Full Pharmacology Notes: 14 Drugs & Substances

1. Propofol

• Highly lipophilic; rapid redistribution from CNS to peripheral tissues accounts for its short duration after a single bolus
• Context-sensitive half-time increases with prolonged infusion
• Metabolized by hepatic conjugation; clearance exceeds hepatic blood flow (extrahepatic/pulmonary metabolism contributes)
• Available as a lipid emulsion (10 mg/mL in soybean oil/lecithin)

• Induction of general anesthesia: 1-2.5 mg/kg IV (children: 2.5-3.5 mg/kg)
• Maintenance of anesthesia: 100-200 mcg/kg/min infusion; target plasma levels 3-8 mcg/mL
• ICU sedation: 25-75 mcg/kg/min; target plasma levels 1-2 mcg/mL
• Procedural sedation; treatment of refractory status epilepticus
• Antiemetic (subanesthetic dose: 10-20 mg IV bolus or 10 mcg/kg/min)

• Cardiovascular: hypotension (decreased SVR and cardiac contractility), bradycardia
• Respiratory: apnea, respiratory depression (dose-dependent)
• Pain on injection (common; mitigated by lidocaine pre-treatment or larger vein use)
• Propofol Infusion Syndrome (PRIS): rare but life-threatening - metabolic acidosis, rhabdomyolysis, cardiac failure, renal failure; associated with high-dose/prolonged infusions
• Hypertriglyceridemia (lipid vehicle)
• Contraindicated in patients with egg/soy allergy (relative)

2. Fospropofol

• Water-soluble; supplied as sterile aqueous solution 35 mg/mL (Lusedra)
• Two-compartment model for fospropofol; three-compartment for released propofol
• Slower onset and longer duration than propofol directly (must first be converted)
• Because formaldehyde is a metabolite, there are theoretical concerns, though clinically manageable

• FDA-approved (Dec 2008) for monitored anesthesia care (MAC) in adults undergoing diagnostic/therapeutic procedures
• Addresses the injection pain and lipid emulsion disadvantages of propofol

• Paresthesia and pruritus (perineal/perianal): common (>50%) - due to phosphate accumulation at injection site; not seen with propofol
• Less injection pain than propofol
• Respiratory depression, hypotension (same as propofol but with delayed onset)
• Formaldehyde metabolite (monitored at therapeutic doses; not clinically significant at approved doses)
• Schedule IV controlled substance (in the US)

3. Thiopental

• Highly lipid-soluble; rapid CNS uptake followed by redistribution to peripheral tissues accounts for short duration after a single dose
• Elimination half-life: 10-12 hours (prolonged accumulation with infusions)
• Metabolized by hepatic CYP450 to inactive metabolites (pentobarbital as a minor active metabolite)
• Highly protein-bound (~80%)
• Alkaline solution (pH ~10.5); precipitates with acidic solutions (e.g., succinylcholine, opioids)

• Rapid induction of anesthesia (3-5 mg/kg IV)
• Treatment of elevated intracranial pressure (ICP) - reduces cerebral metabolic rate
• Refractory status epilepticus (pentobarbital coma)
• Cerebral protection (reduces CMRO2)
• Note: largely replaced by propofol in clinical practice

• Cardiovascular: hypotension (less than propofol); minimal vasodilation
• Respiratory depression / apnea
• No analgesia; may cause paradoxical excitation at sub-anesthetic doses
• Porphyria: absolute contraindication (induces porphyrin synthesis)
• Histamine release - potential bronchospasm
• Tissue necrosis if extravasated (highly alkaline)
• Intra-arterial injection causes severe vasospasm/ischemia
• Not suitable for maintenance (context-sensitive half-time very long with infusions)

4. Etomidate

• Supplied in 35% propylene glycol (2 mg/mL); pH 6.9
• Rapid onset; redistribution-dependent termination (comparable to thiopental and propofol)
• Clearance ~5x that of thiopental; shorter elimination half-time
• Metabolized by ester hydrolysis to inactive metabolites - 78% urine, 22% bile; <3% excreted unchanged
• Duration: ~100 seconds per 0.1 mg/kg dose
• Highly protein-bound

• Induction of anesthesia, particularly when hemodynamic stability is critical: sepsis, trauma, cardiac disease
• Induction dose: 0.3 mg/kg IV
• Useful in patients with poor cardiovascular reserve (preferred over propofol/thiopental in hemodynamically unstable patients)
• Safe in malignant hyperthermia susceptible patients

