disease-modifying antirheumatics

define and give examples

Disease-modifying antirheumatic drugs (DMARDs) is a category of otherwise unrelated drugs defined by their use in rheumatoid arthritis to slow down disease progression.

Given to patients who are refractive to NSAID's (which are not disease-modifying, just treat the inflammation but not underlying cause).

Examples:

Methotrexate

Gold salts

Azathioprine

Chloroquine

Sulfasalazine

Penicillamine

Gold sodium thiomalate

Drug Class: Antirheumatic

Mechanism of Action: suppressive effect on the synovitis of active rheumatoid disease. Gold alters the morphology and functional capabilities of human macrophages, thereby inhibiting the production of monocyte chemotactic factor, IL-8 & IL-1beta.

Indications: Patients who are nonresponsive to NSAIDs when treating active rheumatoid arthritis

Contraindications: SLE

Pharmacokinetics: total body half-life is approximately 1 year. beneficial effects may not be observed until after months of therapy

Side Effects: Dermatitis

Major drug interactions: Penicillamine

Azathioprine

Trade Name: Imuran

Drug Class: Immunosuppresant, DMA

Mechanism of Action: antimetabolite, It interferes with purine nucleic acid metabolism.

Indications: 1) prevention of rejection in renal transplantation.

2) severe, active rheumatoid arthritis refractive to NSAID's.

Contraindications: Pregnancy

Pharmacokinetics: Azathioprine is a prodrug that is metabolized to mercaptopurine

Side Effects: hematologic (leukopenia and/or thrombocytopenia) and gastrointestinal (nausea & vomiting), secondary infections.

Major drug interactions: Dose should be reduced by 1/3 to 1/4 if allopurinol is also taken

Chloroquine

Trade Name:Aralen

Drug Class: Antimalarial, DMA

Mechanism of Action: eliciting parasite toxicity due to the build up of heme.

Indications: 

• Malaria and extraintestinal amebiasis
• Effective against nonfalciparum and sensitive falciparum malaria

Contraindications: psoriasis or porphyria

Pharmacokinetics: Give orally, Excretion of chloroquine is quite slow, increased with low urine pH

Side Effects: nausea, vomiting, Pruritis (itch) is common, primarily in Africans

Major drug interactions: Antidiarrheal agents (kaolin) & calcium- and magnesium-containing antacids interfere with chloroquin absorption.

Penicillamine

Trade Names: Cuprimine, Depen ®

Drug Class: Heavy metal chelator

Mechanism of Action: Copper chelator

Indications: 1) adults with severe, active rheumatoid arthritis refractory to conventianal therapy.

2) Wilson's disease (a genetic disorder with accumulation of copper) & cystinuria.

Contraindications: pregnancy, history of penicillamine-related aplastic anemia or agranulocytosis. Potential for causing renal damage

Pharmacokinetics: two or three months may be required before the first evidence of a clinical response is noted

Side Effects: a high incidence of untoward reactions, some of which are potentially fatal. associated with fatalities due to aplastic anemia, agranulocytosis, thrombocytopenia, Goodpasture's syndrome, and myasthenia gravis. Other side effects: drug fever, rash, lupus-like syndromes with positive antinuclear antibody tests, iron deficiency, decreased normal healing, decreased tensile strength of the skin due to alterations in collagen

Major drug interactions: gold salts (penicillamine will chelate them)

Notes: penacillamine is a metabolite of penicillin. It is rarely used because of its toxicity.

Methotrexate

Trade Names: Rheumatrex, Methotrex, Trexall ®

Drug Class: Antimetabolite / Immunosuppressant / Antineoplastic/DMR

Mechanism of Action: a folic acid antagonist that inhibits dihydrofolate reductase (DHFR), interfering with the synthesis of thymidylate, purine nucleotides & serine/methionine, interferes with the formation of DNA, RNA and proteins. Actively proliferating tissues ( malignant cells, bone marrow, fetal cells, buccal and intestinal mucosa, and urinary bladder cells) are more sensitive to this effect of methotrexate. Methotrexate may impair malignant growth without irreversible damage to normal tissues. 

The mechanism of action in rheumatoid arthritis is unknown; it may affect immune function. 

