Give me high yield pharmacology notes on all the drugs under these topics use katzung as the guide book for the drugs . This is for quick revision before the exam 11)Proton Pump Inhibitors (PPIs), H2 Blockers & Antacids. 11) Drugs for liver Failure & Biliary management 12)Dopaminergic drugs & Cholinesterase tors. 13) Thrombolytics, Sedatives & General Anesthetics Bisphosphonates, Xanithine Oxidase tors & DMARDS 15) Estrogens, Progesting & Androgen therapy

Reading File

Finding Sources

Reading File

Here are your complete high-yield pharmacology revision notes, all sourced from Katzung's Basic & Clinical Pharmacology, 16th Edition:

HIGH-YIELD PHARMACOLOGY REVISION NOTES

Based on Katzung's Basic & Clinical Pharmacology, 16th Edition

TOPIC 11A: PROTON PUMP INHIBITORS (PPIs), H2 BLOCKERS & ANTACIDS

Physiology of Acid Secretion (Foundation)

Parietal cell has 3 receptors: Gastrin (CCK-B), Histamine (H2), Acetylcholine (M3)
Gastrin & ACh → ↑cytosolic Ca²⁺ → protein kinase activation → H⁺/K⁺-ATPase (proton pump) on canalicular surface secretes acid
Histamine → ↑cAMP via adenylyl cyclase → also activates proton pump
ECL cells (near parietal cells) receive gastrin/ACh → release histamine (indirect pathway)
Key concept: Gastrin's main effect is INDIRECT (via ECL histamine release); ACh is a direct stimulant

ANTACIDS

Agent	Mechanism	Key Points
Sodium bicarbonate	Rapidly neutralizes HCl → CO₂ + NaCl	Fast but short-lived; causes belching; may cause metabolic alkalosis; CI in CHF, HTN
Calcium carbonate (Tums)	Neutralizes HCl → CO₂ + CaCl₂	Belching; milk-alkali syndrome with dairy products; risk of hypercalcemia
Magnesium hydroxide	Forms MgCl₂	No gas; causes osmotic diarrhea
Aluminum hydroxide	Forms AlCl₃	No gas; causes constipation
Mg + Al combos (Maalox, Mylanta)	Combined	Balance diarrhea vs constipation; avoid in renal insufficiency (both absorbed/excreted renally)

Duration: 1-2 hours only (short-lived)
Drug interaction: Do NOT give within 2 hours of tetracyclines, fluoroquinolones, itraconazole, iron (chelation/pH effect reduces absorption)
Single dose of 156 mEq antacid 1 hour post-meal neutralizes for ~2 hours

H2 RECEPTOR ANTAGONISTS (H2RAs)

Drugs: Cimetidine, Ranitidine, Famotidine, Nizatidine

Property	Detail
MOA	Competitive block of H2 receptors on parietal cells → ↓cAMP → ↓acid secretion
Duration	6-10 hours (much longer than antacids)
Efficacy in GERD	Relieves infrequent heartburn; < 50% healing of erosive esophagitis
Peptic ulcer	Largely replaced by PPIs for acute PUD

Adverse Effects (< 3% incidence - very safe):

Diarrhea, headache, fatigue, myalgia, constipation
Mental status changes (confusion, hallucinations, agitation) with IV use - especially in elderly or those with renal/hepatic dysfunction
Cimetidine-specific: inhibits CYP450 → multiple drug interactions; anti-androgenic effects (gynecomastia, impotence); crosses BBB (confusion)

Clinical Uses:

Infrequent heartburn / dyspepsia (OTC)
Prophylactic before meals for heartburn
Stress ulcer prophylaxis in ICU (IV continuous infusion preferred over bolus)
Nonulcer dyspepsia

PROTON PUMP INHIBITORS (PPIs)

Drugs: Omeprazole, Esomeprazole, Lansoprazole, Dexlansoprazole, Pantoprazole, Rabeprazole

Property	Detail
MOA	Irreversibly inhibit H⁺/K⁺-ATPase (proton pump); prodrugs activated in acid environment
Activation	Require acidic milieu to be activated to sulfenamide form; take 30-60 min before meals
Duration	~24 hours per dose (irreversible binding); full effect in 3-4 days
Superiority	Stronger acid suppression than H2RAs; superior for erosive GERD, PUD, H. pylori eradication

Clinical Uses:

GERD - preferred for erosive esophagitis (vs H2RAs which heal <50%)
Peptic ulcer disease - faster symptom control and higher healing rates than H2RAs
H. pylori eradication - PPI + 2 antibiotics × 14 days (triple therapy)
NSAID-induced ulcers - co-prescribe if NSAID cannot be stopped
Zollinger-Ellison syndrome (high dose)
Stress ulcer prophylaxis - preferred oral agent in ICU

Adverse Effects (long-term use):

↑risk of C. diff, community-acquired pneumonia, hypomagnesemia
Bone fracture (hip, spine) with chronic use
↓absorption of vitamin B12, iron, calcium
Rebound acid hypersecretion on abrupt withdrawal
Possible ↑risk nosocomial pneumonia (acid suppression → bacterial overgrowth)

