Pharmacology

What are some basic drug properties?

• Absorption, distribution, metabolism, elimination

What is first-order kinetics?

• Drug dose determines quantity eliminated (dose-dependent elimination)

What is zero-order kinetics?

• Also known as Hoffman elimination: constant drug quantity eliminated per unit time

What is the primary role of the P450 system?

• Primary drug oxidizers

What are some of the inducers of the P450 system?

• Cigarette smoke, phenobarbital, rifampin, ethanol, INH, phenytoin, etc

What are some of the inhibitors of the P450 system?

• Grapefruit, erythromycin, nelfinavir, itraconazole, etc

What is half-life of a drug?

• Purpose of dosing by half-life is to achieve steady-state concentration. Typical drugs reach steady state after 5 half-lives

What is a Phase I reaction?

• Nonsynthetic reaction, for example, oxidation/reduction, NOT conjugation

What is a Phase II reaction?

• Synthetic reaction, for example, conjugation, methylation, sulfation, etc

ESOPHAGUS

What are some treatments for achalasia?

• Calcium channel blockers, long-acting nitrates, botulinum toxin injections

What is the management for esophageal varices bleeding?

• Vasopressin (splanchnic vasoconstrictor at V1 receptors, increases factor VIII and VWF via extrarenal V2 receptors). Propanolol/Nadolol (preventative role; inhibits B2 adrenergic splanchnic vasodilation). Nitrates (reduce portal venous pressure)

What are some treatment options for reflux disease?

• Selective H₂ blockers (cimetidine, ranitidine, etc) = 24-hour acid reduction by 70%.

• Proton pump inhibitors (pantoprazole, omeprazole, etc) = 10% rebound hyperacidity after discontinuing due to hypergastrinemia

What are the D₂ agonists motility agents and how do they work?

• Domperidone and metoclopramide, they increase lower esophageal sphincter (LES) tone, increase antrum contraction, increase small bowel peristalsis (beware of extrapyramidal symptoms [EPS] and tardive side effects)

How does erythromycin work as motility agent?

• Motilin agonists, it amplifies Phase III activity via migrating motor complex

What are the general categories of antiemetics?

• Serotonin receptor antagonist (ondansetron)

• Compazine (ill-defined μ-opiate agonists [MOA])

• Nonselective antihistamine/H₁ blocker (Phenergan)

• Substance P antagonist (aprepitant)

How do you treat peptic ulcer disease?

• See H₂ blockers and proton pump inhibitors (PPIs) above

• Misoprostol (prostaglandin E₂) increases mucin production, decreases intracellular cyclic AMP (cAMP), and therefore acid reduction—used in "type 5" ulcers

• Sucralfate = sucrose plus aluminum hydroxide (coats gastric lining, resists pepsin)

• Bismuth (adjunct to antibiotics in setting of Helicobacter pylori)

What is the treatment for Helicobacter pylori?

• PPI plus 2 antibiotics (usually Clarithromycin plus either amoxicillin or metronidazole)

• Bismuth occasionally used as adjunct. (Note: Gastric mucosa-associated lymphoid tissue [MALT] can be treated by Helicobacter pylori eradication)

What chemotherapeutic agent is used for gastrointestinal stromal tumors (GIST)?

• Imatinib (Gleevec): tyrosine kinase inhibitor at Philadelphia chromosome

List of medications used in the management of inflammatory bowel disease.

• Corticosteroids, Sulfasalazine, Mesalamine, Metronidazole, immunosuppression (azathioprine, 6-mercaptopurine, cyclosporine, methotrexate)

Bowel preparations

• Magnesium based (mag-citrate, mag-hydroxide, mag-sulfate, etc)

• Phosphate based (fleets phospha-soda, sodium phosphate, etc)

• Both exert main mechanism of action by osmotic draw of fluid into bowel lumen phosphate preparations moderately absorbed, caution in renal impairment

• Lactulose, sorbitol, mannitol: all act by osmotic MOA

• Polyethylene glycol (Golytely, Miralax): nonabsorbable long-chain polyethylene glycol molecules. Bowel mixed with isotonic electrolyte solutions to prevent metabolic derangement

Used to relax the sphincter of Oddi in setting of common bile duct stones and also for intestinal smooth muscle relaxation to accommodate sizers/staplers:

• Glucagon

What dyes can be used to evaluate integrity of viscus, ureter, etc?

• Methylene blue, indigo carmine

This can be used as an adjunct to determine intestinal perfusion:

• Fluorescein

This agent aids in sentinel lymph node biopsy (some patients have severe anaphalytic reaction, risk less than 1%):

• Lymphazurin

Pancreatic enzyme replacement:

• Pancreatin

• Lipase, protease, amylase formulations (viokase, ku zyme, pancrease, Creon, Ultrase)

What prophylaxis may be used in the setting of necrotizing pancreatitis (controversial)?

• Adequate penetrance of pancreas tissue: imipenem, third-generation cephalosporins, piperacillin, mezlocillin, fluoroquinolones, metronidazole

What drugs are implicated in pharmacologic pancreatitis?