• Adrenocortical suppression: inhibits 11-beta-hydroxylase (and to a lesser extent 17-alpha-hydroxylase), reducing cortisol and aldosterone synthesis; single induction dose suppresses adrenal function for 6-8 hours; continuous infusion associated with increased mortality in ICU patients - limits use for sedation infusions
• Myoclonus on induction (involuntary movements; not a seizure)
• Nausea and vomiting (postoperative)
• Pain on injection (propylene glycol vehicle)
• No histamine release; minimal cardiovascular effects
• No significant respiratory depression at induction doses compared to barbiturates

5. Nitrous Oxide (N₂O)

• Inhibits NMDA (N-methyl-D-aspartate) glutamate receptors - primary mechanism for analgesia and anesthesia
• Mild GABA-A potentiation
• Activates descending noradrenergic pain pathways
• Minimal effect on GABA at clinically relevant concentrations (unlike other inhaled agents)

• Blood:gas partition coefficient = 0.46 (extremely low - very rapid onset and offset)
• Minimum alveolar concentration (MAC) = 104% (cannot produce surgical anesthesia alone at atmospheric pressure)
• Eliminated unchanged via lungs; minimal hepatic metabolism
• 34x more soluble than nitrogen - expands air-filled cavities

• Analgesic adjunct (50:50 mixture with O₂ = "Entonox" - used in obstetrics, minor procedures)
• Adjunct to general anesthesia to reduce requirement for other agents ("MAC-sparing")
• Rapid induction (used for "mask induction" in children combined with volatile agents)
• Safe in malignant hyperthermia

• Diffusion hypoxia: on discontinuation, rapid outflow of N₂O into alveoli dilutes O₂; prevented by 100% O₂ for 5-10 minutes at end of anesthesia
• Expansion of air-filled spaces: contraindicated in pneumothorax, pneumocephalus, bowel obstruction, middle ear surgery, retinal gas bubble, air embolism
• Vitamin B12 inactivation: irreversibly oxidizes cobalt in vitamin B12, inhibiting methionine synthase; can cause megaloblastic anemia, subacute combined degeneration of the spinal cord with prolonged/repeated exposure
• Bone marrow suppression with chronic exposure (occupational)
• PONV (postoperative nausea and vomiting): high incidence
• Mild sympathomimetic effect (offsetting cardiovascular depression)
• Weak anesthetic; cannot be used alone for surgical anesthesia

6. Dantrolene

• Available IV (for malignant hyperthermia) and oral (for chronic spasticity)
• IV: onset within minutes
• Half-life: ~4-8 hours (IV)
• Hepatically metabolized; metabolites excreted in bile and urine

• Malignant hyperthermia (MH) - treatment of choice: 2.5 mg/kg IV rapid bolus, repeat every 5 minutes until symptoms controlled (max 10 mg/kg per episode); continue 24 hours post-episode to prevent recurrence
• MH prophylaxis: 2.5 mg/kg IV given slowly 1 hour prior to anesthesia in susceptible patients
• Chronic spasticity (oral): multiple sclerosis, spinal cord injury, cerebral palsy
• Neuroleptic malignant syndrome (NMS) - off-label

• Hepatotoxicity: most serious side effect with chronic oral use (rare with short IV courses)
• Muscle weakness (generalized skeletal muscle weakness - dose-dependent)
• Drowsiness, dizziness, fatigue
• Phlebitis at IV injection site
• IV formulation contains mannitol and NaOH (alkaline)

7. Entacapone

1. Plasma half-life of levodopa increases
2. More levodopa crosses the blood-brain barrier (BBB) into the CNS
3. Brain dopamine concentrations increase
4. 3-OMD levels fall - 3-OMD competes with levodopa for active transport across the BBB, so its reduction further boosts levodopa delivery

• Oral; short half-life (requires dosing with each levodopa/carbidopa dose)
• Available in fixed combination: levodopa + carbidopa + entacapone (Stalevo)

• Adjunctive therapy in Parkinson disease to treat motor fluctuations ("wearing-off" phenomenon) - taken with each levodopa/carbidopa dose
• Reduces "off" time, prolongs "on" time, and enhances motor scores

• Increased levodopa side effects (because more levodopa reaches CNS): dyskinesias, nausea, confusion, hallucinations, orthostatic hypotension
• Orange-brown urine discoloration (harmless but notable)
• Diarrhea (may be severe; often delayed weeks-months after initiation)
• No hepatotoxicity (unlike tolcapone, which requires liver monitoring)
• Does not cause NMS (but abrupt withdrawal of entacapone with levodopa can)