Key Drug Interaction:

PPIs + Clopidogrel: PPIs (especially omeprazole, esomeprazole, lansoprazole) inhibit CYP2C19 → ↓clopidogrel activation → ↓antiplatelet effect
Prefer pantoprazole or rabeprazole if co-prescribing with clopidogrel (minimal CYP2C19 inhibition)

MUCOSAL PROTECTIVE AGENTS

Sucralfate:

Salt of sucrose + sulfated aluminum hydroxide
In acid: forms viscous paste that binds to ulcer base for up to 6 hours
Negatively charged sucrose sulfate binds positively charged ulcer proteins → physical barrier
Also stimulates mucosal prostaglandins and bicarbonate
Dose: 1 g QID on empty stomach (1 hour before meals)
Clinical use: ICU stress bleeding prophylaxis (preferred by some due to lower pneumonia risk vs PPIs/H2RAs)
< 3% absorbed; remainder excreted in feces

Misoprostol (prostaglandin E1 analog):

Stimulates mucus/bicarbonate; inhibits acid secretion
Used for NSAID-induced ulcer prevention
ADR: diarrhea, cramping; contraindicated in pregnancy (uterotonic)

TOPIC 11B: DRUGS FOR LIVER FAILURE & BILIARY MANAGEMENT

(Katzung covers hepatic encephalopathy management and biliary drugs)

Hepatic Encephalopathy - Pharmacotherapy

Drug	MOA	Use
Lactulose	Poorly absorbed disaccharide → colonic acidification → traps NH₄⁺ as NH₄⁺ (not absorbed); also cathartic	1st-line for HE; reduces ammonia levels
Rifaximin	Non-absorbable antibiotic → ↓gut ammonia-producing bacteria	Adjunct or alternative to lactulose; preferred for maintenance/prevention
Neomycin	Non-absorbable aminoglycoside → ↓urease-producing gut bacteria	Older agent; risk of nephrotoxicity with long-term use
Zinc supplements	Cofactor for urea cycle enzymes	Used in zinc-deficient cirrhotic patients

Liver Failure: Supporting Drugs

Spironolactone ± furosemide: ascites management (aldosterone antagonism)
Propranolol / Nadolol (non-selective beta-blockers): primary/secondary prophylaxis of variceal bleeding (↓portal pressure)
Terlipressin / Octreotide: variceal bleeding - splanchnic vasoconstriction
N-acetylcysteine (NAC): acetaminophen overdose - replenishes glutathione; also used in non-acetaminophen acute liver failure

Biliary Management

Drug	Use
Ursodeoxycholic acid (UDCA)	Primary biliary cholangitis (PBC); small cholesterol gallstones (dissolution); biliary dyskinesia
Cholestyramine (bile acid sequestrant)	Pruritus in cholestasis; also ↑cholesterol elimination
Obeticholic acid	PBC - farnesoid X receptor (FXR) agonist
Fibrates (bezafibrate)	PBC add-on therapy

TOPIC 12: DOPAMINERGIC DRUGS & CHOLINESTERASE INHIBITORS

Dopaminergic Drugs - Parkinson's Disease

Pathophysiology: ↓dopamine in substantia nigra → imbalance of dopaminergic/cholinergic systems in basal ganglia. Motor features at Braak stage 3. Benefits of dopaminergic drugs mostly depend on D2 receptor stimulation.

LEVODOPA + CARBIDOPA (★ Most important)

Property	Detail
MOA	Levodopa = precursor; crosses BBB via L-amino acid transporter (LAT); converted to dopamine by DOPA decarboxylase in brain
Carbidopa	Peripheral DOPA decarboxylase inhibitor → prevents peripheral conversion → more levodopa reaches brain; also reduces peripheral ADRs
Only 1-3% of oral levodopa reaches brain (most metabolized peripherally without carbidopa)
Absorption	Rapid from small intestine; food (especially amino acids) delays absorption and competes for BBB transport
Half-life	1-3 hours plasma; metabolites = HVA (homovanillic acid) and DOPAC

Adverse Effects of Levodopa:

GI: Nausea, vomiting (↓by taking with food or ↑carbidopa dose)
Cardiovascular: Postural hypotension; cardiac arrhythmias
Dyskinesias (involuntary movements): Common with long-term use; dose-dependent
On-Off phenomena: Random fluctuations between mobility and akinesia (long-term)
Wearing-off (end-of-dose deterioration): Drug effect wanes before next dose
Psychiatric: Hallucinations, psychosis, confusion (especially elderly); impulse control disorders
Contraindicated with non-selective MAO inhibitors (hypertensive crisis)

High-yield mnemonic - Levodopa ADRs: HAD PVD - Hallucinations, Arrhythmia, Dyskinesia, Postural hypotension, Vomiting, Dystonias

DOPAMINE AGONISTS

Non-ergot (preferred, fewer side effects): Pramipexole, Ropinirole (oral); Rotigotine (patch); Apomorphine (injectable, for acute off episodes) Ergot-derived (avoid due to fibrosis risk): Bromocriptine, Pergolide, Cabergoline

