Orris

Give me pharmacologic notes on all drugs from katzung on this chapters and drugs only that i mention everything from moa to everything u can find on the book 1. Bisphosphonates, Xanthine oxidised inhibitors, DMARDS all drugs under this 2. Estrogens, Progestins and Androgen therapy 3. Dopaminergic drugs and cholinerterases inhibitors

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Here are the complete pharmacologic notes compiled directly from Katzung's Basic and Clinical Pharmacology, 16th Edition.

PHARMACOLOGIC NOTES - KATZUNG 16th Edition

SECTION 1: DRUGS USED IN GOUT & RHEUMATIC DISEASE

A. BISPHOSPHONATES

(Katzung Ch. 42 - Agents That Affect Bone Mineral Homeostasis, pp. 1217-1219)

Drugs in Class

Alendronate, Risedronate, Ibandronate (oral), Pamidronate, Zoledronate (IV), Etidronate

Mechanism of Action

Bisphosphonates bind to hydroxyapatite crystals in bone. They inhibit formation and dissolution of hydroxyapatite crystals within and outside the skeletal system. They also inhibit osteoclast activity. The amino-bisphosphonates (alendronate, risedronate) specifically inhibit farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway that is critical for osteoclast survival - this is the primary mechanism of the nitrogen-containing bisphosphonates. Non-amino bisphosphonates (etidronate) are incorporated into non-hydrolyzable ATP analogs, inducing osteoclast apoptosis.
Additional cellular effects include:
  • Inhibition of 1,25(OH)2D production
  • Inhibition of intestinal calcium transport
  • Inhibition of glycolysis in bone cells
  • Changes in acid and alkaline phosphatase activity

Pharmacokinetics

  • Oral bioavailability: <10% of oral dose absorbed; food reduces absorption further → must be taken on empty stomach
  • ~50% of absorbed drug accumulates in bone; remainder excreted unchanged in urine
  • Drug retained in bone for months to years (depends on bone turnover rate)
  • Intravenous forms (pamidronate, zoledronate, ibandronate) bypass GI absorption problem and allow larger doses with less frequent administration (zoledronate: once per year IV infusion)
  • Dose reduction required in renal impairment

Clinical Uses

  1. Osteoporosis (primary indication)
  2. Hypercalcemia of malignancy
  3. Paget disease of bone
  4. Bone metastases (high-dose IV zoledronate)
  5. Prevention of skeletal events in cancer

Adverse Effects

  • Esophageal and gastric irritation (oral forms - alendronate, risedronate, ibandronate) - patient must take with full glass of water and remain upright for ≥30 min
  • Osteonecrosis of the jaw (ONJ) - rare at usual doses (~1/100,000 patient-years); more frequent with high-dose IV zoledronate used for bone metastases
  • Atypical subtrochanteric femur fractures - rare, associated with long-term use (>5 years); suggests drug holiday after 5 years (3 years for zoledronate) if fracture risk permits
  • Flu-like syndrome - after first IV infusion of zoledronate; generally does not recur with subsequent infusions
  • Mineralization defect - etidronate at higher than approved doses
  • Renal toxicity with IV use

Drug Holiday

After 5 years of oral therapy (3 years for zoledronate), a drug holiday is recommended if fracture risk is not deemed high, because rare side effects (ONJ, atypical fractures) become more common beyond 5 years.

B. XANTHINE OXIDASE INHIBITORS

(Katzung Ch. 36 - Drugs Used in Gout, pp. 1028-1033)

1. ALLOPURINOL

MOA: Xanthine oxidase is responsible for the conversion of xanthine and hypoxanthine to uric acid. Allopurinol is metabolized to oxypurinol (alloxanthine), both of which are inhibitors of xanthine oxidase. This decreases the synthesis of uric acid. As xanthine and hypoxanthine accumulate, they are more readily excreted by the kidney. The result is a fall in serum and urinary uric acid levels.
Pharmacokinetics:
  • Well absorbed orally (~80%)
  • Allopurinol has a short half-life (~2 h); metabolite oxypurinol has a long half-life (~18-30 h) - responsible for prolonged action
  • Dose reduction required in renal impairment
  • Inhibits CYP enzymes (especially CYP2C9) → important drug interactions
Clinical Uses:
  • Chronic tophaceous gout and recurrent gouty attacks
  • Prevention of uric acid nephropathy in patients receiving chemotherapy (tumor lysis)
  • Recurrent uric acid renal calculi
  • Hyperuricemia associated with renal failure
Adverse Effects:
  • Hypersensitivity rash (common; ~2% of patients) - can progress to toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS), especially in patients with HLA-B*5801 allele (common in Asians)
  • GI upset, nausea, diarrhea
  • Acute gouty flare on initiation (due to mobilization of urate)
  • Drug interactions:
    • Azathioprine and 6-mercaptopurine: allopurinol inhibits their metabolism via xanthine oxidase → severe toxicity (bone marrow suppression) - dose of azathioprine/6-MP must be reduced by 75%
    • Warfarin: inhibits CYP2C9 → increased anticoagulant effect
    • Ampicillin: increased risk of skin rash
  • Hepatotoxicity (rare)
Contraindications: Avoid combining with azathioprine/6-MP without dose reduction.

2. FEBUXOSTAT

MOA: Selective, non-purine inhibitor of xanthine oxidase (inhibits both oxidized and reduced forms of xanthine oxidase - unlike allopurinol which only inhibits the oxidized form). Does not incorporate into purines.
Pharmacokinetics:
  • Well absorbed orally
  • Extensively metabolized by glucuronidation and oxidation
  • Eliminated in both urine and feces (can be used in mild-to-moderate renal impairment without dose adjustment)
  • Half-life ~5-8 hours
Clinical Uses:
  • Chronic hyperuricemia in patients with gout
  • Alternative to allopurinol in patients who cannot tolerate it
Adverse Effects:
  • Liver function test abnormalities
  • GI symptoms (nausea, diarrhea)
  • Acute gout flares on initiation
  • Cardiovascular events - a post-marketing trial (CARES trial) found an increase in cardiovascular mortality versus allopurinol; FDA added black box warning; use with caution in patients with established cardiovascular disease
  • Rash (less common than allopurinol)
Drug Interactions: Same concerns with azathioprine/6-MP as allopurinol. Does not significantly inhibit CYP enzymes.