Indications: Psoriasis, Rheumatoid arthritis, Neoplastic diseases: Acute lymphocytic leukemia (ALL), choriocarcinoma, Burkitt's lymphoma, breast, head & neck tumors. Given either alone or in combination with other drugs. High dose therapy can be effective against osteogenic sarcoma, although you must give a leucovorin “rescue” after high dose therapy to protect bone marrow cells (leucovorin does not penetrate cancer cells as easily).

Contraindications: Methotrexate can cause fetal death or teratogenic effects when administered to pregnant women.

Pregnancy: Pregnancy Risk Category X. Absolutely contraindicated in pregnancy.

Side Effects: Ulcerative stomatitis, leukopenia, nausea, and abdominal distress.

Many others on another flashcard.

Major drug interactions: 

1) Leucovorin (folinic acid) is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate.

2)NSAIDs, penicillins & cephalosporins interfere with the renal clearance of methotrexate.

Drug Resistance: tumor cell resistance has been attributed to: 

1) decreased cellular uptake (which may be related to incresed activity of P-glycoprotein)

2) decreased polyglutamate formation

3) synthesis of increased levels of DHFR through gene amplification

4) altered DHFR with reduced affinity for methotrexate.

Sulfasalazine

Trade Name: Azulfidine EN-Tabs ®
Mechanism of Action: Anti-inflammatory & immunomodulatory effects on T & B cells, by unclear mechanism. DMA
Indications: rheumatoid arthritis, ulcerative colitis

Adalimumab

Trade Name: Humira ®

Drug Class: Rheumatoid arthritis
Mechanism of Action:Recombinant human anti-TNF monoclonal antibody. Complexes with soluble TNF-α, prevents its interaction with p55 and p75 surface receptors. Results in a down-regulation of macrophage & T cell function.
Indications: Treatment of rheumatoid arthritis and similar inflammatory disorders
Pharmacokinetics: given sub.cutaneously
Side Effects: increased risk for macrophage-dependent infection (e.g. tuberculosis), invasive fungal infections and other opportunistic infections.

1. Possibility of serious toxic (and potentially fatal) reactions. Methotrexate should be used only in life threatening neoplastic diseases or severe recalcitrant psoriasis or rheumatoid arthritis which is not responsive to other forms of therapy.
2. Include the use of antimetabolite (Leucovorin) therapy
3. Patients should be closely monitored for bone marrow, liver, kidney & lung toxicity.
4. Methotrexate has been reported to cause fetal death & congenital abnormalities. Not recommended for women of child bearing potential unless the benefits outweigh the risks.
5. Unexpected bone marrow suppression, aplastic anemia & GI toxicity have been reported with high doses of methotrexate & concurrent use of NSAIDs.
6. Methotrexate causes liver toxicity, fibrosis & cirrhosis, but generally only after prolonged use.
7. Malignant lymphomas, which may regress following withdrawal of methotrexate may occur with low dose treatment.
8. Diarrhea & ulcerative stomatitis require interruption of therapy, otherwise hemorrhagic enteritis & death from intestinal perforation may occur.
9. Similar to other cytotoxic drugs, methotrexate cay cause a ”tumor lysis syndrome” in patients with rapidly growing tumors. Appropriate measures should be taken should this occur.
10. Severe & occasionally fatal skin reactions have been reported.
11. Potentially fatal opportunistic infections (e.g. Pneumocystis jiroveci pneumonia) may occur.
12. Methotrexate combined with radiotherapy may increase the risk for necrosis of soft tissues & osteonecrosis.

Infliximab

Trade Name: Remicade ®

Drug Class: Monoclonal Antibody & TNF-α antagonist

Mechanism of Action:

1) Binds with high affinity to the soluble and transmembrane forms of TNF-α and inhibits binding of TNF-α with its receptors.

2) Biological activities attributed to TNF-α include: induction of pro-inflammatory cytokines IL-1 and 6, increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neut's and eo's, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or chondrocytes.

Indications:

1)Rheumatoid arthritis: in combination with methotrexate, is indicated for reducing signs and symptoms, inhibiting the progression of structural damage and improving physical function in patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to methotrexate.

2) Crohn’s disease: for reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in patients with fistulizing Crohn’s disease.

Pharmacokinetics: parenteral administration (iv)

Side Effects: increased incidence of lymphoma. increased risk for developing serious infections that may lead to hospitalization or death.