• Anti-inflammatories: Sulfasalazine, Sulindac, Salicylates

• Immunosuppressants: Azathioprine, 6-mercaptopurine

• Diuretics: diazoxide, ethacrynic acid, furosemide, thiazides

• Antibiotics: Didanosine, metronidazole, tetracycline, nitrofurantoin, pentamidine, Trimethoprim-sulfamethoxazole

List the antihyperthyroid agents:

• Thionamides: Methimazole and Propothiouracil: inhibit oxidation of iodide to iodine. PTU, as well, prevents T₄ to T₃ conversion

• >Agranulocytosis most common serious adverse side effect of thionamides

• Ionic inhibitors: Lugol iodine (potassium iodide): inhibits thyroglobulin proteolysis as well as TH release. May reduce gland vascularity if resection planned

• Radioactive ablation (I¹³¹) electron-generating concentration of isotope leads to cytotoxicity

• Imaging

• Technetium 99, Iodine¹²³, PET (fluorodeoxyglucose), SestaMIBI

• Hormone replacement

• Levothyroxine, liothyronine

• advantage of liothyronine is lessened suppression of TRH/TSH axis

What is the treatment of hypercalcemia?

• IVF rehydration

• Loop diuretic

• Bisphosphonates (Pamidronate, Zoledronic acid)

• Vitamin D analogues (calcitriol, doxercalciferol, cinacalcet)

How do you treat hypoparathyroid tetany (severe hypocalcemia)?

• IV calcium gluconate, oral calcium, vitamin D, magnesium

What is the Cosyntropin test?

• 0.25 mg Cosyntropin IV, after 30 minutes rise in cortisol to minimum 20 mcg/dL

What is the treatment of adrenal insufficiency?

• Glucocorticoid = hydrocortisone

• Mineralocorticoid = fludrocortisone

• Sex steroid replacement: DHEA (primarily in women)

Which medications may suppress ACTH secretion?

• Metyrapone, octreotide, ketoconazole

Treatment includes administration of K⁺ sparing diuretic (spironolactone):

• Hyperaldosteronism

Treated preoperatively with α-adrenergic blockade (phenoxybenzamine) calcium channel blockers can be used as adjunct but avoid β-blockers:

• Pheochromocytoma

Medications indicated for claudication:

• Cilostazol: cellular phosphodiesterase inhibitor

• Pentoxyfylline: increases RBC pliability/flexibility

List the antiplatelets:

• Aspirin: irreversible block of thromboxane production

• Dipyridamole: increases platelet cAMP

• Ticlodipine and Clopidogrel: inhibits ADP-induced aggregation

• Glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tinofiban)

List the anticoagulants:

• Heparin-inhibits antithrombin—dose-dependent half-life: 100, 400, 800 u/kg = 1, 2.5, 5 hours

• Low-molecular-weight heparin (enoxaparin, dalteparin, etc)

• Direct thrombin inhibitor (lepirudin, bivalirudin, argatroban). Caution lepirudin in renal failure (use argatroban), dose reduces argatroban in liver failure (use lepirudin).

• Ximelagatran = first approved oral thrombin inhibitor

• Factor Xa inhibitors (danaparoid, fondaparinux) 24-hour half-life

• Warfarin—inhibits Vitamin K-dependent cofactors: II, VII, IX, X, C, and S

List the available thrombolytics and their functions:

• Plasminogen: enhances fibrinolysis

• Streptokinase: binds plasminogen enhancing conversion to plasmin

• Tissue plasminogen activator: self-explanatory

• Aminocaproic acid: potential antidote in case of overdose. Competes for lysine-binding sites and blocks interaction of plasmin with fibrin

How does protamine work? Dosage?

• Binds heparin ionically. Dose = 1 to 1.5 mg/100 units reduce as time after heparin administration increases. Half-life is unknown.

Functions via the GABA receptor (agonists):

• Benzodiazepines/Barbiturates

It induces hypnotic state, has a caloric content of 1.1 kcal/mL (lipid), and is contraindicated in patients with egg allergy:

• Propofol

Opioids work via which receptors?

• μ, κ, δ

What are the conscious altering medications?

• Ketamine—increases intracerebral pressure; do not use in head injury

• Etomidate—large infusions adrenal suppressing

Name the depolarizing paralytic agent:

• Succinylcholine (risk of malignant hyperthermia—stop drug, give dantrolene. Patients with atypical pseudocholinesterases can have unusual prolonged duration of action)

What are the nondepolarizing agents?

• Competitive acetylcholine inhibitors (rocuronium, pancuronium, mivacurium, cis-atracurium, etc). Cis-atracurium undergoes Hoffman elimination, making it safe in patients with liver/renal dysfunction

What is the role of a "reversal" agent and how do they work?

• Intended to curb effect of paralytics (neostigmine, edrophonium) act by blocking acetylcholinesterase, leaving more acetylcholine to overcome original competing drug

Used preoperatively (antimuscarinic) to reduce salivary, tracheobronchial, and pharyngeal secretions:

• Glycopyrrolate, atropine

List the inhaled agents:

• Nitrous oxide halothane, enflurane, isoflurane, sevoflurane

What is minimal alveolar concentration (MAC)?

• Lowest degree of drug concentration causing 50% of patients to not respond to noxious stimuli. High MAC is less potent. Low MAC is highly lipid soluble (think brain tissue) and highly potent

What is the mechanism of action of most local anesthetics?

• Blocks sodium channel ATPase increasing threshold for action potential.

• (Note: general maximum dose of lidocaine is 7 mg/kg if using with epinephrine, 4.5 mg/kg if using preparation without epinephrine