OTHER GOUT DRUGS (Katzung Ch. 36)

COLCHICINE
  • MOA: Binds to tubulin and prevents microtubule polymerization → inhibits neutrophil migration and phagocytosis of urate crystals; reduces IL-1β secretion; inhibits NLRP3 inflammasome activation
  • Use: Acute gout (most effective within 12-24h of attack onset); prophylaxis of gout flares
  • Pharmacokinetics: Oral; metabolized in liver (CYP3A4); excreted in bile and urine; T½ ~20 h
  • Adverse Effects: GI (diarrhea, nausea, vomiting) - dose-limiting; myopathy and neuropathy with chronic use; bone marrow suppression (rare)
  • Drug Interactions: CYP3A4 inhibitors (clarithromycin, ketoconazole) increase colchicine toxicity; P-glycoprotein inhibitors also increase levels
PROBENECID (Uricosuric)
  • MOA: Inhibits renal tubular reabsorption of uric acid (blocks URAT1 transporter in the proximal tubule) → increases urinary uric acid excretion
  • Use: Chronic gout in under-excretors of uric acid (urine uric acid <800 mg/day)
  • Not useful in gout with renal failure (GFR <30); requires adequate urine flow
  • Adverse Effects: GI irritation; precipitation of uric acid stones (must maintain adequate hydration and alkaline urine); rash; fever
PEGLOTICASE
  • MOA: Recombinant uricase (PEGylated) that converts uric acid to allantoin (more soluble) → rapid reduction in serum uric acid
  • Use: Refractory gout unresponsive to other therapies (IV every 2 weeks)
  • Adverse Effects: Infusion reactions, gout flares, hemolysis and methemoglobinemia in G6PD-deficient patients

C. DMARDs (DISEASE-MODIFYING ANTIRHEUMATIC DRUGS)

(Katzung Ch. 36, pp. 1013-1033)
RA is a progressive immunologic disease that causes systemic effects, shortens life, and reduces mobility/quality of life. DMARDs may take 2 weeks to 6 months to show clinical effect. Divided into:
  • csDMARDs (conventional synthetic): methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, cyclophosphamide, cyclosporine, mycophenolate mofetil
  • tsDMARDs (targeted synthetic): tofacitinib, baricitinib, upadacitinib (JAK inhibitors)
  • bDMARDs (biologic): abatacept, rituximab, tocilizumab, sarilumab, anakinra, canakinumab, rilonacept, TNF-α blockers (5 drugs)

1. ABATACEPT (boDMARD - T cell modulator)

MOA: Soluble fusion protein = Fc region of IgG1 fused to extracellular domain of CTLA-4. Binds to CD80 and CD86 on antigen-presenting cells (APCs) → blocks their interaction with CD28 on T cells → prevents T cell co-stimulation and activation.
Pharmacokinetics:
  • SC or IV administration
  • SC bioavailability: 79% relative to IV
  • Clearance: 0.28 mL/h/kg; Vd: 0.11 L/kg
  • Terminal half-life: 14.3 days
Clinical Uses:
  • RA (monotherapy or with methotrexate/another csDMARD)
  • Psoriatic arthritis (PsA)
  • Polyarticular juvenile idiopathic arthritis (JIA, ≥2 years)
  • Prophylaxis of acute graft-versus-host disease (aGVHD) in HSCT
  • Off-label: SLE, Sjögren syndrome, type 1 diabetes, inflammatory bowel disease, dermatomyositis
Dosing: Weight-adjusted. IV: 500 mg (≤60 kg), 750 mg (60-100 kg), 1000 mg (>100 kg) monthly. SC: 125 mg/week.
Adverse Effects: Infections (serious bacterial, fungal, viral); COPD exacerbations; immunogenicity; injection site reactions.

2. ANAKINRA (IL-1 Inhibitor)

MOA: Recombinant human IL-1 receptor antagonist → competitively blocks IL-1α and IL-1β from binding to the IL-1 receptor → inhibits IL-1-mediated inflammatory cascades.
Clinical Uses: RA; Still disease; acute gout flares (100 mg/day SC × 3 days per ACR 2012 guidelines)
Pharmacokinetics: SC only; short half-life (~4-6 h); renally excreted.
Adverse Effects: Injection site reactions (most common); infections (especially with concurrent TNF-α blockers - avoid combination); neutropenia.

3. CANAKINUMAB (IL-1β monoclonal antibody)

MOA: Human IgG1 monoclonal antibody that selectively binds and neutralizes IL-1β → reduces inflammation.
Clinical Uses: Systemic JIA; Still disease; acute gout (150 mg SC single dose per ACR guidelines); CAPS (cryopyrin-associated periodic syndromes).
Adverse Effects: Serious infections; neutropenia; hypersensitivity. Given less frequently than anakinra (long half-life ~26 days).

4. RILONACEPT (IL-1 Trap)

MOA: Dimeric fusion protein that acts as a decoy receptor for IL-1α and IL-1β (and IL-18). Binds these cytokines extracellularly before they can engage cell-surface receptors.
Clinical Uses: CAPS; gout flare prophylaxis when initiating urate-lowering therapy (investigational).

5. RITUXIMAB (B-cell cytotoxic agent)

MOA: Chimeric IgG1 monoclonal antibody targeting CD20 on pre-B cells and mature B cells → causes B-cell depletion via complement-dependent cytotoxicity, antibody-dependent cell cytotoxicity (ADCC), and apoptosis.
Clinical Uses:
  • RA (in combination with methotrexate; typically after failure of TNF-α blockers)
  • Non-Hodgkin lymphoma; CLL; vasculitis (GPA); pemphigus vulgaris
Pharmacokinetics: IV infusion; long terminal half-life (~18-22 days); B-cell depletion persists 6-9 months.
Adverse Effects: Infusion reactions (fever, chills, hypotension, bronchospasm - premedicate with methylprednisolone, diphenhydramine, acetaminophen); severe infections (PML with JC virus - rare); hepatitis B reactivation; progressive multifocal leukoencephalopathy (PML); cytopenias; late-onset neutropenia.

6. TOCILIZUMAB & SARILUMAB (Anti-IL-6 receptor antibodies)

MOA: Both are monoclonal antibodies targeting the IL-6 receptor (IL-6R) → block both membrane-bound and soluble IL-6R → prevent IL-6-mediated pro-inflammatory signaling (JAK-STAT pathway).
Clinical Uses (Tocilizumab):
  • RA (IV or SC); polyarticular and systemic JIA
  • Giant cell arteritis (SC)
  • Cytokine release syndrome (CRS) from CAR-T therapy
  • COVID-19 (severe)
Pharmacokinetics: Tocilizumab IV: half-life concentration-dependent (~11-13 days at therapeutic doses); SC: ~13 days.
Adverse Effects:
  • Serious infections (bacterial, fungal, viral); GI perforations (especially with NSAIDs/corticosteroids)
  • Elevated liver enzymes; neutropenia; thrombocytopenia
  • Hyperlipidemia
  • Infusion reactions (IV form)
  • Masks fever (important clinical concern - may obscure signs of infection)

