicillins, fluoroquinolones, sulfonamides; contraindications and notable interactions.

  • Be aware of safety frameworks (Beers Criteria, PLLR labeling), and the evolving landscape of drug safety in geriatrics and pregnancy.

  • Understand CAM and OTC considerations, how to counsel patients on interactions, and when to refer to specialists (e.g., ophthalmology for drug-induced vision changes).

  • Remember practical prescribing essentials: E-prescribing, Five Rights, and understanding formularies and cost considerations for adherence.

Appendix: Key Formulas and Notations (LaTeX)

  • Pharmacokinetics terms:

    • t_{1/2} = half-life

    • AUC = area under the curve

    • C_{ ext{max}} = maximum concentration

    • C{ ext{min}} or C{ ext{ trough}} = trough concentration

  • Hypertension stages (ACC/AHA 2021):

    • Normal: ext{SBP} < 120 ext{ mmHg} ext{ and } ext{DBP} < 80 ext{ mmHg}

    • Elevated: ext{SBP} = 120 ext{–}129 ext{ mmHg} ext{ and } ext{DBP} < 80 ext{ mmHg}

    • Stage 1: ext{SBP} = 130 ext{–}139 ext{ mmHg or } ext{DBP} = 80 ext{–}89 ext{ mmHg}

    • Stage 2: ext{SBP} ext{≥ } 140 ext{ mmHg or } ext{DBP} ext{≥ } 90 ext{ mmHg}

  • INR targets for anticoagulation:

    • AF without mechanical valve: ext{INR}
      ightarrow [2.0, 3.0]

    • Prosthetic valves: ext{INR}
      ightarrow [2.5, 3.5]

  • Medication safety dosing notes (examples):

    • maximum daily acetaminophen dose: 3{,}000 ext{–}4{,}000 ext{ mg} ext{ per day}

    • aspirin dosing: acute management vs secondary prevention ranges (illustrative rather than formulaic)

  • Molecular and enzyme references:

    • CYP450 families: ext{CYP1A2}, ext{CYP2C9}, ext{CYP2C19}, ext{CYP2D6}, ext{CYP2E1}, ext{CYP3A4}

Note: This set of notes covers key concepts, classes, safety considerations, monitoring requirements, and practical guidelines from the provided transcript. Use these as a consolidated study reference, and refer back to the original content for any specific drug-name lists or table references mentioned in lectures.