Pharm Quiz 5 Part 2

Antibiotic Resistance

• Genetic mutations in bacterial DNA can alter antibiotic target sites, diminishing drug binding or modifying metabolic pathways, which reduces drug effectiveness.
• Organisms can change the structure of channels or pores that antibiotics use to enter cells, leading to resistance against penicillins and tetracyclines.
• Some bacteria produce enzymes like β-lactamases that degrade or modify and deactivate antibiotics.
• Certain Haemophilus influenzae strains produce beta-lactamase, which destroys penicillin and ampicillin, thus making them resistant to ampicillin.
• Gram-negative bacteria can develop or enhance efflux pump systems that pump antibiotics out of the cell, lowering the intracellular drug concentration.
• Efflux pumps prevent the accumulation of tetracycline antibiotics and are present in MRSA.
• Changes in the bacterial cell wall or membrane can reduce antibiotic uptake, limiting access to internal targets.
• Gram-negative bacteria have an outer lipopolysaccharide membrane, which acts as a barrier for many antibiotics, with channels (porins) allowing entry for lipophilic or small drugs.
• Resistant bacterial strains have less permeable outer membranes or porin channels, exemplified by Pseudomonas aeruginosa's resistance to gentamicin.
• Bacteria can produce a different protein target site where the antibiotic normally binds, preventing the antibiotic from binding and killing the bacteria.
• MRSA has an altered penicillin binding protein, preventing methicillin from binding, thus the bacteria will not be killed.
• Adaptability of bacteria underscores the importance of judicious antibiotic use, development of new therapies, and infection control measures to mitigate the spread of resistance.

Bactericidal vs. Bacteriostatic Agents

• Bactericidal agents kill bacteria/microorganisms by destroying the bacterial cell wall, interfering with essential cellular processes, or disrupting the bacterial membrane.
• Examples of bactericidal agents include penicillins, cephalosporins, and aminoglycosides.
• Bacteriostatic agents inhibit bacterial growth and reproduction without directly killing them.
• Bacteriostatic agents are less aggressive, allowing the immune system to clear the infection by interfering with protein synthesis or metabolic pathways.
• Examples of bacteriostatic agents include tetracyclines, macrolides, and sulfonamides.

Migraine Headache Treatment

Acute (Abortive) Treatment

• First-line treatment for mild to moderate migraines includes NSAIDs:

  • 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 like Excedrin Migraine contain aspirin, acetaminophen, and caffeine; dosage is 2 tablets.

• Limit overuse due to the risk of medication overuse headache/rebound headache.

• First-line treatment for moderate to severe migraines includes Triptans:

  • 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, has a longer half-life and slower onset
  • Frovatriptan: 2.5 mg PO, has the longest half-life, useful for menstrual migraines

• Triptans are contraindicated in patients with:

  • Cardiovascular disease
  • Uncontrolled hypertension
  • Pregnancy
  • Basilar or hemiplegic migraine

• Second-line treatment if triptans are ineffective or contraindicated includes Gepants:

  • Rimegepant: 75 mg PO (oral dissolving tablet)
  • Ubrogepant: 50-100 mg PO
  • Zavegepant: 10 mg intranasal

• Gepants have no vasoconstrictive effects making them safer for cardiovascular patients.

• Alternative Second-Line Treatments include Ditans:

  • Lasmiditan: 50-200 mg PO
  • Less vasoconstriction than triptans, good for patients with CV risk, but causes significant sedation; patients should avoid driving for 8 hours after use.

• Ergot Alkaloids:

  • Dihydroergotamine: 1 mg IV/IM/SC or 0.5-1 mg intranasal
  • Ergotamine + Caffeine: 1-2 mg PO or PR

• Ergot Alkaloids are reserved for refractory cases due to more side effects than triptans.

• Anti-emetics as 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):

  • Dexamethasone: 10-24 mg IV/PO

• IV 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, good for hypertensive or anxious patients.
    • Metoprolol: 50-200 mg/day PO
    • Atenolol: 50-100 mg/day PO
  • Antiepileptics:
    • Topiramate: 25-100 mg/day PO, is weight-neutral
    • Valproate: 500-1500 mg/day PO, causes weight gain
  • Tricyclic Antidepressants:
    • Amitriptyline: 10-50 mg QHS, good for comorbid depression, insomnia, or fibromyalgia.
    • Nortriptyline: 10-50 mg QHS
  • SNRIs:
    • Venlafaxine: 37.5-150 mg/day, may be preferred in patients with anxiety or depression.

• Second-Line Preventive Medications:

  • Calcium Channel Blockers:
    • Verapamil: 120-240 mg/day PO, used for hemiplegic migraine or cluster headaches.
  • Angiotensin II Receptor Blockers:
    • Candesartan: 4-16 mg/day PO
  • Onabotulinumtoxin A:
    • 31 injections every 12 weeks for chronic migraine (≥ 15 headache days/month)
  • CGRP Monoclonal Antibodies:
    • 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

• CGRP Monoclonal Antibodies are highly effective, well-tolerated, and long-acting but expensive and require insurance prior authorization.