7. TNF-α BLOCKING AGENTS (5 drugs)

All approved for RA (and other indications):
DrugTypeRouteKey Features
EtanerceptTNF-α receptor fusion protein (TNF receptor 2 + IgG1 Fc)SCBinds TNF-α and TNF-β; t½ ~4 days
InfliximabChimeric IgG1 monoclonal Ab vs TNF-αIVFirst TNF-α blocker; also for IBD
AdalimumabFully human IgG1 monoclonal Ab vs TNF-αSCMost widely used; broad indications
Certolizumab pegolPEGylated Fab fragment of humanized anti-TNF-α AbSCNo Fc region; safe in pregnancy (minimal placental transfer)
GolimumabFully human IgG1 monoclonal Ab vs TNF-αSC (and IV for RA)Once monthly dosing
MOA (all): Bind and neutralize soluble and/or membrane-bound TNF-α → prevent TNF-α from engaging its receptors (TNFR1/TNFR2) → reduce downstream NF-κB activation and pro-inflammatory cytokine production.
Clinical Uses: RA, PsA, AS, Crohn's disease (infliximab, adalimumab, certolizumab), UC, plaque psoriasis, JIA.
Adverse Effects (class):
  • Serious infections (most important) - bacterial (especially intracellular organisms), fungal (histoplasmosis, coccidioidomycosis), TB
  • Reactivation of latent TB - screen with TST/IGRA before starting; treat LTBI first
  • Hepatitis B reactivation - screen before starting
  • Demyelinating disorders (MS exacerbation) - avoid in demyelinating disease
  • Heart failure exacerbation (avoid in NYHA III-IV)
  • Lupus-like syndrome
  • Lymphoma risk (particularly hepatosplenic T-cell lymphoma with combination IBD therapy)
  • Injection site reactions (SC); infusion reactions (IV infliximab)
  • Anti-drug antibodies (especially infliximab) - reduced by co-administration of methotrexate

8. METHOTREXATE (csDMARD - anchor drug for RA)

MOA: Folic acid analog. Inhibits dihydrofolate reductase (DHFR) → reduces availability of tetrahydrofolate → impairs synthesis of thymidylate and purines → anti-proliferative effect. At low doses used in RA: also increases extracellular adenosine levels → anti-inflammatory effect independent of folate pathway.
Pharmacokinetics:
  • Oral, IM, or SC; weekly dosing (NOT daily for RA)
  • Good oral bioavailability at low doses; reduced with food; IV for cancer doses
  • Eliminated mainly by renal excretion (dose reduce in renal impairment)
  • Half-life ~3-10 h (plasma); but polyglutamate forms accumulate in cells
Clinical Uses: RA (first-line anchor csDMARD); PsA; psoriasis; JIA; vasculitis; ectopic pregnancy; choriocarcinoma; various cancers.
Adverse Effects:
  • GI (nausea, mucositis, stomatitis) - most common; reduced by folic acid supplementation
  • Hepatotoxicity (fibrosis, cirrhosis with long-term use) - monitor LFTs; liver biopsy after cumulative dose threshold
  • Pulmonary toxicity (pneumonitis) - acute or chronic; stop drug if suspected
  • Bone marrow suppression (pancytopenia)
  • Teratogenicity (Pregnancy Category X - absolute contraindication)
  • Drug interactions: NSAIDs reduce renal excretion → increased toxicity; trimethoprim and other DHFR inhibitors increase toxicity; probenecid reduces renal clearance

9. HYDROXYCHLOROQUINE / CHLOROQUINE (Antimalarials as csDMARDs)

MOA: Accumulate in lysosomes → raise intralysosomal pH → interfere with lysosomal processing of antigens → reduce MHC class II antigen presentation → reduce autoimmune T-cell activation. Also inhibit Toll-like receptor signaling (TLR7/9).
Clinical Uses: SLE (reduce flares, organ damage, mortality); RA (mild disease, combination csDMARD therapy); malaria.
Adverse Effects:
  • Retinal toxicity (maculopathy) - most important; irreversible; requires baseline and regular ophthalmologic screening (every 1-5 years based on risk); dose-dependent (safe at ≤5 mg/kg/day HCQ)
  • GI symptoms
  • Skin rash
  • Rare: neuromyopathy, cardiomyopathy, blood dyscrasias
  • Note: rarely causes severe toxicity compared to other DMARDs; safe in pregnancy

10. SULFASALAZINE (csDMARD)

MOA: Metabolized by colonic bacteria to 5-aminosalicylic acid (5-ASA) and sulfapyridine. The sulfapyridine moiety appears to be the active component in RA. Inhibits folate synthesis, reduces T-cell proliferation, and decreases pro-inflammatory cytokines.
Clinical Uses: RA; AS; IBD (Crohn's, UC).
Adverse Effects: GI intolerance (nausea, vomiting); rash; hematologic (leukopenia, hemolytic anemia - G6PD deficiency risk); reversible male infertility (oligospermia); hepatotoxicity; monitor CBC.

11. LEFLUNOMIDE (csDMARD)

MOA: Prodrug → active metabolite teriflunomide. Inhibits dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway → reduces proliferation of activated T and B lymphocytes.
Clinical Uses: RA (second-line); PsA.
Pharmacokinetics: Oral; long half-life of active metabolite (~14-18 days); enterohepatic recirculation. Cholestyramine washout procedure can rapidly eliminate drug.
Adverse Effects: Diarrhea; alopecia; hypertension; hepatotoxicity; teratogenicity (Category X); peripheral neuropathy. Requires cholestyramine washout (8g TID × 11 days) before pregnancy or switching drugs.

12. TOFACITINIB (tsDMARD - JAK inhibitor)

MOA: Selective inhibitor of Janus kinase 1 (JAK1) and JAK3 → blocks signal transduction through common gamma chain cytokine receptors (IL-2, IL-4, IL-7, IL-9, IL-15, IL-21) → reduces T and B lymphocyte activation; also inhibits JAK1/JAK2-dependent signaling (interferon, IL-6).
Pharmacokinetics: Oral (5 mg BID or 11 mg extended-release daily); half-life ~3 h; hepatic metabolism (CYP3A4).
Clinical Uses: RA; PsA; UC; polyarticular JIA; AS.
Adverse Effects:
  • Serious infections (herpes zoster reactivation - higher risk than bDMARDs)
  • Increased risk of MACE (major adverse cardiovascular events) and thrombosis (VTE, PE) - post-marketing safety trial; black box warnings added; avoid in patients with high cardiovascular risk
  • Possible increased malignancy risk
  • Hyperlipidemia; elevated creatinine; anemia; neutropenia

13. AZATHIOPRINE (csDMARD)

MOA: Prodrug → metabolized to 6-mercaptopurine (6-MP) → converted to active thioguanine nucleotides → inhibit de novo purine synthesis → suppress T and B lymphocyte proliferation.
Clinical Uses: RA (less commonly used); SLE; transplant rejection; IBD; vasculitis; myositis.
Adverse Effects: Bone marrow suppression (dose-dependent); GI intolerance; hepatotoxicity; increased malignancy (lymphoma); teratogen in animals. Critical interaction with allopurinol/febuxostat (inhibit xanthine oxidase → failure to metabolize 6-MP → toxicity; reduce dose by 75%).

14. CYCLOSPORINE (csDMARD)

MOA: Binds to cyclophilin (an intracellular receptor) → cyclophilin-cyclosporine complex inhibits calcineurin → prevents dephosphorylation of NFAT (nuclear factor of activated T cells) → blocks transcription of IL-2 and other cytokines → selective inhibition of T-cell activation.
Clinical Uses: RA (severe, refractory); organ transplant rejection; psoriasis; nephrotic syndrome.
Adverse Effects: Nephrotoxicity (most important, dose-dependent); hypertension; gingival hyperplasia; hypertrichosis; neurotoxicity; hyperlipidemia; elevated uric acid (can precipitate gout); narrow therapeutic index.

