Pharmacology_4 Inflamatory and Related

8/12/2019 Pharmacology_4 Inflamatory and Related

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Flash cards by Seetal K. Dhaliwal H. SSection VI

1by Seetal K Dhaliwal H. S


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Histamine:

by Seetal K Dhaliwal H. S

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nasal & bronchial mucus production, contraction of bronchioles, pruritus & pain.

gastric acid secretions gastrointestinal ulcers.


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Antihistamines (Anti-H1):

Drug M Block Sedation Antimotion Other characteristics

Diphenhydramine/

diphenhydrinate

+++ +++ +++ Widely used OTC drug (used

orally)

Scopolamine ++ 0 +++ Transdermal antimotion patch

Promethazine +++ +++ ++ Some block & local anesthetic

action

Chlorphenoramine ++ ++ ++ Possible CNS stimulation

Meclizine ++ ++ ++++ Highly effective in antimotion

sickness

Hydroxyzine ++ +++ ++ Commonly used as sedative

Loratidine +/- 0 0 No CNS entry

Fexofenadine +/- 0 0 No CNS entry


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Drugs used in Peptic Ulcer Disease (PUD):


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H2 Antagonist:

Cimetidine, Ranitidine, Famotidine, Nizatidine take H2 blockers before u DINE. Table for

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Reversible block of H2 receptors H+ secretion by parietal cells

Used in peptic ulcers, gastritis, mild esophageal reflux.

Toxicity: Cimetidine is CYP450 inhibitor & has antiandrogen effects (prolactin release,

gynecomastia, impotence, libido in males); can cross BBB (confusion, dizziness, headaches)

& placenta. Cimetidine & Ranitidine Renal excretion of creatinine.

Proton Pump Inhibitors:

Omeprazole, Lansoprazole; Irreversibly inhibit H+/K+ ATPase in stomach parietal cells.

Used for peptic ulcers (better than H2 blockers), gastritis, esophageal reflux, Zollinger-

Ellison syndrome.

Bismuth, Sucralfate:

Binds ulcer, protecting it from acid & pepsin.

Used in ulcer healing & travelers diarrhea.

BMT triple H.pylorithearapy: Bismuth, Metronidazole, Tetracycline (or Amoxicillin)


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Misoprostol:

A PGE1 analog. mucus & HCO3-, and HCl.

Used to prevent NSAID-induced peptic ulcers; maintenance of PDA (Alprostradil); also usedto induce labor.

Toxicity: Diarrhea. Contraindicated in childbearing women (abortifacient).

Muscarinic Antagonists:

Propantheline, Pirenzepine; Block M1 receptors on ECL cells ( histamine secretion) & M3receptors on parietal cells ( H+secretion).

Used for peptic ulcers (rarely). Caused tachycardia, dry mouth, difficulty focusing eyes.

Metoclopramide:

D2 receptor antagonist. resting tone, contractility, LES tone, motility. Does NOT influence

colon transport time.

Used in Diabetics & post-surgery gastroparesis.

Toxicity: parkinsonian effects. Restlessness, drowsiness, fatigue, depression, nausea,

diarrhea. Drug interaction with Digoxin & Diabetic agents. Contraindicated in patients with

small bowel obstruction


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Infliximab:

A monoclonal Ab to TNF, proinflammatory cytokine.

Used Crohns disease (IBD), rheumatoid arthritis. Toxicity: Respiratory infection (including activation of latent TB), fever, hypotension.

Sulfasalazine:

A combination of Sulfapyridine (antibacterial) & 5-aminosalicylic acid (anti-inflammatory).Activated by colonic bacteria.

Used ulcerative colitis (IBD) & Crohns disease (IBD).

Toxicity: malaise, nausea, sulfa allergy, reversible oligospermia.

Laxatives:

MgSO4: water retaining intraluminal pressure.

Bisacodyl: direct intestinal wall stimulant.

Methylcellulose: collects water & swells bulk.

Docusate: detergentstool softener

Mineral oil: lubricant

Lactulose: hyperosmotic (also indicated for systemic encephalopathy)


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Antacids: (all cause hypOkalemia)

Can affect absorption, bioavailability or urinary excretion of other drugs by altering

gastric & urinary pH or by delaying gastric emptying.

