Histamine (general and receptors) 

Released from mast cells and basophils by type I hypersensitivity rxns, drugs, venom, and trauma

Present at high levels in lungs, skin, and GI tract 

H1 (Gq protein):

inc. capillary dilation --> dec. BP

inc. capillary permeability --> inc. edema

inc. bronchiolar smooth muscle contraction

inc. in peripheral nociceptive receptors --> pain and pruritus

dec. AV nodal conduction

H2 (Gs protein):

inc. gastric acid secrection --> inc. gastric ulcers

inc. SA nodal rate, positive inotropism, automaticity

H1 antagonists

MOA: competitive antagonists of histamine

All require hepatic metabolism

Uses: allergic rxns, hay fever, rhinitis, urticaria, motion sickness, vertigo, N/V w/ pregnancy, pre-op sedation, OTC sleep aids, Parkinsons (acute extrapyramidal symptoms - only 1st gen X BBB)

AE: extensions of M block and sedation (additive w/ other CNS depressants)

Diphenhydramine

H1 antagonist 

MOA: +++ on M block, sedation and antimotion

widely used OTC

Promethazine

H1 antagonist

MOA: +++ M block and sedation / ++ antimotion

Used for some alpha block and local anesthetic action

Chlorpheniramine

H1 antagonist

MOA: ++ M block, sedation, antimotion

SE: possible CNS stimulation

Meclizine

H1 antagonist

MOA: ++ M block, sedation / ++++ antimotion

Uses: highly effective in motion sickness used in N/V of pregnancy

Hydroxyzine

H1 antagonist

MOA: ++ M block, antimotion / +++ sedation

Uses: commonly used for sedative

Loratadine

2nd generation H1 antagonist

MOA: +/- m block (NO CNS entry)

Fexofenadine

2nd generation H1 antagonist

MOA: +/- M block (NO CNS entry)

H2 antagonists

Cimetidine, Ranitidine, Famotidine

MOA: Inhibits the H2 receptor for histamine supressing the secretory response of the proton pump after food stimulation and at night

Uses: PUD (less effective than PPI's), GERD

SE: GI distress, dizziness, somnolence, slurred speech in elderly

Cimetidine: major inhibitor of P450 so increases drug effects of quinidine, phenytoin, TCA's warfarin

can also dec. androgens --> gynecomastia & dec. libido

Omeprazole (other -prazoles)

MOA: irreversible, direct inhibitors of the proton pump (K+/H+ antiport) in the gastric parietal cell

Uses: PUD, GERD, Zollinger-Ellison syndrome (gastrin secreting tumor), eradication regimen for H. pylori

SE: dec. bioavailability of drugs that require acid for absorption (fluoroquinolones, ketoconazole)

inhibits P450 only small ability  

Misoprostol

MOA: PGE1 analog --> inc. mucus and bicarb secretion and dec. HCl secretion

Uses: NSAID induced GI ulcers (NSAIDS inhibit prostaglandins)

Sucralfate

MOA: polymerizes on GI luminal surface to form a protective gel-like coating of ulcer beds requires an acid pH

Uses: inc healing and dec. ulcer recurrence

Bismuth Subsalicylate

MOA: binds selectively to ulcer coating it and protecting it from acid and pepsin

Uses: combined w/ metronidazole and tetracycline to eradicate H. pylori

Aluminum hydroxide

Antacid

MOA: neutralize protons in gut of lumen

SE: constipation, can inc. oral absorption of weak bases and dec. absorption of weak acids (all antacids)

Toxicity: hypophosphatemia, osteodystrophy, dementia

Calcium Carbonate

Antacid

MOA: neutralize protons in gut lumen

SE: alkalosis, acid rebound, constipation

Toxicity: hypercalcemia

Magnesium Hydroxide

Antacid

MOA: neutralize protons in gut lumen

SE: acid rebound, diarrhea

Toxicity: hypermagnesemia (loss of DTR's, respiratory paralysis)

Sodium Bicarbonate

Antacid

MOA: neutralize proton in gut lumen

SE: alkalosis, acid rebound, "gas"

Laxatives

Magnesium sulfate: H2O retaining --> inc. intraluminal pressure

Bisacodyl: direct intestinal wall stimulant

Methylcellulose: collects H2O & swells --> inc. bulk

Docusate: detergent --> stool softner

Mineral oil: lubricant

Lactulose: hyperosmotic

Antidiarrheals

Loperamide & Diphenoxylate

Opioids that are poorly absorbed

Nausea and vomiting (receptors & drugs)

5HT anatonists: ondansetron

DA antagonists: prochlorperazine, metoclopramide

H1 antagonists: diphenhydramine, meclizine, promethazine

Muscarinic antagonists: scopolamine

Cannabinoids: dronabinol

NK-1 receptor antagonist: aprepitant (NK-1 used for substance P)

5HT 1 receptors (drugs that act on)

Usu. found in CNS and smooth muscle

Buspirone: partial agonist at 5HT 1a receptors (anxiolytic)

Sumatriptan: agonist at 5HT 1d receptors in cerebral vessels --> dec. migraine pain