15. MYCOPHENOLATE MOFETIL (csDMARD)

MOA: Hydrolyzed to mycophenolic acid (MPA) → inhibits inosine monophosphate dehydrogenase (IMPDH) → selective depletion of guanosine nucleotides in lymphocytes (T and B cells are dependent on de novo purine synthesis) → inhibits lymphocyte proliferation.
Clinical Uses: SLE nephritis (first-line); organ transplantation; refractory RA; vasculitis; myositis.
Adverse Effects: GI (nausea, diarrhea, vomiting - most common); bone marrow suppression; teratogenicity; increased infections.

SECTION 2: ESTROGENS, PROGESTINS, AND ANDROGEN THERAPY

(Katzung Ch. 40 - Gonadal Hormones & Inhibitors, pp. 1124-1165)

A. ESTROGENS

Natural Estrogens

Three main endogenous forms:
  • Estradiol (E2, 17β-estradiol) - major secretory product of ovary; highest receptor affinity and most potent
  • Estrone (E1) - formed in liver and peripheral tissues (adipose) from estradiol and androstenedione
  • Estriol (E3) - most abundant in pregnancy; weakest; formed from estrone/estradiol

Mechanism of Action

Estrogens cross cell membranes (lipid soluble) and bind to nuclear estrogen receptors - two isoforms:
  • ERα - growth-promoting; found in uterus, breast, liver, bone
  • ERβ - antigrowth/dominant negative inhibitor of ERα; phytoestrogens act via ERβ
Receptor binding → release from heat shock proteins (Hsp90) → receptor dimerization (ERα-ERα, ERβ-ERβ, or ERα-ERβ) → binds estrogen response elements (EREs) in promoter regions → transcription of target genes (genomic effect). Rapid non-genomic effects also occur (e.g., Ca²+ uptake, uterine blood flow) via intracellular signaling pathways.

Pharmacokinetics

  • Circulating estradiol binds strongly to SHBG (sex hormone-binding globulin) and with lower affinity to albumin; only free fraction is active
  • Metabolized in liver to estrone and estriol → conjugated to glucuronide/sulfate → excreted in bile → enterohepatic recirculation (active metabolites reabsorbed from intestine)
  • Oral route has high hepatic:peripheral ratio (high first-pass effect) → greater liver effects (increased clotting factors, CBG, SHBG, angiotensinogen)
  • Transdermal route avoids first-pass → does not significantly increase renin substrate, CBG, TBG, or serum lipid changes; 50-100 mcg transdermal ≈ 0.625-1.25 mg oral conjugated estrogens in gonadotropin suppression, endometrial, and vaginal effects

Physiologic Effects

  • Reproductive tract: Growth and maturation of vagina, uterus, fallopian tubes; development of female secondary sex characteristics; proliferation of endometrium; breast development
  • Bone: Inhibit bone resorption; maintain bone mineral density; loss after menopause accelerates bone loss
  • Metabolic:
    • Increase HDL, slightly decrease LDL, reduce total cholesterol
    • Increase plasma triglycerides
    • Decrease hepatic oxidation of lipids to ketones
    • Increase synthesis of hepatic binding proteins (CBG, SHBG, TBG, ceruloplasmin, angiotensinogen, fibrinogen)
  • Coagulation: Enhance coagulability - increase factors II, VII, IX, X; decrease antithrombin III; increase plasminogen; decrease platelet adhesiveness
  • CNS/Other: Influence behavior and libido; induce progesterone receptor synthesis; promote sense of well-being; modulate sympathetic control of smooth muscle; facilitate extracellular fluid retention → edema, compensatory sodium/water retention

Clinical Uses of Estrogens

  1. Primary hypogonadism / Turner syndrome - replacement at age 11-13 years; promotes secondary sex characteristics, growth, prevents osteoporosis
  2. Postmenopausal hormonal therapy (HRT) - relieves vasomotor symptoms, prevents urogenital atrophy, prevents osteoporosis; combined with progestin in women with intact uterus (to prevent endometrial hyperplasia)
  3. Hormonal contraception (combined with progestins)
  4. Dysmenorrhea, endometriosis (suppress ovulation)
  5. Carcinoma of the prostate (palliative, now rarely used)
  6. Abnormal uterine bleeding

Adverse Effects

  • Nausea and breast tenderness (most common; minimize with lowest effective dose)
  • Thromboembolism (VTE, DVT, PE, stroke) - due to procoagulant effects; increased with oral route, smoking, obesity
  • Endometrial carcinoma - estrogen alone (without progestin) in women with intact uterus
  • Breast cancer - risk increase with prolonged combined estrogen-progestin HRT (WHI data)
  • Cardiovascular events - increased risk of MI and stroke (especially in older women starting HRT late after menopause)
  • Cholestasis, gallbladder disease
  • Hypertension (due to increased angiotensinogen → renin-angiotensin activation)
  • Migraine headaches (increased frequency)
  • Hyperpigmentation

Contraindications

  • Estrogen-dependent neoplasms (endometrial carcinoma, breast cancer)
  • History of thromboembolic disease
  • Undiagnosed vaginal bleeding
  • Liver disease
  • Heavy smokers (especially if >35 years old and using OCP)

Preparations

  • Conjugated equine estrogens (CEE, Premarin): oral, 0.3-1.25 mg/day
  • Ethinyl estradiol: oral (OCP)
  • Estradiol: transdermal patch (25-100 mcg/day), topical gel, vaginal preparations
  • Estradiol valerate, estradiol cypionate: IM

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

TAMOXIFEN

MOA: Competitive partial agonist/antagonist at estrogen receptor. Tissue-specific effects depend on coregulators, receptor isoforms (ERα vs ERβ), and receptor heterodimers present. Acts as antagonist at breast; agonist at bone, uterus, and cardiovascular system.
Active Metabolite: 4-hydroxytamoxifen (endoxifen) - formed via CYP2D6; more potent SERM. Strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine) reduce efficacy of tamoxifen.
Pharmacokinetics: Oral; half-life 7-14 hours (initial); predominantly hepatic excretion; dose 10-20 mg twice daily.
Clinical Uses:
  • Palliative treatment of breast cancer in postmenopausal women (ER+)
  • Adjuvant therapy for breast cancer (5 years post-surgery)
  • Chemoprevention of breast cancer in high-risk women
  • Prevents loss of lumbar spine bone density (bone agonist effect)
Adverse Effects:
  • Hot flushes, nausea/vomiting (25%)
  • Endometrial carcinoma (agonist effect on uterus - increased risk with prolonged use)
  • Thromboembolic events (VTE, DVT, PE)
  • Ocular toxicity (retinopathy, cataracts) with high doses
  • Adjuvant therapy >5 years shows no additional benefit; resistant tumor cells may recognize it as agonist
Toremifene: Structurally similar to tamoxifen; same properties, indications, and toxicities.