8. Warfarin

• Protein C and S inhibition occurs first (shorter half-lives) - can cause a transient hypercoagulable state at initiation
• Full anticoagulation requires 5-7 days (must await existing factor clearance)

• Oral; nearly complete absorption
• Highly protein-bound (99% to albumin)
• Metabolized by CYP2C9 (primarily), CYP1A2, CYP3A4
• Genetic polymorphisms in CYP2C9 (metabolism) and VKORC1 (target sensitivity) significantly affect dosing
• Narrow therapeutic index; extensive drug-drug and drug-food interactions
• Half-life: ~36-42 hours
• Monitoring: INR (target 2-3 for most indications; 2.5-3.5 for mechanical heart valves)

• Atrial fibrillation (stroke prevention)
• Venous thromboembolism (DVT/PE) treatment and prophylaxis
• Mechanical heart valves
• Antiphospholipid syndrome

• Bleeding (major risk; all sites)
• Warfarin-induced skin necrosis (rare; due to early protein C depletion - occurs 3-8 days after initiation, especially in protein C deficient patients)
• Teratogenicity: contraindicated in pregnancy (fetal warfarin syndrome - nasal hypoplasia, stippled epiphyses, CNS abnormalities)
• Numerous drug interactions (CYP inducers/inhibitors, antibiotics affecting gut flora and vitamin K)
• Reversal: Vitamin K (slow), fresh frozen plasma, 4-factor PCC (prothrombin complex concentrate) for urgent reversal

9. Clopidogrel

• Oral prodrug; peak effect ~6-8 hours after loading dose
• CYP2C19 polymorphisms: loss-of-function alleles (CYP2C19*2, *3) reduce active metabolite levels, leading to clopidogrel resistance and increased thrombotic risk; common in East Asian populations
• Drug interactions: PPIs (especially omeprazole) reduce activation via CYP2C19 inhibition

• Acute coronary syndromes (ACS) - dual antiplatelet therapy (DAPT) with aspirin
• Coronary stent placement (prevents in-stent thrombosis)
• Ischemic stroke / TIA
• Peripheral arterial disease
• Alternative to aspirin in aspirin-intolerant patients

• Bleeding (GI, intracranial)
• TTP (Thrombotic Thrombocytopenic Purpura): rare but serious; more common than with ticlopidine but rarer than with ticlopidine
• Rash, diarrhea
• Resistance (pharmacogenomic - CYP2C19 variants)
• Pre-operative: should be held 5-7 days before elective surgery due to irreversible platelet inhibition
• Interactions: increased bleeding with anticoagulants, NSAIDs, SSRIs; reduced efficacy with CYP2C19 inhibitors

10. Aminocaproic Acid (Epsilon-Aminocaproic Acid, EACA)

• Control of bleeding in states of hyperfibrinolysis:
  • Liver transplantation (reperfusion period)
  • Cardiac surgery (on cardiopulmonary bypass)
  • Trauma-associated coagulopathy with fibrinolysis
  • Urologic bleeding (especially post-prostatectomy)
  • Hemophilia (adjunct)
  • Oral/dental bleeding in patients with coagulopathy
  • Subarachnoid hemorrhage (historically, to prevent re-bleeding before surgical clipping - less commonly used now)
• Epistaxis: systemic antifibrinolytics reduce bleeding severity

• Thrombosis: dangerous in patients with hypercoagulable states (DIC with fibrinolysis as a compensatory mechanism - use requires confirmation of primary fibrinolysis)
• Nausea, diarrhea (GI upset)
• Hypotension (with rapid IV infusion)
• Myopathy/rhabdomyolysis (rare; with prolonged high doses)
• Contraindicated in DIC (unless with concurrent heparin), upper urinary tract bleeding (clot retention in renal pelvis/ureters)

11. Cholecystokinin (CCK)

1. Gallbladder contraction (bile release into duodenum)
2. Pancreatic enzyme secretion (amylase, lipase, proteases) - most potent stimulus
3. Slows gastric emptying (allows digestion to catch up)
4. Augments secretin-stimulated bicarbonate secretion from pancreas
5. Satiety signal (CCK-B in the hypothalamus/vagus nerve)
6. Stimulates pancreatic and intestinal growth (trophic effects)
7. Stimulates SGLT1 via GLP-2 (indirect)

• CCK is inhibited by somatostatin
• Stimulated by: dietary fat, protein, acidic chyme, VIP, GRP (gastrin-releasing peptide)
• CCK analogue (sincalide) used diagnostically for hepatobiliary scintigraphy and gallbladder function testing
• Elevated CCK in celiac disease (due to impaired fat/protein absorption stimulating persistent CCK release)
• Exocrine pancreatic insufficiency: CCK remains elevated (negative feedback not closed)