Etanercept

Trade Name: Enbrel ®

Drug Class: Monoclonal Antibody / TNF receptor fusion protein

Mechanism of Action:

A dimer of human IgG1 and the TNF receptor. Binds to both TNF-alpha and TNF-beta, inhibiting TNF-mediated inflammation.

Indications: Adult rheumatoid arthritis, polyarticular course junvenile rheumatoid arthritis, psoriatic arthritis. May be used in combination with methotrexate.

Pharmacokinetics: Shorter duration of action compared to imfliximab & must begiven s.c. twice a week.

Side Effects:  increased risk for developing serious infections that may lead to hospitalization or death. Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients.

Adalimunab

Infliximab

Etanercept

Colchicine

Trade Name: generic

Drug Class: A plant alkaloid used in the treatment of gout

Mechanism of Action:

1) Binds 
to 
microtubular
 protein 
tubulin
 in
 the 
PMN
 inhibiting 
chemotactic 
and
 chemokinetic 
responses 
of 
the 
neutrophil.

2) Inhibits 
leukotriene
 B4 
formation; 
inhibits 
release 
of 
histamine
 from 
mast cells.

Indications:

Colchicine 
is 
used 
for  acute attacks of gout 
and 
prophylactic prevention of gout.
 Good
 relief
 of 
pain.

It is often effective in aborting an attack when taken at the first sign of articular discomfort.

Contraindications: patients with a known hypersensitivity to the drug, and in those with serious gastrointestinal, renal, hepatic, or cardiac disorders, and in those with blood dyscrasias.

Pharmacokinetics: rapidly absorbed after oral administration.Enter the intestinal tract in bile and intestinal secretions.

Side Effects:

1) diarrhea, nausea, vomiting.

2) Bone marrow depression, hair loss, peripheral neuritis & myopathy.

Pregnancy: Pregnancy Category D

Major drug interactions: Inhibited by acidifying agents, potentiated by alkalinizing agents. Colchicine may increase sensitivity to the CNS depressants. Response to sympathomimetic agents may be enhanced by colchicine.

Allopurinol

Trade Names: generic, Zyloprim ®

Drug Class: Xanthine oxidase inhibitor

Mechanism of Action:

Inhibits xanthine oxidase, resulting in a decrease in synthesis of uric acid

Indications:

1) Reserved 
for
 chronic treatment 
of 
severe
 tophaceous gout,
 renal
 urate
 stones, 
hyperuricemia
 not 
controlled 
by
 uricosuric
 agents
.

2) An important adjuvant in cancer chemotherapy of blood dyscrasias. Allopurinol treatment should be discontinued when the potential for overproduction of uric acid is no longer present.

Contraindications:

Patients who have developed a severe reaction to allopurinol.

Pharmacokinetics:

Metabolized to alloxanthine, which inhibits xanthine oxidase with a long duration of action. Allopurinol thus can be given once daily.

Side Effects:

1)Skin rash. Skin reactions can be severe and sometimes fatal. Therefore, treatment with allopurinol should be discontinued immediately if a rash develops.

2) GI
 side 
effects, 
neuritis
 and
 bone 
marrow
 depression
 can 
occur, 
can 
cause
 cataracts
 & 
acute
 gouty
 flare‐ups.

Notes:

1) Treatment of gout with allopurinol and uricosuric agents is begun with the expectation that it will be continued for years, if not for life.

2)Treatment of patients with 'blood dyscrasias” such as leukemia, lymphoma and other malignancies with cancer chemotherapy will result in elevated levels of serum purines that are released from “killed” cancer cells. These purines will be converted by xanthine oxidase to uric acid, resulting in potentially massively high blood levels of uric acid, and the development of kindney stones (renal caculi) and other harmful effects if this enzyme isn't inhibited by allopurinol.

Probenecid

Trade Name: generic

Drug Class: Uricosuric drug

Mechanism of Action:

1) Act at the anionic transport sites of the renal tubule. Uric acid is freely filtered by the golmerulus.

2) Inhibit the active transport sites that cause net reabsorption of uric acid in the proximal tubule of the kidney. As the excretion of uric acid increases, the body's pool of urate decreases and uric acid can be uptaken from joints into the blood --> relief of arthritis and re-mineralization of bone.

