Pharm Quiz 5 part 2

Antibiotic Resistance

• Genetic mutations in bacterial DNA can alter antibiotic target sites, reduce drug binding, or modify metabolic pathways, decreasing the efficacy of the drug.
• Bacteria can alter the channel structure or pores that antibiotics use to enter the cell, exhibiting resistance to penicillins and tetracyclines.
• Some bacteria produce enzymes like β-lactamases that degrade or modify antibiotics, deactivating them.
• Certain strains of Haemophilus influenzae produce beta-lactamase, which destroys penicillin and ampicillin.
• Gram-negative bacteria can develop or enhance systems (efflux pumps) that pump antibiotics out of the cell, reducing the intracellular drug concentration.
• Efflux pumps prevent accumulation of tetracycline antibiotics, exemplifying how resistance develops.
• Changes in the bacterial cell wall or membrane can decrease antibiotic uptake, limiting access to internal targets.
• Gram-negative bacteria have an outer lipopolysaccharide membrane, creating a barrier to many antibiotics.
• The outer membrane contains porin channels through which lipophilic or small drugs can enter.
• Resistant bacterial strains possess less permeable outer membranes or porin channels.
• Pseudomonas aeruginosa is resistant to gentamicin due to this mechanism.
• Bacteria can produce a different protein target site where the antibiotic normally binds, preventing the antibiotic from binding and killing the bacteria.
• Methicillin-resistant Staph. aureus (MRSA) has an altered penicillin-binding protein, preventing methicillin from binding and killing the bacteria.

Bactericidal versus Bacteriostatic Agents

• Bactericidal agents kill bacteria/microorganisms.
• They destroy the bacterial cell wall, interfere with essential cellular processes, or disrupt the bacterial membrane, leading to cell death.
• Examples of bactericidal agents include penicillins, cephalosporins, and aminoglycosides.
• Bacteriostatic agents inhibit the growth and reproduction of bacteria without directly killing them.
• They are less aggressive than bactericidal agents.
• Bacteriostatic action allows the immune system to clear the infection.
• These agents typically interfere with protein synthesis or metabolic pathways.
• Examples of bacteriostatic agents include tetracyclines, macrolides, and sulfonamides.

Migraine Headache Treatment

• Acute (Abortive) Treatment aims to stop the migraine once it has started.

First-Line Treatment (Mild to Moderate Migraine)

• NSAIDs (Nonsteroidal Anti-Inflammatory Drugs):
  • Ibuprofen: 400-800 mg PO
  • Naproxen: 500-750 mg PO
  • Aspirin: 900-1000 mg PO
  • Diclofenac: 50-100 mg PO
  • Acetaminophen: 1000 mg PO
• Combination Analgesics:
  • Excedrin Migraine (Aspirin + Acetaminophen + Caffeine): 2 tablets
• Avoid overuse of these medications to prevent medication overuse headache or rebound headache.

First-Line Treatment (Moderate to Severe Migraine)

• Triptans (Serotonin 5-HT1B/1D Receptor Agonists):
  • Sumatriptan: 25-100 mg PO, 6 mg SC, or 20 mg intranasal
  • Rizatriptan: 5-10 mg PO
  • Zolmitriptan: 2.5-5 mg PO or 5 mg intranasal
  • Eletriptan: 20-40 mg PO
  • Naratriptan: 1-2.5 mg PO (longer half-life, slower onset)
  • Frovatriptan: 2.5 mg PO (longest half-life, useful for menstrual migraines)
• Contraindications for Triptans:
  • Cardiovascular disease (CAD, history of MI, stroke)
  • Uncontrolled hypertension
  • Pregnancy
  • Basilar or hemiplegic migraine

Second-Line Treatment (If Triptans Are Ineffective or Contraindicated)

• Gepants (CGRP Receptor Antagonists):
  • Rimegepant: 75 mg PO (oral dissolving tablet)
  • Ubrogepant: 50-100 mg PO
  • Zavegepant: 10 mg intranasal
• Advantages over triptans:
  • No vasoconstrictive effects, making them safer for cardiovascular patients.