Property	Detail
MOA	Direct D2/D3 receptor agonists (no conversion required)
Advantage over Levodopa	Longer half-life → smoother response, fewer fluctuations; used alone early or as adjunct
D3 selective	Pramipexole (also used in restless legs syndrome)

ADRs of Dopamine Agonists:

Nausea, postural hypotension, hallucinations, psychosis
Impulse control disorders (gambling, hypersexuality, binge eating) - HIGH YIELD
Sudden sleep attacks - especially pramipexole, ropinirole; warn patients not to drive
Ergot-specific: Pulmonary/retroperitoneal fibrosis, erythromelalgia (red, painful, swollen feet/hands), cardiac valve fibrosis (pergolide - withdrawn)
Withdrawal syndrome: Anxiety, panic attacks, depression - taper slowly
Contraindicated: Psychotic illness, recent MI, peptic ulceration

MONOAMINE OXIDASE B INHIBITORS (MAO-B-I)

Drug	Details
Selegiline (deprenyl)	Selective irreversible MAO-B inhibitor; retards dopamine breakdown; adjunct to levodopa; dose: 5 mg at breakfast + 5 mg at lunch; can cause insomnia if taken late
Rasagiline	More potent MAO-B inhibitor; monotherapy for early PD (1 mg/d) or adjunct (0.5-1 mg/d); possible but unproven neuroprotective effect (ADAGIO trial)

At normal doses: selective MAO-B (safe with levodopa)
At high doses: inhibits MAO-A as well (risk of hypertensive crisis with tyramine/"cheese effect")

CATECHOL-O-METHYLTRANSFERASE (COMT) INHIBITORS

Drug	Details
Entacapone	Peripheral COMT inhibitor; used adjunct with levodopa to reduce "wearing off"; ↑levodopa bioavailability
Tolcapone	Central + peripheral COMT inhibitor; hepatotoxic (monitor LFTs) - restricted use
Opicapone	Once-daily peripheral COMT inhibitor

ANTICHOLINERGIC (ANTIMUSCARINIC) DRUGS

Drugs: Benztropine, Trihexyphenidyl, Biperiden, Orphenadrine, Procyclidine

MOA: Block M1 muscarinic receptors → restore dopamine/ACh balance in basal ganglia
Best for: Tremor and rigidity (less effective for bradykinesia)
NOT preferred in elderly or cognitively impaired (anticholinergic CNS effects)
ADRs: Dry mouth, urinary retention, constipation, blurred vision, confusion, tachycardia, mydriasis
Taper slowly on withdrawal (prevent acute parkinsonism exacerbation)

AMANTADINE

Originally antiviral; mechanism includes ↑dopamine release + weak NMDA receptor antagonism
Used for early mild PD and for treating levodopa-induced dyskinesias
Also useful in drug-induced parkinsonism
ADRs: Livedo reticularis (skin mottling), ankle edema, confusion

CHOLINESTERASE INHIBITORS (for Alzheimer's / Myasthenia Gravis)

(Katzung Chapter 12 - also relevant from block 2 for organophosphate context)

For Alzheimer's Disease:

Drug	Class	Key Points
Donepezil	Piperidine; reversible AChE inhibitor	1st-line; once daily; minimal hepatotoxicity; used all stages
Rivastigmine	Carbamate; reversible; inhibits both AChE + BuChE	Transdermal patch (↓GI ADRs); also for Parkinson's dementia
Galantamine	Reversible AChE inhibitor + nicotinic receptor modulator	Mild-moderate AD
Tacrine	Oldest; rarely used now	Significant hepatotoxicity

MOA: Inhibit acetylcholinesterase → ↑ACh at synapses → improve cognitive function
ADRs: Nausea, vomiting, diarrhea (cholinergic excess - peripheral), bradycardia
Memantine (NMDA antagonist) - used in moderate-severe AD, often combined with donepezil

Cholinesterase Inhibitors for Myasthenia Gravis / Reversal:

Drug	Duration	Use
Edrophonium	Ultra-short (5-10 min)	Tensilon test (diagnosis of MG); too short for therapy
Neostigmine	Intermediate	Reversal of NMB after surgery; treatment of MG; does NOT cross BBB
Pyridostigmine	Intermediate	Preferred for chronic MG treatment; does NOT cross BBB
Physostigmine	Short-intermediate	Crosses BBB; used for atropine/scopolamine overdose

Organophosphate poisoning antidote: Atropine (blocks muscarinic effects) + Pralidoxime (2-PAM) (regenerates AChE if given early, before "aging")

TOPIC 13: THROMBOLYTICS, SEDATIVES & GENERAL ANESTHETICS

THROMBOLYTICS (Fibrinolytics)