RALOXIFENE

MOA: SERM - antagonist at breast and uterus; agonist at bone and lipid metabolism. Does not stimulate breast or endometrial hyperplasia.
Uses: Osteoporosis (prevention and treatment in postmenopausal women); breast cancer risk reduction.
Adverse Effects: Does NOT prevent hot flushes (may worsen them); increased risk of VTE (similar to tamoxifen); leg cramps.

B. PROGESTINS

Natural Progestins: Progesterone

  • Synthesized in ovary (corpus luteum), testis, adrenal cortex, and placenta from cholesterol
  • Serves as precursor to estrogens, androgens, and adrenocortical steroids
  • Normal non-pregnant women: luteal phase plasma levels 0.5-2 mcg/dL
  • Males: ~0.03 mcg/dL
  • Pregnancy: levels continue rising to term

Mechanism of Action

Binds to intranuclear progesterone receptors (PR-A and PR-B) → receptor-hormone complex binds progesterone response elements (PREs) → regulates gene transcription. Estrogen induces PR synthesis. Rapid non-genomic effects also occur.

Physiologic Effects

  • Uterus: Converts proliferative endometrium (estrogen effect) to secretory endometrium; reduces uterine contractility (relaxes myometrium); necessary for implantation
  • Cervix: Thickens cervical mucus → impedes sperm penetration
  • Vagina: Promotes secretory changes
  • Breast: Promotes lobular-alveolar development (in concert with estrogen)
  • CNS: Slight thermogenic effect (rises 0.5°C at ovulation - used in basal body temperature method)
  • Metabolic: Competes with aldosterone at renal tubule → mild natriuresis; slightly decreases HDL

Clinical Uses

  1. Hormonal contraception (combined OCP, progestin-only "mini-pill", implants, IUD, injectables)
  2. HRT - combined with estrogen in postmenopausal women with intact uterus (protects against endometrial hyperplasia/cancer)
  3. Endometriosis - suppress endometrial tissue
  4. Dysfunctional uterine bleeding - regulate and stop bleeding
  5. Endometrial carcinoma (medroxyprogesterone acetate - palliative)
  6. Threatened or habitual abortion (progesterone support in luteal phase insufficiency)
  7. Premenstrual syndrome

Progestin Preparations

DrugRouteDuration
ProgesteroneVaginal, IMShort-acting
Medroxyprogesterone acetate (MPA)Oral, IM (depot 3 months)Medium to long
Norethindrone, norgestrelOral (OCP)Daily tablets
LevonorgestrelOral, IUD, implantVaries
DesogestrelOral (OCP)Daily
NorgestimateOral (combined OCP)Daily
EtonogestrelImplant (Nexplanon)3 years
Daily progestin tablets - minipill; used in breastfeeding women, those who cannot use estrogen.
Implantable progestin - subdermal etonogestrel implant; highly effective; 3 years; reversed immediately on removal.

Adverse Effects of Progestins

  • Irregular uterine bleeding/spotting (especially progestin-only methods)
  • Depression, mood changes
  • Androgenic effects with some older progestins (acne, hirsutism) - less with newer progestins
  • Decreased HDL (some progestins)
  • Weight gain
  • Breast tenderness

C. ANDROGEN THERAPY

(Katzung Ch. 40, pp. 1150-1165)

Natural Androgens

  • Testosterone - principal androgen secreted by Leydig cells of testis; also produced in adrenal cortex and ovary (smaller amounts)
  • Dihydrotestosterone (DHT) - formed in target tissues by 5α-reductase; most active androgen in prostate and skin
  • Androstenedione and DHEA - weaker androgens from adrenal cortex; converted peripherally to testosterone

Mechanism of Action

Testosterone enters cells → either acts directly on androgen receptor (AR) or is converted by 5α-reductase to DHT (more potent at AR) → AR-DHT complex acts as transcription factor → binds androgen response elements (AREs) → gene expression changes. In some tissues (brain, bone), testosterone is converted by aromatase to estradiol (explains some bone/CNS effects of androgens).

Physiologic Effects

  • Male sexual development: At puberty - development of all secondary sex characteristics (penis/scrotum enlargement, growth of pubic/axillary/facial hair, deepening of voice, increase in muscle mass, bone growth/fusion)
  • Erythropoiesis: Stimulate erythropoietin production → increase RBC production
  • Anabolic effects: Decrease urinary nitrogen excretion → increase protein synthesis (more pronounced in women and children than normal men)
  • Spermatogenesis: Required for sperm production
  • Feedback on hypothalamus/pituitary: Large doses suppress LH/FSH secretion

Androgen Preparations for Replacement Therapy

DrugRouteDosage
MethyltestosteroneOral / Sublingual25-50 mg/day oral; 5-10 mg/day SL
FluoxymesteroneOral2-10 mg/day
Testosterone enanthateIM200 mg q2 weeks (adult)
Testosterone cypionateIM200 mg q2 weeks (adult)
TestosteroneTransdermal patch/gel (1%)2.5-10 mg/day; 5-10 g/day gel
Testosterone propionate: Potent but short duration; not practical for long-term use.
Testosterone undecanoate: Oral or IM; oral not recommended due to association with liver tumors.
Transdermal testosterone: Avoids first-pass metabolism; skin patches or gels for scrotal or other skin areas.

Clinical Uses of Androgens

A. Androgen Replacement Therapy in Men (Hypogonadism):
  • Primary hypogonadism, hypopituitarism
  • Delayed puberty (short course of low-dose androgen)
  • Started at puberty; initiated with long-acting agents (testosterone enanthate or cypionate)
  • Initial dose 50 mg IM every 4 weeks → gradually increased → adult dose 200 mg q2 weeks
B. Women:
  • Low libido (postmenopausal)
  • Endometriosis (rarely)
  • Metastatic breast cancer (palliative, rarely used now)
C. Anemia: Aplastic anemia (before erythropoietin became available); anemias of renal failure.
D. Catabolic States / Wasting: HIV wasting syndrome; severe burns; prolonged immobilization.
E. Hereditary Angioedema: Attenuated androgens (danazol, stanozolol) increase C1 esterase inhibitor levels → prevent episodes.
F. Anabolic Steroid Abuse in Sports: Use of supra-physiologic doses for performance enhancement; banned; causes suppression of gonadotropins, testicular atrophy, acne, premature closure of epiphyses in adolescents.