Oral absorption of weak bases (quinidine); oral absorption of weak acids (warfarin),

azoles, fluoroquinolones & tetracylines (via chelation by Ca carbonate)

Overuse can also cause the following problems:

1. Aluminium Hydroxide Constipation & hypOphosphatemia; proximal muscle weakness,

osteodystrophy, seizures.

2. Magnesium Hydroxide Diarrhea, hyporeflexia, hypotension, cardiac arrest.

3. Calcium carbonate Hypercalcemia, rebound acid .

Antidiarrheals:

Loperamide & diphenoxylate (with atropine) are opioids that are poorly absorbed

Adsorbants: kaolin, pectin


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Antiemetics:


5-HT3 antagonist:

Ondansetron (caused headache & constipation), and Granisetron

DA antagonists:

Prochlorperazine & Metoclopromide

H1 antagonists:

Diphenhydramine, Meclizine, Promethazine

Muscarinic antagonists:

Scopolamine

Cannabinoids:

Dronabinol

NK1-receptor antagonist:

Aprepitant (NK1 is a receptor to substance P)

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Drugs acting on Serotonergic systems:


5-HT1(a-h):

Found in CNS (inhibitory) & smooth muscle (excitatory/inhibitory)

BUSPIRONE (agonist of 5-HT1a) anxiolytic & GAD.

SUMATRIPTAN (agonist of 5-HT1d) migraine pain.

5-HT4: TEGASEROD (agonist of 5-HT4) used in IBS when associated with

constipation)

5-HT2 (a-c):

Found in CNS (excitatory) too (2) excited

OLANZEPINE (antagonist at 5-HT2a) psychosis symptoms.

CYPROHEPTADINE (antagonist at 5-HT2) used in carcinoid

tumors, postgastrectomy & anorexia nervosa. Also has H1 blocking

action (used in seasonal allergies).

5-HT3:

ONDANSETRON (antagonist at 5-HT3) antiemesis.

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Drugs used in migraine headaches:


Ergot alkaloid: Ergotamine:

Partial agonist at & 5-HT2 receptors.

Vasoconstrictive actions pulsation in cerebral vessels

Used in acute migraine attacks

Side effects: GI distress, prolonged vasoconstiction

ischemia & gangrene, abortion near term.

Analgesics: ASA, other NSAIDs, acetaminophen, oral or injectable opioid

analgesics & butorphanol (spray).

Prophylaxis: Propanolol, verapamil, amitriptyline, valproic acid.

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Ergonovine:

Causes uterine

smooth muscle

contraction.

Given IM after

placental delivery.


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Eicosanoid

Pharmacology:

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Eicosanoid Pharmacology:


Aspirin:

Irreversibly inhibits COX TXAs & PGEs

Low dose (


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Eicosanoid Pharmacology:


COX-2 inhibitors (celecoxib):

Reversibly inhibits COX-2 helps maintain gastric mucosa.

Used in RA and OA.

Toxicity: risk of thrombosis. Sulfa allergy.

Anti-leukotrienes (LTs):

Zileutona 5-lipoxygenase pathway inhibitor. Blocks conversion of arachidonic acid to LTs.

Zafirlukast, montelukastblock LT receptors. Especially good for aspirin-induced asthma.

Prostaglandins (PGs):

PGE1 Misoprostol (used in NSAID-induced ulcers); Alprostadil (Maintain PDA open &

causes vasodilation in male impotence)

PGE2

Dinoprostone (causes cervical ripening used as abortifacient)

PGE2 Carboprost (abortifacient); Latanoprost (tx of glaucoma IOP)

PGI2 (prostacyclin) Epoprostenol (platelet stabilizerused in pulmonary HTN)

PGE2 & PGE2 Both in primary dismenorrhea.

Thromboxanes (TXAs):

TXA2 Platelet aggregator & causes bronchoconstriction & vasoconstriction.

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Drugs used in treatment of Gout:


Acute Gout: Colchicine:

Binds & stabilizes tubulin to inhibit polymerization, impairing leukocyte chemotaxis &

degranulation. GI side effects, especially if given orally (Note: Indomethacin is less toxic

& is also used in acute gout).