MOA: Convert plasminogen → plasmin → fibrin degradation

Drug	Details
Streptokinase	Bacterial protein; binds plasminogen → activator complex; antigenic (antibodies, allergic reactions, cannot repeat for 6 months); cheaper
Alteplase (tPA)	Recombinant tissue plasminogen activator; fibrin-selective (activates only clot-bound plasminogen); gold standard for ischemic stroke (within 4.5 hrs) and STEMI
Reteplase	Mutant tPA; longer half-life; can give as 2 IV boluses; less fibrin-selective than alteplase
Tenecteplase	Mutant tPA; longest half-life; single IV bolus; highest fibrin selectivity; lowest risk of systemic bleeding
Urokinase	Directly activates plasminogen; non-fibrin-selective; no antigenicity; used for pulmonary embolism and catheter clearance
Anistreplase (APSAC)	Long half-life; given as slow IV push; largely obsolete

Indications: STEMI, acute ischemic stroke (< 4.5 hrs), massive PE, DVT, occluded catheters

Absolute Contraindications:

Prior intracranial hemorrhage, active internal bleeding
Recent (< 3 months) head trauma/stroke/surgery
BP > 185/110 (ischemic stroke)
Bleeding diathesis, intracranial neoplasm

ADRs: Bleeding (most common), intracranial hemorrhage, reperfusion arrhythmias (after STEMI thrombolysis)

SEDATIVES / SEDATIVE-HYPNOTICS (Katzung Ch. 22)

Definition: Sedative = ↓anxiety (anxiolytic); Hypnotic = promotes sleep (dose-dependent continuum)

BENZODIAZEPINES (BZDs)

MOA: Bind to GABA-A receptor (between α and γ subunits) → ↑frequency of Cl⁻ channel opening → membrane hyperpolarization

Drug	Feature
Diazepam	Long-acting; active metabolites (desmethyldiazepam); anxiety, seizures, alcohol withdrawal, muscle relaxant
Lorazepam	Intermediate; no active metabolites; IV for status epilepticus
Midazolam	Short-acting; water-soluble; IV sedation/pre-op; amnesia effect
Alprazolam	Short-intermediate; preferred for panic disorders and agoraphobia
Triazolam	Short-acting; insomnia; rebound insomnia
Clonazepam	Long-acting; absence/myoclonic seizures, panic disorder
Flurazepam	Long-acting; insomnia (daytime hangover)
Temazepam	Intermediate; insomnia

Advantages: High therapeutic index; CNS-selective; minimal cardiovascular effects; reversible with flumazenil

Disadvantages / ADRs: Tolerance, dependence, rebound insomnia/anxiety on withdrawal, additive CNS depression with alcohol, anterograde amnesia, respiratory depression

Flumazenil: Competitive BZD antagonist at GABA-A (α-γ site); reverses BZD overdose; SHORT duration (< 1 hr) → may need repeat doses; does NOT reverse barbiturates or alcohol

BARBITURATES

MOA: Bind GABA-A at a different site from BZDs → ↑duration of Cl⁻ channel opening (BZDs increase frequency; barbiturates increase duration)

At high doses: can directly activate Cl⁻ channel (without GABA) → very low therapeutic index → respiratory/vasomotor center depression → can cause death (linear dose-response)
Phenobarbital: Long-acting; epilepsy (especially in children and neonates), alcohol withdrawal
Thiopental: Ultra-short IV anesthesia induction
Pentobarbital: Medium-acting; ICU sedation, refractory status epilepticus

ADRs: CNS and respiratory depression, tolerance, physical dependence; induces CYP450 (major drug interactions); no reversal agent

Z-DRUGS (Non-BZD Hypnotics)

Drug	Notes
Zolpidem	α1-selective GABA-A modulator; insomnia; short half-life; less anxiolytic/anticonvulsant
Zaleplon	Ultra-short (1 hr); sleep-onset insomnia; can take in middle of night
Eszopiclone	Longer-acting Z-drug; insomnia

Bind GABA-A only at isoforms containing α1 subunit → more selective hypnosis
Flumazenil can reverse these (same α-γ site)

BUSPIRONE

Partial agonist at 5-HT1A receptors; no BZD cross-tolerance; no sedation, no withdrawal
Used for generalized anxiety disorder (GAD); takes weeks to work (not acute use)
Does NOT work for panic attacks or acute anxiety

GENERAL ANESTHETICS (Katzung Ch. 25)

Stages of Anesthesia (Guedel):

Analgesia (conscious)
Excitement/Delirium (avoid stimulus)
Surgical anesthesia (planes I-IV)
Medullary depression (dangerous)

INHALATIONAL AGENTS

MOA: Primarily potentiate GABA-A and inhibit NMDA receptors; Meyer-Overton correlation: potency ∝ lipid solubility

Minimum Alveolar Concentration (MAC): Concentration at which 50% of patients do NOT move to surgical incision - measures potency. Lower MAC = more potent.