Adverse Effects of Androgens

  • Virilization in women: Acne, hirsutism, deepening of voice (may be irreversible), clitoromegaly, baldness
  • Suppression of spermatogenesis in men (exogenous testosterone suppresses LH/FSH → testicular atrophy)
  • Hepatotoxicity: Especially 17α-alkylated oral androgens (methyltestosterone, fluoxymesterone) → cholestatic jaundice, peliosis hepatis, hepatocellular carcinoma
  • Premature closure of epiphyses in children
  • Erythrocytosis (polycythemia) - monitor hematocrit
  • Prostate: Benign prostatic hyperplasia worsening; possible stimulation of subclinical prostate cancer
  • Cardiovascular: Decreased HDL, increased LDL; fluid retention; hypertension; increased risk of MACE (with exogenous testosterone)
  • Psychologic: Mood swings, aggression, depression

ANDROGEN SUPPRESSION & ANTIANDROGENS

(Katzung Ch. 40, pp. 1156-1165)
Uses: Prostate cancer; BPH; androgen-dependent conditions.
Drugs that suppress androgen production:
  • GnRH agonists (leuprolide, goserelin, buserelin) - pulsatile GnRH stimulates LH; continuous administration causes LH/FSH suppression → medical castration. Note: initial "testosterone flare" in the first few weeks → must co-administer antiandrogen at start
  • GnRH antagonists (degarelix) - immediate LH suppression without initial flare
Drugs that block androgen action:
  • Flutamide, bicalutamide, enzalutamide - competitive AR antagonists; used in prostate cancer (often with GnRH agonist)
  • Spironolactone - aldosterone antagonist with anti-androgen properties; used in acne, hirsutism
  • Cyproterone acetate - potent antiandrogen and progestogen; used in hirsutism, precocious puberty, prostate cancer (not approved in US)
  • 5α-reductase inhibitors (finasteride, dutasteride) - prevent conversion of testosterone to DHT; used in BPH and androgenetic alopecia

SECTION 3: DOPAMINERGIC DRUGS & CHOLINESTERASE INHIBITORS

(Katzung Ch. 28 - Pharmacologic Management of Parkinsonism & Other Movement Disorders, pp. 773-798)

A. DOPAMINERGIC DRUGS (Parkinson's Disease)

Pathophysiology Context

Parkinsonism involves selective loss of dopaminergic neurons in the substantia nigra (nigrostriatal pathway) → reduced striatal dopamine → loss of inhibition of GABAergic output from striatum → relative excess of cholinergic activity. Cardinal features: tremor, bradykinesia, rigidity, postural instability.
Dopamine receptor subtypes:
  • D1/D5 family (adenylyl cyclase stimulating) - located in striatal neurons and presynaptically
  • D2/D3/D4 family - located postsynaptically on striatal neurons and presynaptically on SN axons
  • Antiparkinson benefits mainly depend on D2 receptor stimulation; D1 stimulation may also be required for maximal benefit

1. LEVODOPA (+/- CARBIDOPA)

MOA: Dopamine itself does NOT cross the blood-brain barrier (BBB). Levodopa (L-DOPA) is the immediate metabolic precursor of dopamine → crosses BBB via L-amino acid transporter (LAT) → decarboxylated to dopamine by DOPA decarboxylase (aromatic amino acid decarboxylase, AADC) in the brain → replenishes striatal dopamine.
Why combine with Carbidopa? Carbidopa is a peripheral DOPA decarboxylase inhibitor (does not cross BBB) → prevents peripheral conversion of levodopa to dopamine → reduces peripheral dopamine side effects (nausea, vomiting, hypotension) AND increases the fraction of levodopa reaching the brain (allows 75-80% dose reduction of levodopa).
Standard formulation: Carbidopa/levodopa (Sinemet) 25/100 mg or 10/100 mg tablets. Extended-release formulations: Carbidopa/levodopa CR (Sinemet CR); Rytary (IPX066 - extended-release capsules). Inhaled formulation: Inbrija - levodopa inhalation powder; for intermittent treatment of off-periods.
Pharmacokinetics:
  • Peak plasma level: 1-2 hours after oral dose
  • Competes with dietary large neutral amino acids for intestinal absorption and transport across BBB → taking with protein meal reduces CNS effect (main protein meal recommended in evening)
  • Metabolism: peripheral decarboxylation (blocked by carbidopa); MAO-B and COMT (catechol-O-methyltransferase) also metabolize levodopa and dopamine
  • Half-life: ~1-2 h (short → leads to pulsatile dopamine stimulation over time)
Adverse Effects:
  • GI: Nausea, vomiting (most common early; reduced by carbidopa co-administration; take with small amount of food)
  • Cardiovascular: Postural (orthostatic) hypotension; cardiac dysrhythmias (rarely with carbidopa)
  • Dyskinesias (most important long-term complication): Choreoathetoid movements, peak-dose dyskinesias; result from loss of physiologic buffering of dopamine stimulation
  • Motor fluctuations:
    • Wearing-off (end-of-dose akinesia): Related to timing of dose; managed by adjusting dose/frequency, adding adjunctive medications
    • On-off phenomenon: Unpredictable fluctuations between on-periods (good mobility + dyskinesia) and off-periods (akinesia); not related to dose timing; more common in patients who initially responded well
  • Psychiatric: Hallucinations, psychosis, confusion, vivid dreams, insomnia; depression; impulse-control disorders; mania
  • Mydriasis (may precipitate acute angle-closure glaucoma)
  • Miscellaneous: Abnormalities of smell/taste; brownish discoloration of saliva/urine/vaginal secretions; aggravation of gout; priapism; elevated LFTs, BUN; positive Coombs test with hemolysis
Drug Interactions:
  • Pyridoxine (Vitamin B6): Enhances peripheral decarboxylation → reduces levodopa effect (not a problem when carbidopa is used)
  • MAO-A inhibitors: Contraindicated - can cause hypertensive crisis; discontinue MAO-A inhibitor ≥2 weeks before levodopa
  • Antipsychotics (D2 blockers): Antagonize levodopa effects
  • Anticholinergics: Additive antiparkinson benefit for tremor
Contraindications:
  • Psychotic patients (may exacerbate psychosis)
  • Angle-closure glaucoma
  • Patients with history of malignant melanoma or suspicious skin lesions (levodopa is a melanin precursor)
  • Active peptic ulcer (use with caution - GI bleeding reported)
  • Within 2 weeks of MAO-A inhibitor use

2. CARBIDOPA-LEVODOPA + ENTACAPONE (COMTAN / STALEVO)

Entacapone MOA: COMT (catechol-O-methyltransferase) inhibitor - peripherally active; blocks conversion of levodopa to 3-O-methyldopa (3-OMD) in the periphery → more levodopa available for brain transport → extends half-life of levodopa and smooths motor fluctuations.
Tolcapone: Also a COMT inhibitor but acts both peripherally and centrally (crosses BBB); more potent than entacapone; associated with fatal hepatotoxicity → requires regular LFT monitoring; reserved for patients not responding to entacapone.
Use: Adjunct to levodopa to reduce "wearing-off" motor fluctuations.