Chronic Gout:

Probenecid:

Inhibits reabsorption of uric acid in PCT (also inhibits secretion of penicillinsynergistic).

Allopurinol:

Inhibits xanthine oxidase, conversion of xanthine to uric acid. Also used in lymphoma &

leukemia to prevent tumor lysisassociated urate nephropathy. concentrations of

azathioprine & 6-MP (both normally metabolized by xanthine oxidase).

Probenecid & Allopurinol should not be used to treat acute gout.

Do not give salicylates. All but the highest doses depress uric acid clearance. Even high

doses (56 g/day) have only minor uricosuric activity.

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Drugs used in RA:


Drug Mechanism(s) Side Effects

Hydroxychloroquine Stabilizes lysosomes &

chemotaxis

GI distress, dizziness, blurred vision,

tinnitus, pruritus (cinchonism), hemolysis

in G6PD def.Methotrexate Cytotoxic to lymphocytes Hemototoxic, mucositis, crystalluria

Sulfasalazine Sulfapyridine B-cell functions;5-ASA possibly inhibits COX

GI distress, rash, hemolysis in G6PD def,

SLE-like syndrome.

Glucocorticoids LTs, Ils, & PAF ACTH suppression, cushingoid state,

osteoporosis, GI distress, glaucoma.

Gold Salts lysosomal & macrophage

functions

Dermatitis, hematotoxic, nephrotoxic.

Penicillamine Supresses T cells & circulating

Rheumatoid factor

Proteinuria, hematotoxic, autoimmune

disease

Etanercept Binds TNF Hypersensitivity, injection site reaction,

infections.

Infliximab Monoclonal Ab to TNF Infusion reactions, infections

Leflunomide Inhibits DHOD UMP

ribonucleotides arrestslymphocytes in G1

Alopecia, rash, diarrhea, hepatotoxic,

rarely Steven-Johnson Syndrome.

Anakira IL-1 receptor antagonist Infection, injection-site reaction.

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Glucocorticoids:


the production of LTs & PGs by inhibiting phospholipase A2 & expression of

COX-2.

Used in Addison disease, inflammation, immune suppression, asthma.

Side effects: iatrogenic Cushings syndrome buffalo hump, moon facies, truncle

obesity, skin thinning & easily bruised, osteoporosis, adrenocortical atrophy,

peptic ulcers & even diabetes (with chronic use). Also cause in IOP.

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Drugs Glucocorticoid

Activity

Mineralocorticoid

Activity

Duration

Cortisol 1 1 Short

Prednisone 4 0.3 Medium

Triamcinolone 5 0 Intermediate

Betamethasone 25 0 Long-acting

Dexamethasone 30 0 Long-acting


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Drugs used to treat asthma:


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Non-specific -agonist:

Isoproterenol relaxes bronchial smooth muscle (2); adverse effect istachycardia (1)

2-agonist:

Albuterol relaxes bronchial smooth muscle (2); use during acute attack !!

Salmeterol long-acting for prophylaxis; adverse effects: tremors & arrhythmia.

Methylxanthines:

Theophylline causes bronchodilation by inhibiting PDE, thereby cAMP

hydrolysis. Narrow therapeutic index (cardio- & neurotoxicity). Metabolized by

CYP450. Blocks action of adenosine.

Muscarinic antagonist:

Ipratropium bromide competitive muscarinic block, prevents

bronchoconstriction. Also used in COPD.

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Drugs used to treat asthma:


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Cromolyn & Nedocromil:

Prevents release of mediators from mast cells. Effective ONLY for ASTHMA

PROPHYLAXIS (not during acute attack). Toxicity is rare.

Corticosteroids:

Beclomethasone, prednisone inhibits the synthesis of virtually all cytokines.

Inactivates NF-B, the transcription factor that induces the production of TNF-,

among other inflammatory agents. 1st line therapy for chronic asthma.

Antileukotrienes:

Zileuton A 5-lipoxygenase pathway inhibitor. Blocks conversion of arachidonic

acid to LTs.

Zafirlukast, montelukast Blocks LT receptors. Especially good for aspirin-

induced asthma.