Agent	MAC	Key Properties
Halothane	0.75%	High potency; hepatotoxicity (halothane hepatitis); sensitizes myocardium to catecholamines (arrhythmias); largely replaced
Isoflurane	1.15%	No hepatotoxicity; ↓BP (vasodilation); "coronary steal" concern; widely used
Sevoflurane	1.7-2%	Rapid onset/offset; non-irritating; preferred for inhalation induction (especially children)
Desflurane	6-7%	Fastest recovery; airway irritant (cough, laryngospasm - not for induction); ICU weaning
Nitrous oxide (N₂O)	> 100%	Weak anesthetic (can't achieve surgical anesthesia alone); analgesic; used adjunct; inhibits B12 (methionine synthase) with prolonged use

Malignant Hyperthermia: Triggered by halogenated agents + succinylcholine → uncontrolled skeletal muscle Ca²⁺ release (RYR1 mutation) → hyperthermia, rigidity, rhabdomyolysis

Treatment: Dantrolene (blocks RYR1 Ca²⁺ release) + cooling + bicarbonate

INTRAVENOUS ANESTHETIC AGENTS

Drug	MOA	Key Features
Propofol	Potentiates GABA-A	Most widely used IV induction agent; rapid induction + recovery; antiemetic; propofol infusion syndrome with prolonged ICU use (metabolic acidosis); pain on injection; can cause respiratory depression
Thiopental	Barbiturate; GABA-A ↑duration	Ultra-short; decreases ICP; respiratory depression; no analgesia
Ketamine	NMDA receptor antagonist	Dissociative anesthesia; preserves airway reflexes; bronchodilator (good for asthma); ↑BP and HR; causes hallucinations/"emergence reactions" → give BZD; used in emergency settings; increases ICP (caution in head injury)
Etomidate	GABA-A modulator	Minimal cardiovascular effects → preferred in hemodynamically unstable patients; inhibits adrenal cortisol synthesis (single dose) - avoid prolonged infusion
Midazolam	BZD; GABA-A	Premedication, sedation; provides amnesia and anxiolysis
Dexmedetomidine	α2-agonist (locus coeruleus)	ICU sedation; minimal respiratory depression; analgesic-sparing
Fentanyl/Morphine	Opioid (μ receptor)	Analgesia component of balanced anesthesia

Neuromuscular Blockers (Part of Anesthesia):

Succinylcholine: Depolarizing NMB; fastest onset (60 sec); used for rapid sequence intubation; ADRs: hyperkalemia (burns, denervation), malignant hyperthermia, bradycardia, ↑IOP
Rocuronium, Vecuronium, Atracurium: Non-depolarizing NMB; reversed by neostigmine or sugammadex (for rocuronium/vecuronium)

TOPIC 14: BISPHOSPHONATES, XANTHINE OXIDASE INHIBITORS & DMARDs

BISPHOSPHONATES

Drugs: Alendronate, Risedronate, Ibandronate, Zoledronate (IV), Pamidronate (IV), Etidronate

Property	Detail
MOA	Incorporate into bone → osteoclasts ingest drug → ↓osteoclast activity and ↑apoptosis → ↓bone resorption
Specifics	Nitrogen-containing BPs (all except etidronate): inhibit farnesyl pyrophosphate synthase → ↓prenylation of proteins → osteoclast dysfunction
Absorption	Very poor oral bioavailability (~1%); must be taken fasting with full glass of water; remain upright 30-60 min after
Bone half-life	Years (incorporated into bone matrix)

Clinical Uses:

Osteoporosis (postmenopausal, glucocorticoid-induced)
Paget's disease of bone
Hypercalcemia of malignancy (IV zoledronate/pamidronate)
Bone metastases (reduce skeletal events)

Adverse Effects (HIGH YIELD):

Esophagitis / esophageal ulceration (oral BPs; instruct to remain upright)
Osteonecrosis of the jaw (ONJ) - especially with IV use; risk ↑with dental procedures
Atypical femoral fractures - rare; with long-term use (> 5 years); subtrochanteric/diaphyseal
Hypocalcemia (especially IV)
Acute phase reaction (flu-like symptoms) with IV - first dose
Ibandronate/Zoledronate: nephrotoxicity (monitor creatinine); renal dosing adjustments needed

XANTHINE OXIDASE INHIBITORS (Gout Management)

Pathophysiology: Xanthine oxidase converts hypoxanthine → xanthine → uric acid (end product in humans; no uricase)

ALLOPURINOL

MOA: Structural analog of hypoxanthine; inhibits xanthine oxidase → ↓uric acid synthesis; also metabolized to oxypurinol (active metabolite with longer half-life)
Indications: Chronic gout (urate-lowering), gout with tophi, uric acid nephrolithiasis, tumor lysis syndrome prophylaxis, patients who overproduce urate
ADRs:
- Allopurinol hypersensitivity syndrome (AHS): Rare but severe - SJS/TEN, hepatic necrosis, eosinophilia; associated with HLA-B*5801 (Asian populations - screen before use)
- Rash (most common), GI intolerance
- Precipitates acute gout at initiation (mobilization of urate) → always co-prescribe colchicine or NSAID for first 3-6 months
- ↑toxicity of azathioprine and 6-mercaptopurine (both metabolized by xanthine oxidase; reduce doses by 75%)

FEBUXOSTAT

MOA: Non-purine xanthine oxidase inhibitor; more selective than allopurinol
Metabolized hepatically (safe in renal impairment; useful when allopurinol is not tolerated)
ADRs: Gout flares (same as allopurinol at initiation); liver enzyme ↑; cardiovascular risk (FDA black-box warning - ↑CV mortality vs allopurinol - reserve for allopurinol-intolerant patients)