Alternative Second-Line Treatment

• Ditans (Selective 5-HT1F Agonist):
  • Lasmiditan: 50-200 mg PO
  • Less vasoconstriction than triptans, making it suitable for patients with CV risk.
  • Causes significant sedation, and driving should be avoided for 8 hours after use.
• Ergot Alkaloids (5-HT1 Agonists, Vasoconstrictive):
  • Dihydroergotamine: 1 mg IV/IM/SC or 0.5-1 mg intranasal
  • Ergotamine + Caffeine: 1-2 mg PO or PR
  • Reserved for refractory cases due to more side effects than triptans.
• Anti-Emetics (for nausea/vomiting, adjunctive therapy):
  • Metoclopramide: 10 mg IV/PO
  • Prochlorperazine: 10 mg IV/PO
  • Chlorpromazine: 25 mg IV
  • Ondansetron: 4-8 mg IV/PO
• Corticosteroids (for status migrainosus, persistent migraine >72h):
  • Dexamethasone: 10-24 mg IV/PO
• Intravenous Fluids:
  • Useful for dehydration or migraine associated with nausea/vomiting

Preventive (Prophylactic) Therapy

• Indications for Preventive Therapy:
  • ≥ 4 migraine days per month
  • Severe, disabling migraines
  • Inadequate response to acute treatments
  • Hemiplegic, basilar-type, or menstrual migraines

First-Line Preventive Medications

• Beta-Blockers:
  • Propranolol: 40-160 mg/day PO
  • Metoprolol: 50-200 mg/day PO
  • Atenolol: 50-100 mg/day PO
  • Good for hypertensive or anxious patients.
• Antiepileptics:
  • Topiramate: 25-100 mg/day PO
  • Valproate: 500-1500 mg/day PO
  • Topiramate is weight-neutral, while Valproate causes weight gain.
• Tricyclic Antidepressants (TCAs):
  • Amitriptyline: 10-50 mg QHS
  • Nortriptyline: 10-50 mg QHS
  • Good for patients with comorbid depression, insomnia, or fibromyalgia.
• SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors):
  • Venlafaxine: 37.5-150 mg/day
  • May be preferred in patients with anxiety or depression.

Second-Line Preventive Medications

• Calcium Channel Blockers (CCBs):
  • Verapamil: 120-240 mg/day PO
  • Used for hemiplegic migraine or cluster headaches.
• Angiotensin II Receptor Blockers (ARBs):
  • Candesartan: 4-16 mg/day PO
• Onabotulinumtoxin A (Botox):
  • 31 injections every 12 weeks for chronic migraine (≥ 15 headache days/month).
• CGRP Monoclonal Antibodies (Injectables for Chronic/Refractory Migraine):
  • Erenumab: 70-140 mg SC monthly
  • Fremanezumab: 225 mg SC monthly
  • Galcanezumab: 240 mg loading dose, then 120 mg monthly
  • Eptinezumab: 100-300 mg IV every 3 months
• Pros: Highly effective, well-tolerated, long-acting.
• Cons: Expensive, requires insurance prior authorization.

Non-Pharmacologic Preventive Therapy

• Diet & Lifestyle Changes:
  • Avoid triggers like caffeine, alcohol, processed foods, and artificial sweeteners.
  • Stay hydrated and maintain a consistent sleep schedule.
  • Engage in regular aerobic exercise, yoga, and stress reduction techniques.
• Cognitive Behavioral Therapy (CBT):
  • Beneficial for patients with stress-related migraines.
• Supplements:
  • Magnesium: 400 mg/day
  • Riboflavin (Vitamin B2): 400 mg/day
  • Coenzyme Q10: 100-300 mg/day

Biologic and Non-Biologic DMARDs

• DMARDs (Disease-Modifying Antirheumatic Drugs) are used to treat autoimmune diseases like rheumatoid arthritis.
• DMARDs slow down or modify the course of the disease, rather than just alleviating symptoms.
• There are two main types: biologic DMARDs and non-biologic DMARDs.

Non-Biologic DMARDs

• Non-biologic DMARDs (also called Traditional DMARDs) are small-molecule drugs that suppress the immune system.
• They are usually taken orally, and some can be administered by injection.
• Non-biologic DMARDs are often used as the first-line treatment for diseases like rheumatoid arthritis (RA) and psoriatic arthritis.
• Examples:
  • Methotrexate is the most commonly used DMARD for RA, inhibiting the immune system and reducing inflammation.
  • Sulfasalazine is often used for RA and inflammatory bowel diseases like Crohn’s disease.
  • Hydroxychloroquine is used for diseases like lupus and RA, with a less potent immune-suppressive effect.
  • Leflunomide is used to treat RA by inhibiting the proliferation of immune cells.
  • Azathioprine is often used for inflammatory diseases like lupus.
• Mechanism of Action:
  • Non-biologic DMARDs target the immune system directly, inhibiting certain enzymes or processes involved in immune cell function.
  • They help prevent joint damage by controlling the underlying inflammatory process of autoimmune diseases.
• Side Effects:
  • Gastrointestinal issues
  • Liver toxicity, especially with methotrexate and leflunomide
  • Bone marrow suppression (decreased white blood cells or platelets)
  • Risk of infections due to immune suppression