• Non-Pharmacologic Preventive Therapy:

  • Diet & Lifestyle Changes:
    • Avoid triggers like caffeine, alcohol, processed foods, and artificial sweeteners. Stay hydrated, maintain a consistent sleep schedule, and engage in regular aerobic exercise, yoga, and stress reduction techniques.
  • Cognitive Behavioral Therapy:
    • 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 modify the course of autoimmune diseases rather than just alleviating symptoms.
• The two main types of DMARDs are biologic and non-biologic.

Non-Biologic DMARDs:

• These are small-molecule drugs that act to suppress the immune system, usually taken orally.
• They are often used as the first-line treatment for diseases like rheumatoid arthritis (RA) and psoriatic arthritis.
• Examples :
  • Methotrexate: Most commonly used for RA, inhibits the immune system and reduces inflammation.
  • Sulfasalazine: Often used for RA and inflammatory bowel diseases like Crohn’s disease.
  • Hydroxychloroquine: Used for diseases like lupus and RA, with a less potent immune-suppressive effect compared to methotrexate.
  • Leflunomide: Used to treat RA by inhibiting the proliferation of immune cells.
  • Azathioprine: Often used for inflammatory diseases like lupus.
• They generally work by targeting the immune system directly, inhibiting certain enzymes or processes involved in immune cell function, or reducing inflammation.
• Non-biologic DMARDs 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

• These are derived from living cells and target specific components of the immune system.
• Unlike non-biologic DMARDs, biologics tend to target specific proteins involved in the inflammatory process.
• Examples:
  • TNF inhibitors:
    • Etanercept
    • Adalimumab
    • Infliximab
  • Interleukin inhibitors:
    • Tocilizumab targets interleukin-6 (IL-6).
    • Ustekinumab targets interleukins IL-12 and IL-23.
  • B-cell inhibitors:
    • Rituximab: Targets CD20+ B-cells to reduce immune activity.
  • T-cell costimulation inhibitors:
    • Abatacept: Inhibits T-cell activation.
• Biologic DMARDs target specific molecules or cells involved in the inflammatory process.
• TNF inhibitors block tumor necrosis factor (TNF), a cytokine that plays a central role in inflammation.
• Interleukin inhibitors block specific interleukins (e.g., IL-6, IL-12) involved in inflammatory pathways.
• B-cell inhibitors deplete B-cells, involved in producing antibodies that attack the joints.
• T-cell inhibitors prevent the activation of T-cells, which are key players in autoimmune reactions.
• Side Effects:
  • Increased risk of infections due to immune system suppression
  • Injection site reactions
  • Risk of certain cancers
  • Autoimmune diseases
  • Gastrointestinal issues

Gout Therapy

• Gout is caused by the accumulation of uric acid crystals in the joints, leading to pain, swelling, and redness.
• Therapy focuses on relieving acute symptoms and lowering uric acid levels to prevent future attacks.

Acute Gout Attack Treatment

• The goal is to reduce pain, inflammation, and swelling.
• Nonsteroidal Anti-inflammatory Drugs (NSAIDs):
  • Examples: Ibuprofen, Naproxen, Indomethacin
  • Mechanism: Reduce inflammation and pain; considered the first-line treatment.
  • Considerations: Use cautiously in patients with gastrointestinal issues, kidney problems, or heart disease.
• Colchicine:
  • Mechanism: Reduces the inflammation caused by uric acid crystals and is effective, especially if taken early during a flare.
  • Considerations: Can have gastrointestinal side effects and should be used carefully in people with kidney or liver issues.
• Corticosteroids:
  • Examples: Prednisone, Methylprednisolone
  • Mechanism: Can be taken orally or injected to reduce inflammation and pain and is often used when NSAIDs or colchicine are not effective or contraindicated.
  • Considerations: Long-term use can have significant side effects; typically used for short periods during flare-ups.

Chronic Gout Management

• Long-term therapy focuses on lowering uric acid levels to prevent future flares and reduce joint damage.
• Urate-Lowering Therapy (ULT):
  • Xanthine Oxidase Inhibitors:
    • Allopurinol: Most commonly used to lower uric acid levels by inhibiting xanthine oxidase.
    • Febuxostat: Similar to allopurinol but used in patients who cannot tolerate allopurinol.
    • Considerations: Both can cause skin rashes or gastrointestinal issues; start at low doses to minimize the risk of flares.
  • Uricosuric Agents:
    • Probenecid: Increases the kidney’s ability to excrete uric acid.
    • Lesinurad: A newer drug that also increases uric acid excretion.
    • Considerations: Typically used when xanthine oxidase inhibitors are not effective or appropriate and 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.
    • Considerations: Given via IV infusion and reserved for patients with chronic gout not responding to other medications.
• Lifestyle Changes:
  • Diet: Limiting purine-rich foods and alcohol can help prevent gout attacks; a diet rich in fruits, vegetables, and low-fat dairy products is beneficial.
  • Hydration: Drinking plenty of water helps prevent uric acid crystal formation.
  • Weight Management: Losing weight can help lower uric acid levels and reduce flare frequency.
• Monitoring Uric Acid Levels:
  • Regular blood tests to monitor uric acid levels help guide treatment and ensure uric acid is maintained at a safe level (generally below 6 mg/dL).
• Additional Considerations:
  • Acute Flare Prophylaxis: Colchicine or low-dose NSAIDs may be used during the first few months of urate-lowering therapy to prevent acute gout flares.
  • Kidney Function: It’s essential to monitor kidney function, especially with allopurinol, probenecid, or pegloticase.