Indications:

1)For the treatment of chronic gouty arthritis when complicated by frequent, recurrent acute attacks of gout.

2) Therapy should not be started until 2-3 weeks after an acute attack.

Pharmacokinetics: completely reabsorbed by renal tubules & metabolized very slowly.

Side Effects: GI irritation, allergic dermatitis (rash). Nephrotic syndrome has occured. Rarely causes aplastic anemia.

Major drug interactions:

1) Can elevate plasma levels of various drugs that are weak acids by that mechanism.

2)Interferes with the renal secretion of penicillin and thereby elevates the plasma concentrations of penicillin and other beta-lactams.

3) Aspirin - antagonizes the uricosuric action of probenecid.

Notes:

1) Associated with the increase in uric acid excretion is a risk of forming renal stones. Therefore the urine volume should be maintained at a high level, and at least in early treatment, urine pH should be kept above 6.0 by administering alkalai.

2) Probenicid is also available in a formulation combined with colchicine.

Sulfinpyrazone

Trade Names: generic, Anturane ®

Drug Class: Uricosuric drug

Mechanism of Action: (same as probenecid). Also weakly anti-inflammatory

Indications: Chronic gouty arthritis or intermittent gouty arthritis

Contraindications: Patients with an active peptic ulcer or symptoms of gastrointestinal inflammation or ulceration should not receive the drug.

Pegloticase

Trade Name: (Not available yet - in Phase III trial)

Mechanism of Action: a polyethylene glycol conjugae of uricase (urate oxidase) that converts uric acid into a more soluble compound that is easier to excrete

Summary of Treatment for Chronic Tophaceous Gout (4 points)

1. Graded
 doses
 of
 allopourinol
2. Colchicine, 
uricosuric 
agent 
&
 NSAID  to
 control acute
 gouty
 flare‐up 
and 
pain
3. Alkalinize
 the 
urine
4. Diet with 
reduced 
purine 
content

• Celecoxib - Celebrex ®
• Rofecoxib - Vioxx® (not sold)

• Aspirin
• Acetaminophen
• Ibuprofen
• Naproxen
• Nabumetone
• Diclofenac

• • Prednisone
  • Hydrocortisone
  • Dexamethasone
  • Triamcinolone
  • Methylprednisolone

• Montelukast
• Zafirlukast
• Zileuton

Celecoxib

Trade Name: Celebrex 

Drug Class: COX-2 Selective NSAID

Mechanism of Action:

1) inhibition of prostaglandin synthesis, primarily via inhibition of COX-2. Celecoxib is 10-20 times more selective for COX-2 compared to COX-1.

2)analgesic, antipyretic & anti-inflammatory effects similar to non-selective NSAIDs, but with fewer GI side effects.

3) In general, celecoxibs have little impact on platelet aggregation (which is mediated by Cox-1) & therefore have minimal cardioprotective effects (e.g. minimal effect on platelet function). However they have been associated with a higher than normal incidence of stroke.

Indications:

1)relief from the symptoms of osteoarthritis

2) rheumatoid arthritis in adults

Contraindications:

1) Patients with hypersensitivity to celecoxib

2)Patients with severe renal insufficiency (Cox-2 is constitutively active in the kidney).

Pharmacokinetics: taken orally. Plasma levels of celecoxib occur approximately 3 hrs after an oral dose. Metabolism is primarily mediated via cytochrome P450 2C9. Plasma half life ~11 hrs.

Side Effects: Celecoxib is a sulfonamide & may cause skin rashes. The frequency of other side effects is similar to other NSAIDs.

Major drug interactions:

1) NSAIDs may diminish the effects of ACE inhibitors, furosemide and thiazide diuretics. Fluconazole can double celecoxib levels due to inhibition of cyt P450 2C9. Concomitant administration of aspirin with celecoxib may result in an increased rate of GI ulceration or other complications. It interacts occasionally with warfarin (due to cyt P450 C9 metabolism).

Note: Celecoxib is not considered to be a good substitute for aspirin for cardiovascular prophylaxis (e.g. because it has minimal effects on platelet function).