3. MAO-B INHIBITORS (Selegiline, Rasagiline, Safinamide)

MOA: Selectively inhibit monoamine oxidase type B (MAO-B) in the brain → reduce catabolism of dopamine → increase dopamine concentrations in the striatum. MAO-B is the main enzyme responsible for dopamine breakdown in the CNS. At clinical doses, these drugs are selective for MAO-B (no tyramine/"cheese" effect).
Selegiline:
  • Irreversible MAO-B inhibitor; metabolized to methamphetamine and amphetamine (CNS stimulant metabolites → insomnia, anxiety)
  • Standard dose: 5 mg orally twice daily (with breakfast and lunch) OR 1.25-2.5 mg/day orally dissolving tablet
  • Also available as a transdermal patch (Emsam) - at higher doses affects MAO-A as well
Rasagiline:
  • Irreversible MAO-B inhibitor; cleaner metabolite profile than selegiline (no amphetamine metabolites)
  • 0.5-1 mg once daily oral
Safinamide:
  • Reversible MAO-B inhibitor; also blocks voltage-gated sodium channels and glutamate release
  • Adjunct to levodopa
Clinical Uses (all):
  • Early Parkinson's disease (monotherapy; possible neuroprotective effect - debated)
  • Adjunct to levodopa (reduce off-time, extend levodopa effect)
  • Selegiline proposed (but not proven) to slow disease progression
Drug Interactions (MAO-B inhibitors):
  • Meperidine (pethidine): Risk of serotonin syndrome → contraindicated
  • Tramadol, methadone, propoxyphene: Avoid
  • SSRIs/SNRIs: Risk of serotonin syndrome (avoid or use cautiously)
  • Sympathomimetics: Potential for hypertension

4. DOPAMINE RECEPTOR AGONISTS

Unlike levodopa, they:
  • Do NOT require enzymatic conversion to active metabolite
  • Act directly on postsynaptic dopamine receptors
  • Have no toxic metabolites
  • Do not compete with other substances for transport
  • Longer duration of action than levodopa → smoother dopamine stimulation → lower risk of dyskinesias (especially if used early)
  • Primary mechanism: D2 receptor agonism (and D3 for some)
Ergot-Derived (largely obsolete due to fibrosis):
  • Bromocriptine: D2 agonist and D1 partial antagonist; also used for hyperprolactinemia, acromegaly
  • Pergolide (withdrawn in US), Cabergoline (rare Parkinson's use; primarily for prolactinoma)
  • Risk: Fibrosis (pulmonary, cardiac valve, retroperitoneal) with ergot derivatives
Non-ergot Derived (preferred):
Pramipexole:
  • D3 > D2 agonist
  • Oral; renal elimination; half-life ~8-12 h; dose 0.5-4.5 mg/day in divided doses
  • Uses: Early PD (monotherapy) or adjunct to levodopa; also restless legs syndrome (RLS)
  • Adverse effects: Nausea, orthostatic hypotension, somnolence, sudden sleep attacks (may occur while driving), hallucinations, impulse-control disorders (gambling, hypersexuality, binge eating), peripheral edema
Ropinirole:
  • D2/D3 agonist
  • Oral; hepatic metabolism; half-life ~6 h; IR or extended-release formulations
  • Uses: PD (early or adjunct); RLS
  • Adverse effects: Similar to pramipexole; same impulse-control disorder risk; sudden sleep attacks
Rotigotine:
  • D3 > D2 > D1 agonist
  • Transdermal patch (applied once daily)
  • Advantages: Avoids GI absorption issues; continuous drug delivery
  • Uses: PD (early or adjunct); RLS
  • Adverse effects: Application site reactions; same class effects (hallucinations, impulse-control disorders, somnolence)
Apomorphine:
  • Non-selective dopamine agonist (D1, D2, D3, D4)
  • Subcutaneous injection (not oral - extensive first-pass metabolism)
  • Sublingual film also available
  • Uses: Acute rescue for severe off-periods in PD (not responsive to oral adjustment)
  • Very rapid onset (~10 min); short duration (~90 min)
  • Adverse effects: Severe nausea/vomiting (must pretreat with trimethobenzamide; do NOT use ondansetron - risk of QT prolongation and hypotension); orthostatic hypotension; injection site nodules; may increase dyskinesias

5. AMANTADINE

MOA: Antiviral agent found by chance to have antiparkinson properties. Multiple proposed mechanisms:
  • May potentiate dopaminergic function (increase synthesis, release, or reduce reuptake of dopamine)
  • NMDA glutamate receptor antagonist → antidyskinetic effect (primary mechanism for managing levodopa-induced dyskinesias)
  • Antagonizes adenosine A2A receptors (may inhibit D2 receptor downregulation)
  • Releases catecholamines from peripheral stores
Formulations:
  • Immediate-release (Symmetrel): 100 mg BID-TID
  • Extended-release (Gocovri): once daily at bedtime; (Osmalex ER): 129-322 mg once daily in morning
Pharmacokinetics: Peak plasma levels 1-4 h after oral IR dose; half-life 2-4 h; mostly excreted unchanged in urine; dose reduce in renal impairment.
Clinical Uses:
  • Adjunct in Parkinson's disease (mild benefits for bradykinesia, rigidity, tremor)
  • Reduction of levodopa-induced dyskinesias (major current use)
  • Influenza A prophylaxis/treatment (limited current use due to resistance)
  • Benefits often diminish after a few weeks (tachyphylaxis)
Adverse Effects:
  • CNS: Restlessness, depression, suicidal ideation, irritability, somnolence, insomnia, hallucinations, confusion, psychosis (all reversible on stopping)
  • Livedo reticularis (skin - purplish mottled discoloration; clears within 1 month of stopping)
  • Peripheral edema
  • Orthostatic hypotension; urinary retention; dry mouth; constipation
  • Heart failure exacerbation
  • Convulsions at very high doses
  • Abrupt withdrawal: Can cause acute confusional state, hyperpyrexia, and abrupt worsening of parkinsonism → must taper

6. ISTRADEFYLLINE

MOA: Adenosine receptor antagonist - selective antagonist of A2A receptors (analog of caffeine). Adenosine A2A receptors modulate D2 receptor function in striatum; their blockade → facilitates dopaminergic transmission → reduces off-periods.
Clinical Use: Adjunct to carbidopa-levodopa in adults with PD experiencing off-periods. Dose: 20-40 mg orally once daily.
Adverse Effects: Dyskinesias, dizziness, constipation, nausea, hallucinations, sleeplessness; impulse-control behaviors.

7. ANTIMUSCARINIC DRUGS IN PARKINSONISM (Centrally Acting)

MOA: Block muscarinic receptors in the striatum → reduce relative excess of cholinergic activity in parkinsonism → improve tremor and rigidity; less effect on bradykinesia.
Drugs:
  • Benztropine mesylate (most commonly used)
  • Trihexyphenidyl
  • Biperiden
Use: Particularly useful for tremor; adjunct or in early mild disease; also treat drug-induced (antipsychotic) Parkinsonism and acute dystonic reactions.
Adverse Effects: Dry mouth, blurred vision, urinary retention, constipation, confusion, hallucinations (especially elderly); tachycardia; memory impairment; exacerbate narrow-angle glaucoma; cognitive impairment.