OTHER GOUT DRUGS:

Colchicine: Inhibits microtubule polymerization → blocks neutrophil migration; used for acute gout attacks and prophylaxis; ADRs: diarrhea, nausea (GI main issue); myopathy with long-term use
Probenecid: Uricosuric (blocks renal tubular urate reabsorption via URAT1); requires normal renal function; avoid with salicylates (block uricosuria); initiates with colchicine; CI in urate stones
Rasburicase: Recombinant uricase; converts urate → allantoin; for tumor lysis syndrome; CI in G6PD deficiency (generates H₂O₂)
Pegloticase: PEGylated uricase; for severe refractory gout; infusion reactions common

DMARDs - Disease-Modifying Antirheumatic Drugs

Key principle: Take 2 weeks to 6 months to show effect; modify underlying disease, not just symptoms

Conventional Synthetic DMARDs (csDMARDs)

METHOTREXATE (MTX) - Anchor drug for RA

Property	Detail
MOA	Folate antagonist; inhibits dihydrofolate reductase (DHFR) → ↓purine/pyrimidine synthesis → ↓lymphocyte proliferation; also ↑adenosine (anti-inflammatory)
Dose	Weekly (not daily!) for RA; 7.5-25 mg/week PO or SC
Monitoring	LFTs, CBC (myelosuppression)

ADRs:

Hepatotoxicity / cirrhosis (most serious with long-term use)
Myelosuppression (leukopenia, thrombocytopenia)
Mucositis / oral ulcers
Pneumonitis (interstitial lung disease)
Teratogenic (Category X - folic acid antagonist); contraceptive use mandatory + stop 1-3 months before conception (both sexes)
Rescue: Leucovorin (folinic acid) - bypasses DHFR block; given to manage MTX toxicity
Supplemental folic acid reduces GI and hepatic ADRs (given routinely with MTX)

HYDROXYCHLOROQUINE / CHLOROQUINE

Antimalarials used for mild RA and SLE
MOA: Lysosomal pH alteration → ↓antigen processing and cytokine production
ADR: Irreversible retinopathy (regular eye exams required); safe in pregnancy (SLE)

SULFASALAZINE

Mild-moderate RA, ankylosing spondylitis, IBD
MOA: Inhibits dihydrofolate reductase + inflammatory mediators
ADRs: GI intolerance, headache, rash, myelosuppression; hemolytic anemia in G6PD deficiency; orange discoloration of urine/body fluids; teratogen risk

LEFLUNOMIDE

MOA: Active metabolite A77 1726 inhibits dihydroorotate dehydrogenase → ↓pyrimidine synthesis → T-cell arrest in G1 phase
Half-life: 19 days (enterohepatic recirculation); Cholestyramine accelerates clearance (used in toxicity or before pregnancy)
Equals MTX in efficacy; also used in lupus nephritis
ADRs: Diarrhea (25%), hepatotoxicity, hypertension, alopecia, teratogenic

AZATHIOPRINE

Prodrug → 6-mercaptopurine (6-MP) → inhibits purine synthesis → ↓lymphocyte proliferation
Used in RA, SLE, IBD, transplant rejection
ADRs: Myelosuppression; never combine with allopurinol without 75% dose reduction

CYCLOSPORINE

Calcineurin inhibitor → blocks IL-2 → ↓T-cell activation
ADRs: Nephrotoxicity, hypertension, hirsutism, gingival hyperplasia, neurotoxicity

Biologic DMARDs (bDMARDs)

TNF-α Inhibitors (most widely used class):

Drug	Route	Notes
Etanercept	SC	Soluble TNF receptor fusion protein; does NOT reactivate latent TB (less so than others)
Infliximab	IV	Chimeric anti-TNF antibody; needs MTX to prevent immunogenicity
Adalimumab	SC	Fully human anti-TNF antibody; most widely prescribed
Certolizumab	SC	PEGylated; safe in pregnancy
Golimumab	SC/IV	Once monthly

Class ADRs of TNF inhibitors:

Reactivation of latent TB (screen with TST/IGRA before starting)
Serious infections (fungal, bacterial, viral)
Demyelinating disease (CI in MS)
CHF exacerbation
Drug-induced lupus
Lymphoma risk (small ↑)
Live vaccines contraindicated

Other Biologics:

Drug	MOA	Use
Abatacept	CTLA-4-Ig fusion protein; blocks CD80/CD86-CD28 → ↓T-cell activation	RA, PsA, JIA; IV or SC
Rituximab	Anti-CD20 antibody → depletes B cells	RA (failed TNF-i), GPA, MPA; IV
Tocilizumab / Sarilumab	Anti-IL-6 receptor antibody	RA; ↑LFTs, ↑lipids, neutropenia; cytokine storm syndrome
Anakinra	IL-1 receptor antagonist	RA (less effective), Still's disease, gout flares
Canakinumab	Anti-IL-1β monoclonal Ab	Still's disease, gout flares
Secukinumab / Ixekizumab	Anti-IL-17A	Psoriatic arthritis, AS, plaque psoriasis; CI in IBD
Ustekinumab	Anti-IL-12/23 (anti-p40)	PsA, psoriasis, Crohn's
Belimumab	Anti-BLyS (B-cell survival factor)	SLE
Baricitinib / Tofacitinib / Upadacitinib	JAK inhibitors (tsDMARD)	RA; oral; ↑risk infections, VTE (boxed warning), lipid ↑