• Nausea, abdominal cramping
• Can precipitate acute pancreatitis (theoretically, through premature acinar cell stimulation)

12. Somatostatin

• Pituitary: growth hormone (GH), TSH
• Pancreatic: insulin, glucagon, pancreatic polypeptide
• GI: gastrin, CCK, secretin, VIP, GIP, 5-HT
• Also inhibits cell proliferation and motility

• Acromegaly (reduces GH)
• Carcinoid syndrome (reduces serotonin, substance P)
• VIPoma, glucagonoma (reduces respective hormones)
• Variceal bleeding (reduces portal pressure by splanchnic vasoconstriction)
• Refractory diarrhea (chemotherapy-induced, short bowel syndrome, secretory diarrhea)
• Pancreatic fistulas/pseudocysts (reduces exocrine secretion)
• TSH-secreting pituitary adenomas

• Gallstones (impairs gallbladder motility, reduces bile secretion)
• GI: nausea, cramping, steatorrhea, diarrhea
• Hypoglycemia or hyperglycemia (both can occur depending on relative insulin/glucagon suppression)
• Bradycardia, cardiac conduction abnormalities (rare)
• Injection site pain (SC administration)

13. GLP-2 (Glucagon-Like Peptide-2)

1. Intestinal trophic hormone: stimulates intestinal epithelial proliferation, increases villus height, reduces apoptosis - increases absorptive surface area
2. Reduces intestinal permeability (strengthens tight junctions)
3. Slows gastric emptying and intestinal motility (via local enteric neurons and GLP-1 co-release)
4. Stimulates intestinal blood flow
5. Upregulates SGLT1 (sodium-glucose transporter) expression in response to luminal glucose
6. Reduces bone resorption (bone protective effect)

• Teduglutide (Gattex/Revestive) is a GLP-2 analogue (resistant to DPP-IV degradation) approved for:
  • Short bowel syndrome (SBS) - promotes intestinal adaptation and reduces parenteral nutrition dependence
• GLP-2 levels fall after ileal resection - loss of its trophic stimulus contributes to poor adaptation in SBS
• Stimulated by: luminal fat, carbohydrates; also by GRP, VIP

• Abdominal pain, nausea, vomiting, distension
• Colorectal polyp/neoplasm risk (due to intestinal trophic/proliferative effects - colonoscopy monitoring required)
• Fluid retention, peripheral edema
• Risk of intestinal obstruction (too rapid adaptation)

14. Vasoactive Intestinal Peptide (VIP)

1. Potent intestinal secretagogue: stimulates water and electrolyte secretion into the gut lumen (Na+, Cl-, and water)
2. Smooth muscle relaxant: relaxes intestinal smooth muscle (decreased motility), lower esophageal sphincter, sphincter of Oddi
3. Vasodilator (systemic and splanchnic)
4. Stimulates pancreatic bicarbonate and enzyme secretion (weak)
5. Stimulates bile secretion
6. Stimulates GLP-2, GLP-1, and other hormone release
7. Inhibited by somatostatin

• Watery Diarrhea, Hypokalemia, Achlorhydria
• VIP-secreting pancreatic neuroendocrine tumor (usually malignant)
• Profuse watery secretory diarrhea (>3L/day) - mechanism: cAMP-mediated chloride secretion
• Treatment: octreotide (somatostatin analog - inhibits VIP secretion), surgical resection

• VIP is a co-transmitter with acetylcholine in non-adrenergic, non-cholinergic (NANC) neurons
• In the lung: bronchodilator, vasodilator (role in pulmonary hypertension regulation)
• VIP is inhibited by somatostatin - octreotide treats VIPoma effectively
• Inhibits gastric acid secretion (inhibits parietal cells)

Quick Comparison Table

• Katzung's Basic and Clinical Pharmacology, 16th Ed.
• Morgan & Mikhail's Clinical Anesthesiology, 7th Ed.
• Miller's Anesthesia, 10th Ed.
• Goodman & Gilman's Pharmacological Basis of Therapeutics
• Braunwald's Heart Disease
• Harrison's Principles of Internal Medicine, 22nd Ed.
• Barash, Cullen & Stoelting's Clinical Anesthesia, 9th Ed.
• Lippincott Illustrated Reviews: Pharmacology
• Yamada's Textbook of Gastroenterology, 7th Ed.
• Sleisenger & Fordtran's Gastrointestinal and Liver Disease