SE: of -triptans are asthenia, chest/throat pressure/pain

5HT2 recptors (drugs that act on)

Usu found in CNS (excitatory) in periphery activation --> vasodilation, contraction of GI, bronchial, uterine smooth muscle, and platelet aggregation

Olanzapine: atypical antipsychotics at 5HT2a receptors

Cyprohepatdine: 5HT2 antagonist used in carcinoid, other GI tumors, postgastrectomy, has marked H1 blocking action used for seasonal allergies

5HT3 receptors (drugs that act on)

Usu found in area postrema, peripheral sensory and enteric nerves

MOA: opens ion channels directly w/ no 2nd messengers

Odansetron: + other -setrons, antagonists to dec. emesis in chemo, radiation, and post-op

5HT4 receptor (drugs that work on)

found in GI smooth muscle and myenteric nerves

Tegaserod: agonist ued in irritable bowel syndrome when assoc. w/ constipation  

Ergotamine

Ergot alkaloid, used in migraine HA's acute attacks

MOA: partial agonists at both alpha 1 and 5HT2 recptors in the vasculature (vasoconstrictive action to decrease pulsation in cerebral vessels)

SE: GI distress, prolonged vasoconstriction --> ischemia/gangrene

Prophylaxis for migraines: propranolol, verapamil, amitriptyline, valproic acid

Eicosanoids

Synthesized from arachidonic acid and released from lipids in cell membranes

Membrane phospholipids-->Phospholipase A2--> AA

AA (releases both)

/       \

Cyclooxygenases & Lipoxygenase

(COX 1 & COX 2)             |              

 Endoperoxides       Hydroperoxides

(prostaglandins & thromboxane)          Leukotrienes

Glucocorticoids inhibit phospholipase A2 and COX2

NSAIDS: inhibit cyclooxygenases

COXibs: inhibit COX2

Zileuton: inhibits lipoxygenase

-leukasts: block leukotrienes (pathway for asthma)

Leukotrienes (what drugs inhibit) 

LT (A4, C4, D4) all cause anaphylaxis and bronchoconstriction

Glucocorticoids: dec. phospholipase A2 activity which contributes to both antiinflammatory and immunosuppressive actions

Zileuton: inhibits liopoxygenase to dec. LTs for asthma tx

Zafirlukast: LT receptor antagonist used for tx of asthma

Prostaglandins (receptors & drugs)

PGE1:

Misoprostol: analong for tx of NSAID-induced ulcers

Alprostadil: maintains patency of ductus arteriosus, vasodilation used in male impotence

PGE2: uterine smooth muscle contraction

Dinoprostone: used for cervical ripening/ abortifactant

PGF2alpha: uterine/bronchiolar contraction

Carboprost: abortifacient

Latanoprost: tx of glaucoma

PGI2: prostacyclin, platelet stabilizer/vasodilator

Epoprostenol: used in pulm hypertension

PGE2 & PGF2alpha: both increase in primary dysmenorrhea why NSAIDS may work when they inhibit their synthesis 

Thromboxanes

NSAIDS (general)

Nonselective inhibitors of cyclooxygenases acting on both COX1 and COX2 to dec. formation of PGs and thromboxanes

Analgesic, antipyretic, and antiinflammatory + antiplatelet effects

ASA

MOA: Irreversible inhibition of COX (covalent bond via acetylation of a serine hydroxyl group near active site)

Actions: dose-dependent

Antiplatelet: low dose

Analgesia and antipyresis: moderate dose

antiinflammatory: high doses

Uric acid elimination: dec. tubular secretion so hyperuricemia (low dose) & dec. tubular reabsorption so uricosuria (high dose)

Acid/base balance:

high therapeutic = respiratory alkalosis

toxic = inhibit respiration --> respiratory acidosis + uncoupling of oxidative phosphorylation leads to metabolic acidosis 

SE: Gastic ulcers, salicylism (tinnitus, vertigo, dec. hearing), bronchoconstriction, reye syndrome in kids, inc. bleeding time, renal dysfunction w/ chronic use

Tx overdose: gastic lavage, w/ ventilation, inc urine volume and alkalinization of urine

Other NSAIDS

Ibuprofen, Naproxen, Indomethacin, Ketorolac, Sulindac

Ketorolac has best analgesia

All seem to have minimal effects on acid-base

Indomethacin: thrombocytopenia, agranulocytosis

Sulindac: SJS, hematotoxicity

Selective COX2 inhibitors

Celecoxib, Rofecoxib, valdecoxib

MOA: more effective as an antiinflammatory, less GI toxicity, less antiplatelet action

Cross-hypersensitivity b/n celecoxib and sulfonamides

Acetaminophen

MOA: inhibition of cyclooxygenases in CNS (NO inhibition of COX in peripheral tissues so lacks ability as antiinflammatory)

Uses: antipyretic and analgesic

Overdose: hepatotoxicity metabolized by glucuronyl transferase into toxic metabolite N-acetylbenzoquinoneimine which is inactivated by glutathione (in overdose stores are depleted)