TOPIC 15: ESTROGENS, PROGESTINS & ANDROGEN THERAPY

ESTROGENS

Endogenous: Estradiol (most potent) > Estrone > Estriol (weakest; predominant in pregnancy)

Drug	Type
Estradiol	Natural; various routes (oral, patch, gel, vaginal ring)
Ethinyl estradiol	Synthetic; most common in OCP; highly potent, oral
Mestranol	Prodrug → ethinyl estradiol; older OCPs
Conjugated equine estrogens (Premarin)	Mixed natural; used in HRT
Diethylstilbestrol (DES)	Non-steroidal synthetic; historical; teratogen (vaginal adenocarcinoma in daughters - "DES daughters")

MOA: Bind intracellular estrogen receptors (ERα, ERβ) → dimerization → binds ERE in DNA → gene transcription

Physiologic Effects:

Development of female secondary sex characteristics
Proliferation of endometrium
↑HDL, ↓LDL
Maintenance of bone density (↓osteoclast activity)
Pro-coagulant (↑clotting factors II, VII, IX, X, fibrinogen)
↑SHBG (↓free androgens)
Fluid retention

Clinical Uses of Estrogens:

Contraception (combined OCP)
Hormone Replacement Therapy (HRT) - postmenopausal symptoms (hot flashes, urogenital atrophy)
Primary hypogonadism / Turner syndrome - pubertal induction
Breast cancer (high-dose DES - historical; now SERMs preferred)
Prostate cancer (suppress gonadotropins → ↓testosterone)

Adverse Effects / Risks of Estrogens:

VTE / Thromboembolism (↑clotting factors; particularly ethinyl estradiol in OCPs)
Endometrial hyperplasia/cancer (unopposed estrogen - ALWAYS add progestin in women with intact uterus)
Breast cancer risk ↑ (especially with combined HRT > 5 years)
Nausea, breast tenderness, fluid retention
Hypertension (via ↑renin substrate)
Gallstones (↑cholesterol secretion into bile)
Cholestatic jaundice in susceptible individuals
Migraine exacerbation
DES in pregnancy: vaginal clear-cell adenocarcinoma in female offspring; vaginal adenosis

Contraindications:

Known/suspected breast or estrogen-dependent cancer
History of VTE or thrombophilia
Undiagnosed vaginal bleeding
Active liver disease
Pregnancy
History of stroke or coronary artery disease (combined OCP)

SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)

Drug	Agonist at	Antagonist at	Use
Tamoxifen	Bone, uterus, liver	Breast	Breast cancer treatment/prevention; risk of endometrial cancer + VTE (agonist at uterus); hot flashes
Raloxifene	Bone	Breast, uterus	Postmenopausal osteoporosis; breast cancer prevention; no endometrial cancer risk (neutral at uterus); ↑VTE risk
Clomiphene	Pituitary (↑LH/FSH release)	Hypothalamus/pituitary (antagonist)	Ovulation induction (anovulatory infertility); anti-estrogenic at pituitary → ↑GnRH → ↑FSH/LH
Bazedoxifene	Bone	Breast, uterus	Paired with conjugated estrogen for HRT

PROGESTINS

Endogenous: Progesterone

Drug	Type	Notes
Medroxyprogesterone acetate (MPA)	17-OH progesterone derivative	Oral contraception, HRT, endometriosis, endometrial cancer
Norethindrone, Norgestrel, Levonorgestrel	19-nortestosterone derivatives	OCPs; some androgenic activity (↑LDL, acne)
Desogestrel, Norgestimate, Drospirenone	3rd/4th generation	Less androgenic; drospirenone = antimineralocorticoid (↓fluid retention, ↑K⁺ - monitor with ACEi)
Progesterone (micronized)	Natural	HRT, luteal phase support in ART; less androgenic than synthetics

MOA: Bind intracellular progesterone receptors → ↓uterine motility, secretory endometrial changes, ↑cervical mucus viscosity

Physiologic Effects:

Converts proliferative → secretory endometrium
↑basal body temperature (0.5°C)
↑cervical mucus viscosity (barrier to sperm)
↓uterine contractility (maintains pregnancy)
Thermogenic

Clinical Uses of Progestins:

Contraception (combined OCP, progestin-only "mini pill," Depo-Provera, Mirena IUD, implants)
HRT (add to estrogen to prevent endometrial hyperplasia)
Endometriosis (suppress growth)
Dysfunctional uterine bleeding
Endometrial cancer (high-dose MPA/megestrol)

Emergency Contraception: Levonorgestrel (Plan B) - inhibits/delays ovulation; works up to 72 hours (↓efficacy with increased weight); or ulipristal acetate (selective progesterone receptor modulator - up to 5 days)