B. CHOLINESTERASE INHIBITORS

(Katzung Ch. 7 & Ch. 60 - Cholinomimetics & Drugs for Dementia)

Classification by Duration of Action

SHORT-ACTING (ALCOHOL): EDROPHONIUM

MOA: Alcohol group → reversibly binds to the active site of acetylcholinesterase (AChE) via electrostatic and hydrogen bonds only - NOT covalent; very brief binding (minutes).
Effects: Amplifies all actions of ACh:
  • Increased parasympathetic activity (muscarinic: bradycardia, miosis, increased GI motility, increased secretions)
  • Enhanced somatic neuromuscular transmission (nicotinic: improved muscle strength)
Route/Properties: Parenteral only; quaternary amine → does NOT enter CNS; very short duration of action (5-10 min).
Uses:
  • Diagnosis of myasthenia gravis (Tensilon test) - brief improvement in muscle strength
  • Acute reversal of non-depolarizing neuromuscular block (curariform)
  • Differentiation of myasthenic crisis from cholinergic crisis
Toxicity: Parasympathomimetic excess (bradycardia, bronchoconstriction, excessive secretions, GI cramps); additive with other parasympathomimetics.

INTERMEDIATE-ACTING (CARBAMATES)

All form reversible covalent (carbamylate ester) bonds with AChE → slower hydrolysis than acetylcholine bond → intermediate duration (hours).

NEOSTIGMINE

  • Quaternary amine → does NOT enter CNS
  • Duration: 2-4 hours
  • Routes: Oral and parenteral
  • Uses: Myasthenia gravis; postoperative ileus; neurogenic urinary retention; reversal of non-depolarizing neuromuscular blockade
  • Toxicity: Parasympathomimetic excess (SLUDGE/DUMBELS symptoms); Interactions: additive with parasympathomimetics

PYRIDOSTIGMINE

  • Like neostigmine but longer-acting (4-6 hours)
  • Quaternary amine; oral and IV
  • Primary use: myasthenia gravis (drug of choice for chronic management)
  • Also used as nerve agent prophylaxis (Gulf War use)

PHYSOSTIGMINE

  • Natural alkaloid; tertiary amine → ENTERS CNS
  • Duration ~1-2 hours
  • Uses:
    • Reversal of anticholinergic toxicity (atropine overdose, tricyclic antidepressant toxicity)
    • Glaucoma (topically - historical)
    • Alzheimer's (historical; replaced by better drugs)
  • Toxicity: CNS effects (seizures at high doses); bradycardia

RIVASTIGMINE

  • Like physostigmine but longer acting (8-10 hours); tertiary amine → enters CNS
  • Inhibits both AChE and butyrylcholinesterase (BuChE)
  • Available: Oral capsules and transdermal patch (reduces GI side effects)
  • Primary use: Alzheimer's disease and Parkinson's disease dementia (PDD)
  • Toxicity: GI (nausea, vomiting, diarrhea) - common; reduced with patch; weight loss; headache

LONG-ACTING (ORGANOPHOSPHATES)

Form irreversible covalent bonds with AChE (phosphorylation of serine at active site) → permanent inhibition until new enzyme is synthesized or pharmacologic reversal with pralidoxime (PAM) occurs (if given early).

ECHOTHIOPHATE

  • Topical ophthalmic (now largely obsolete)
  • Historical use: Glaucoma (reduces intraocular pressure by increasing aqueous humor drainage)
  • Toxicity: Brow ache, uveitis, blurred vision; systemic absorption → cholinergic crisis

ORGANOPHOSPHATE INSECTICIDES AND NERVE AGENTS

  • Malathion: Insecticide; relatively safe for mammals (metabolized by other enzymes); some use as ectoparasiticide (head lice)
  • Parathion: Dangerous agricultural insecticide; no antidote-specific treatment beyond atropine + pralidoxime
  • Sarin (and other nerve agents - soman, tabun, VX): Chemical warfare agents; extreme toxicity; massive cholinergic crisis
Treatment of Organophosphate Poisoning:
  1. Atropine (muscarinic antagonist) - effective at muscarinic sites only; given in large doses until secretions dry up
  2. Pralidoxime (2-PAM) - reactivates AChE if given before "aging" (phosphorylation becomes irreversible); active at both muscarinic and nicotinic sites; give EARLY; studies conflicting on outcome benefit
  3. Benzodiazepines for seizures
  4. Remove contaminated clothing; decontaminate skin

CHOLINESTERASE INHIBITORS IN ALZHEIMER'S DISEASE

(Katzung Ch. 60, pp. 1653-1658)
Rationale: Loss of cholinergic neurons in AD → marked decrease in choline acetyltransferase and cholinergic markers → inhibiting AChE increases available ACh → partially compensates for lost cholinergic neurons.
Three approved AChE inhibitors for AD:

DONEPEZIL

  • Reversible, selective AChE inhibitor (does not significantly inhibit BuChE)
  • Tertiary amine; enters CNS
  • Long half-life: ~70 hours → once-daily dosing (5 mg/day initial; increase to 10 mg/day after 4-6 weeks; 23 mg/day for moderate-severe AD)
  • Oral (tablet or orally-disintegrating tablet)
  • Hepatic metabolism (CYP2D6, CYP3A4)
  • Uses: Mild to moderate AD; also approved for moderate-severe AD; sometimes used in PDD and Lewy body dementia
  • Adverse effects: GI (nausea, diarrhea, vomiting - especially at dose increase); bradycardia and syncope (cardiac concern); insomnia; muscle cramps; anorexia

GALANTAMINE

  • Reversible AChE inhibitor with additional allosteric potentiating activity at nicotinic ACh receptors (nAChR) (unique dual mechanism)
  • Tertiary amine; oral (IR twice daily or extended-release once daily)
  • Hepatic metabolism (CYP2D6, CYP3A4)
  • Half-life ~7 hours
  • Uses: Mild to moderate AD
  • Adverse effects: GI (nausea, vomiting - dose-limiting); bradycardia; weight loss; syncope

RIVASTIGMINE

(Covered above under carbamates)
  • Inhibits both AChE and BuChE
  • For AD and Parkinson's disease dementia
  • Transdermal patch preferred to reduce GI adverse effects

NMDA RECEPTOR ANTAGONIST IN ALZHEIMER'S DISEASE

MEMANTINE

  • MOA: Non-competitive NMDA glutamate receptor antagonist → blocks excessive glutamate activity and calcium influx → neuroprotective effect (reduces excitotoxicity)
  • Oral; half-life ~60-80 hours; renal excretion
  • Uses: Moderate-to-severe Alzheimer's disease; often used in combination with donepezil
  • Adverse effects: Dizziness, headache, confusion; less GI side effects than AChE inhibitors; generally well tolerated
  • Combination: Donepezil + memantine (Namzaric) - approved for moderate-severe AD

INDIRECT MODULATORS OF ACETYLCHOLINE RELEASE

AMIFAMPRIDINE (3,4-Diaminopyridine / 4-AP)

  • MOA: Potassium channel antagonist → increases excitability of presynaptic neuron at NMJ → increased ACh release
  • Uses: Lambert-Eaton myasthenic syndrome (LEMS); congenital myasthenic syndromes
  • Oral; acetylated then renally excreted; duration ~2.5 h
  • Toxicity: Seizure activity; may prolong QT interval; paresthesias; numbness; insomnia
Source: All notes directly extracted from Katzung's Basic and Clinical Pharmacology, 16th Edition (ISBN 9781260463309), Chapters 28, 36, 40, 42, 60, and 7.
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