Antidote: N-acetylcysteine w/in first 12h

DMARDs

Disease modifying antirheumatic drugs

Hydroxychlorquine: stabilizes lysosomes and dec. chemotaxis (SE: cinchonism)

Methotrexate: cytotoxic to lymphocytes (SE: hematotoxicity, mucositis, crystalluria)

Sulfasalazine

Glucocorticoids

Gold salts: dec. lysosomal and macrophage functions (SE: dermatitis, hematotoxicity, nephrotoxicity)

Penicillamine: supresses T cells and circulating rheumatoid factor (SE: proteinuria, hematotoxicity)

Etanercept: binds TNF (SE: hypersensitivity)

Infliximab: monoclonal antibody to TNF (SE: infusion rxns, infxns)

Leflunomide

Anakinra 

Colchicine

MOA: binds to tubulin --> dec. microtubular polymerization, dec. LTB4, and dec. leukocyte and granulocyte migration

Uses: acute inflammatory gout

SE: diarrhea and GI pain w/ longer use = hematuria, alopecia, myelosuppression, gastritis, and peripheral neuropathy

Allopurinol

MOA: prodrug converted by xanthine oxidase to alloxanthine which inhibits enzyme --> purines and uric acid formation (so dec. blood & urine levels!!) 

Uses: prophylaxis of chronic gout

SE: GI distress, peripheral neuropathy, rash, vasculitits, stone formation, inhibits 6-mercaptopurine metabolism --> bone marrow suppression 

Probenecid

MOA: inhibits proximal tubular reabsorption of urate, but ineffective if GFR < 50ml/min (so blood levels of uric acid dec and urine levels increase!!!)

SE: GI distress, rash, nephrotic syndrome, crystallization of high excretion of uric acid

Glucocorticoids

Cortisol (short + mineralocorticoid activity)

Prednisone (medium duration)

Triamcinolone (intermediate)

Betamethasone & Dexamethasone (long-acting)

MOA: dec. leukocyte migration, dec. phagocytosis, dec. capillary permeability, inhibits PLA2 (dec. PGs and LTs)

Uses: antiinflammatory and immunosuppressive

SE: suppression of ACTH, iatrogenic cushingoid syndrome, hyperglycemia (d/t inc. gluconeogenesis) osteoporosis, inc. GI acid and pepsin release, electrolyte imbalance w/ cortisol, dec. skeletal growth in kids, dec. wound healing, inc. glaucoma/cataracts, inc. mental dysfunction

Early asthmatic responses

Late asthmatic responses

3 stimuli for bronchoconstriction (+ which drugs inhibit)

1. Ach (Ipratropium is the inhibitor)

2. Adenosine (Theophylline is the inhibitor)

3. Leukotrienes ("lukasts" and zileuton are the inhibitors)

Stimuli for bronchodilation (+ drugs that encourage)

1. B2 activators (beta agonists)

2. Phosphodiesterase inhibitors (Theophylline) "inhibit the breakdown of cAMP to AMP so around longer"

Beta 2-receptor agonists

albuterol, metaproterenol, terbutaline

Uses: relief of acute bronchoconstriction and in prophylaxis of exercise-induced asthma

salmeterol

Uses: longer-acting so not for acute attacks, but use as prevention of nighttime attacks

SE: aerosol forms have low potential for systemic toxicity but can cause anxiety, muscle tremors, and CV toxicity w/ overuse

Ipratropium

MOA: Muscarinic blocker

Uses: bronchodilation in acute asthma (esp. COPD) and may be safer than B-blockers in pts w/ CV dz.

DOC: for bronchospasm caused by B-blockers

Theophylline

MOA: (2) inhibits phosphodiesterase --> increases amt of time cAMP is around and is an antagonist to adenosine

Uses: mainly adjunctive, caffeine derivative 

Toxicities: narrow therapeutic window --> nausea, diarrhea, CV (inc. HR, arrhythmias), and CNS excitation

DI: leads to increased toxicity (esp. w/ P40 inhibitors like erythromycin, cimetidine, and fluoroquinolones)

Cromolyn & Nedocromil

MOA: prevent degranulation of pulmonary mast cells, and dec. release of histamine, PAF, and LTC4 from inflammatory cells

Uses: prophylactic esp. for sxs of bronchial hyperactivity d/t allergens

Beclomethasone, flunisolide, triamcinolone

MOA: surface-active glucocorticoids that block mediator release and dec. bronchial hypersensitivity by dec. PGs, LTs, and ILs

Uses: both acute attacks and prophylaxis

SE: may cause oropharyngeal candidiasis and dec in long bone growth in kids

Prednisone (oral & IV): generally reserved for severe acute attacks

Zafirlukast, Montelukast

MOA: antagonists at LTD4 receptors

Uses: slow onset, so used prophylactically for antigen, exercise, or drug-induced asthma

SE: diarrhea, HA, increased infxns

Zileuton

MOA: selective inhibitor of lipoxygenases, dec. formation of ALL LTs

Uses: more rapid onset, and adjunctive to steroids

SE: asthenia, HA, and inc. LFTs