ADRs of Progestins:

Breakthrough bleeding, amenorrhea
Depression, mood changes
Weight gain, fluid retention
Androgenic effects (acne, hirsutism) with 19-norprogesterone derivatives
↑insulin resistance
Drospirenone: hyperkalemia (antimineralocorticoid)

ANDROGEN THERAPY

Endogenous: Testosterone (testes - Leydig cells, adrenals - DHEA/androstenedione)

Key Androgens & Derivatives:

Drug	Route	Notes
Testosterone (various)	IM (cypionate, enanthate), transdermal patch/gel, implantable pellets	Hypogonadism replacement
Methyltestosterone	Oral	Hepatotoxic (17α-alkylated)
Oxandrolone, Stanozolol	Oral	Anabolic steroids; hepatotoxic
Nandrolone	IM	Less androgenic, more anabolic; used in anemia
Danazol	Oral	Impeded androgen; used for endometriosis, hereditary angioedema; suppresses pituitary FSH/LH
DHT (dihydrotestosterone)	Gel	Active form; not converted to estrogen

MOA: Testosterone → DHT (via 5α-reductase in skin, prostate, genital skin) → binds androgen receptor (AR) → gene transcription. Also aromatized to estradiol in peripheral tissues.

Clinical Uses of Androgens:

Male hypogonadism (primary or secondary)
Delayed puberty in males (short course)
Anemia (stimulate EPO and erythropoiesis)
Catabolic states / wasting syndromes (HIV wasting, cachexia)
Hereditary angioedema (danazol)
Endometriosis (danazol)

Adverse Effects of Androgens (HIGH YIELD):

Virilization in women: Acne, hirsutism, voice deepening, clitoromegaly, menstrual irregularity
Feminization in men (via aromatization to estradiol): Gynecomastia, testicular atrophy, ↓sperm production
Hepatotoxicity (especially 17α-alkylated oral androgens: methyltestosterone, stanozolol, oxymetholone)
Peliosis hepatis and hepatocellular carcinoma with 17α-alkylated androgens
Polycythemia (↑EPO → ↑Hct → ↑VTE risk)
Prostate stimulation (CI in prostate cancer)
Premature closure of epiphyses in adolescents
Cardiovascular: ↑LDL, ↓HDL (especially anabolic steroids); HTN; LVH
Behavioral: Aggression, mood changes
Suppression of spermatogenesis (via ↓FSH via negative feedback)

Anti-androgens / Androgen Blockers:

Drug	MOA	Use
Finasteride	5α-reductase type II inhibitor → ↓DHT	BPH (low dose 5 mg), male pattern baldness (1 mg); gynecomastia ADR
Dutasteride	5α-reductase type I + II inhibitor → ↓DHT more completely	BPH
Flutamide, Bicalutamide, Enzalutamide	Competitive AR antagonists	Prostate cancer (anti-androgen blockade); flutamide hepatotoxic
Spironolactone	Androgen receptor antagonist (also aldosterone antagonist)	Hirsutism, PCOS, CHF, hyperaldosteronism
Cyproterone acetate	AR antagonist + progestogenic	Hirsutism, prostate cancer; not available in USA
GnRH agonists (Leuprolide, Goserelin)	Continuous use → ↓LH/FSH → ↓testosterone	Prostate cancer, endometriosis, precocious puberty; initial testosterone flare (add anti-androgen at start)
GnRH antagonists (Degarelix, Relugolix)	Block GnRH receptor → immediate ↓LH/FSH	Prostate cancer; no initial flare

QUICK COMPARISON TABLES

PPIs vs H2 Blockers vs Antacids

Parameter	Antacids	H2 Blockers	PPIs
MOA	Neutralize acid	Block H2 receptor	Irreversibly block H⁺/K⁺-ATPase
Onset	Minutes	30-60 min	1-4 days (full effect)
Duration	1-2 hours	6-10 hours	~24 hours
Erosive GERD healing	No	<50%	80-90%
Best for	Occasional heartburn	Mild-moderate GERD	GERD, PUD, ZES, H. pylori

Bisphosphonates vs SERMs in Osteoporosis

Parameter	Bisphosphonates	Raloxifene
Mechanism	↓osteoclast activity	Estrogen agonist at bone
Endometrium	Neutral	Antagonist (no cancer)
VTE risk	Minimal	↑ (similar to estrogen)
Breast cancer risk	Neutral	↓ (protective)
Route	Oral/IV	Oral

DMARD Selection for RA

Step	Treatment
1st line	Methotrexate (± hydroxychloroquine, sulfasalazine)
Inadequate MTX response	Add biologic: TNF-inhibitor (adalimumab, etanercept)
Failed TNF-i	Switch to: abatacept, rituximab, tocilizumab, or JAK inhibitor
Seronegative mild RA	Hydroxychloroquine monotherapy

Sources: Katzung's Basic & Clinical Pharmacology, 16th Edition (Katzung BG) - Chapters 22, 25, 28, 35, 36, 40, 42, 62.

This is a shared conversation. Sign in to Orris to start your own chat.