20Drugs used to treat asthma:


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Flash cards by Seetal K. Dhaliwal H. SSection VII

21by Seetal K Dhaliwal H. S


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Anticoagulants:Heparin Warfarin

Structure Large anionic, acidic polymer Small lipid-soluble molecule

Route of

administration

Parental (IV, SC) Oral

Site of action Blood Liver

Onset of action Rapid (seconds) Slow. Limited by t1/2 of normal

clotting factors.

Mechanism of action Activates antithrombin, which

action of IIa (thrombin) & Xa

Impaires synthesis of vit K-

dependent factors II, VII, IX & X.

Duration of action Acute (hours) Chronic (days)

Inhibits coagulation

in vitro

YES NO

Treatment of acute

overdose

Protamine sulfate IV Vitamin K & Fresh frozen

plasma

Monitoring PTT (intrinsic) HEPAR IN our

body

PT (extrinsic) WAR happens

EXTRINSICally

Crosses placenta NO YES (teratogenic)


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A ti l t


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Anticoagulants: Heparin:

Immediate anticoagulant for pulmonary embolism, stroke, acute coronary syndrome, MI,DVT. Used during pregnancy, does not cross placenta. Follow PTT.

Toxicity: bleeding, thrombocytopenia (HIT), osteoporosis, drug2 interactions.

Newer LMW Heparins (enoxaparin) act more on Xa, have better bioavailability & 24times longer t1/2. Can be administered SC & without laboratory monitoring.

HIT heparin binds to platelets, causing autoantibody production that destroys platelets &overactivates the remaining ones, resulting in a thrombocytopenic, hypercoagulable state.

Lepirudin, Bivalirudin:

Hirudin derivatives, directly inhibit thrombin. Used as an alternative to Heparin foranticoagulating patients with HIT.

Warfarin (Coumadin):

Interferes with normal -carboxylation of vit K-dependent clotting factors II, VII, IX, X, andprotein C & S (in protein C deficiency hypercoagulability occurs dermal vascularthrombosis & skin necrosis). Metabolized by CYP450.

Used in chronic anticoagulation. Not used in pregnancy (crosses placenta).

Toxicity: bleeding, teratogenic, skin/tissue necrosis, drug2

interactions.by Seetal K Dhaliwal H. S

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Thrombolytics (or fibrinolytics):

Streptokinase, urokinase, alteplase (tPA), APSAC (anistreplase)

Mechanism of action:

Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves

thrombin fibrin clots. PT & PTT, no change in platelet count.

Clinical use:

Early MI, early ischemic stroke.

Toxicity:

Bleeding. Contraindicated in patients with active bleeding, history of intracranial

bleeding, recent surgery, known bleeding diatheses, or severe HTN.

Antifibrinolysins (antidote for thrombolytic overdose):

Aminocaproic acid or tranexamic acid.


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Aspirin (ASA): Acetylates & irreversibly inhibits COX to prevent conversion of arachidonic acid to TXA2

(platelet aggregator). bleeding time. No effect on PT & PTT.

Antipyretic, analgesic, anti-inflammatory, anti-platelet drug (used especially post-MI).

Toxicity: gastric ulceration, bleeding, hyperventilation, Reyes syndrome, tinnitus (CN VIII).

Ticlopidine & Clopidogrel:

Inhibit platelet aggregation by irreversibly blocking ADP receptors. Inhibit fibrinogen

binding by preventing glycoprotein IIb/IIIa expression..

Used in acute coronary syndrome, coronary stenting. incidence or recurrence of

thrombotic stroke. Toxicity: neutropenia (ticlopidine).

Abciximab, eptifibatide, & tirofiban:

Monoclonal Ab binds gp IIb/IIIa on activated platelets, preventing aggregation.

Used in acute coronary syndromes, percutaneous transluminal coronary angioplasty.

Toxicity: bleeding thrombocytopenia b S t l K Dh li l H S

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Platelet aggregation by: ADP, 5HT, TXA2, thrombin, 2 agonists.

Platelet aggregation by: PGI2, cAMP, ASA, ticlopidine, Clopidogrel, gp IIb/IIIa blockers.

Pharmacology_4 Inflamatory and Related

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