Biologic DMARDs

• Biologic DMARDs (also called Biologics) are derived from living cells and target specific components of the immune system.
• They target specific proteins involved in the inflammatory process.
• Examples:
  • TNF inhibitors (Tumor Necrosis Factor Inhibitors): Etanercept, Adalimumab, Infliximab
  • Interleukin inhibitors: Tocilizumab (targets IL-6), Ustekinumab (targets IL-12 and IL-23)
  • B-cell inhibitors: Rituximab (targets CD20+ B-cells)
  • T-cell costimulation inhibitors: Abatacept (inhibits T-cell activation)
• Mechanism of Action:
  • Biologic DMARDs target specific molecules or cells involved in the inflammatory process.
  • TNF inhibitors block tumor necrosis factor (TNF).
  • Interleukin inhibitors block specific interleukins (e.g., IL-6, IL-12).
  • B-cell inhibitors deplete B-cells.
  • T-cell inhibitors prevent the activation of T-cells.
• Side Effects:
  • Increased risk of infections
  • Injection site reactions
  • Risk of certain cancers (e.g., lymphoma, skin cancer)
  • Autoimmune diseases (e.g., lupus-like reactions)
  • Gastrointestinal issues

Gout Therapy

• Gout is inflammatory arthritis caused by uric acid crystal accumulation in joints, typically the big toe.
• It leads to severe pain, swelling, and redness, often affecting one joint at a time.
• Therapy focuses on relieving acute symptoms during a flare and lowering uric acid levels long-term to prevent future attacks.

Acute Gout Attack Treatment (Relieving Symptoms)

• Goal is to reduce pain, inflammation, and swelling.
• Nonsteroidal Anti-inflammatory Drugs (NSAIDs):
  • Examples: Ibuprofen, Naproxen, Indomethacin
  • Mechanism: Reduce inflammation and pain; first-line treatment for acute attacks.
  • Considerations: Use cautiously in patients with gastrointestinal issues, kidney problems, or heart disease.
• Colchicine:
  • Mechanism: Reduces inflammation caused by uric acid crystals, effective if taken early during a flare.
  • Considerations: Can cause gastrointestinal side effects like nausea and diarrhea; use carefully in people with kidney or liver issues.
• Corticosteroids:
  • Examples: Prednisone, Methylprednisolone
  • Mechanism: Taken orally or injected directly into the inflamed joint to reduce inflammation and pain.
  • Considerations: Used when NSAIDs or colchicine are not effective or contraindicated; long-term use can have significant side effects.

Chronic Gout Management (Lowering Uric Acid Levels)

• Prevents future gout flares and reduces the risk of joint damage by lowering uric acid levels in the blood.
• Urate-Lowering Therapy (ULT):
  • Xanthine Oxidase Inhibitors:
    • Allopurinol is the most commonly used medication to lower uric acid levels.
    • Febuxostat is similar to allopurinol and often used in patients who cannot tolerate allopurinol.
    • Considerations: Both medications can cause skin rashes or gastrointestinal issues and should be started at low doses to minimize the risk of flares.
  • Uricosuric Agents:
    • Probenecid increases the kidney’s ability to excrete uric acid.
    • Lesinurad is a newer drug that also increases uric acid excretion.
    • Considerations: Should not be used in patients with kidney stones or severe kidney dysfunction.
  • Pegloticase:
    • Mechanism: Breaks down uric acid into a more easily excreted substance. Used for severe, refractory gout.
    • Considerations: Typically given via IV infusion.
• Lifestyle Changes:
  • Diet: Limiting purine-rich foods (e.g., red meats, shellfish, organ meats) and alcohol can help prevent gout attacks.
  • Hydration: Drinking plenty of water helps prevent uric acid crystal formation.
  • Weight Management: Losing weight if obese can help lower uric acid levels and reduce flare frequency.
• Monitoring Uric Acid Levels:
  • Regular blood tests should be conducted to ensure that uric acid is maintained at a safe level (generally below 6 mg/dL) to prevent future flares.

Additional Considerations in Gout Management

• Acute Flare Prophylaxis:
  • Use of colchicine or low-dose NSAIDs during the first few months of urate-lowering therapy to prevent acute gout flares.
• Kidney Function:
  • Monitor kidney function, especially when using medications like allopurinol, probenecid, or pegloticase.