Rofecoxib

Trade Name: Vioxx ® (not available in the US)

Drug Class: COX-2 Selective NSAID

Mechanism of Action: inhibition of prostaglandin synthesis, primarily via inhibition of COX-2 and at therapeutic concentrations in humans, celecoxib produces relatively little inhibition of the COX-1 isoenzyme.

Indications: (not available in the US)

1)For relief of the signs and symptoms of osteoarthritis

2) For the management of acute pain in adults

3) For the treatment of primary dysmenorrhea.

Contraindications: known hypersensitivity to rofecoxib

Side Effects: increased incidence of myocardial infarctions (Vioxx was recalled from the market in Sept 2004 due to evidence that it may increase the incidence of myocardial infarctions).

                Montelukast

Trade Name: Singulair ®

Drug Class: Leukotriene Inhibitor

Mechanism of Action:

an LTD4-receptor antagonist

Indications:

1) for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 6 years of age and older.

2) It is NOT indicated for use in the reversal of bronchospasm in acute asthma attacks.

Pharmacokinetics:

effective orally, taken once a day (typically in the evening)

Zafirlukast

Trade Name: Accolate ®

Drug Category: Leukotriene receptor antagonist

Mechanism of Action:

Leukotriene receptor antagonist

Pharmacokinetics:

twice daily dosing, food can affect bioavailability (take 1 hr before or >2 hrs after meals)

Side Effects:

cases of life-threatening hepatic failure have been reported

Notes:

less commonly prescribed compared to montelukast because of more frequent dosing requirements & known (but relatively uncommon) severe toxicity.

Zileuton

Trade Name: Zyflo ®

Drug Class: Leukotriene pathway inhibitor

Mechanism of Action:

orally active inhibitor of 5-lipoxygenase, the enzyme that catalyzes the formation of leukotrienes from arachidonic acid

Indications:

prophylaxis and chronic treatment of asthma in adults and children 12 years of age and older. (It is not indicated for use in the reversal of bronchospasm in acute asthma attacks).

Pharmacokinetics:

effective orally - 4 times a day dosing.

Beclomethasone

Trade Names: QVAR, Vanceril ®

Drug Class: Glucocorticoid (Aerosol)

Mechanism of Action:

1) Binds to intracellular glucocorticoid receptors and modulates gene expression. Approximately 20% of expressed genes in a cell are regulated by glucocorticoids.

2) Glucocorticoids have multiple anti-inflammatory effects, inhibiting both inflammatory cells and release of inflammatory mediators.

3) Improvement in asthma control following inhalation can occur within 24 hours of beginning treatment in some patients, although maximum benefit may not be achieved for 1 to 2 weeks, or longer. This is associated with the inhibition of lung infiltration by eosinophils.

Indications:

1) the maintenance treatment of asthma as prophylactic therapy

2) indicated for asthma patients who require systemic corticosteroid administration, where adding beclomethasone aerosol may reduce or eliminate the need for the systemic corticosteroids. (Inhaled beclomethasone probably acts topically at the site of deposition in the bronchial tree after inhalation. An average daily dose of 4 puffs twice daily of beclomethasone (400 μg/day) is the equivalent of 10–15 mg/day of oral prednisone for the control of asthma, with far fewer systemic effects).

3) Beclomethasone is NOT indicated for the relief of acute bronchospasm.

Dexamethasone

Trade Names: generic, Decadron-LA ®

Drug Class: Glucocorticoid, Anti-Inflammatory

Mechanism of Action: (see beclomethasone). Glucocorticoids dramatically reduce the manifestations of inflammation due to their profound effects on the concentration, distribution, and function of peripheral leukocytes and to their suppressive effects on the inflammatory cytokines and chemokines and on other lipid and glucolipid mediators of inflammation.

Indications:

1) used for its potent anti-inflammatory effects in disorders of many organ systems.

2) Examples: rheumatic disorders, arthritis, lupus erythrematosus, bronchial asthma & ulcerative colitis.

3) Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli.

4) At equipotent anti-inflammatory doses, dexamethasone almost completely lacks the sodium-retaining property of hydrocortisone and closely related derivatives of hydrocortisone.

Contraindications: 1) Systemic fungal infections. 2) Hypersensitivity to this drug.

Pharmacokinetics: Available in oral, aerosol and topical forms. Topical corticosteroids can be absorbed from normal intact skin. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys.

Side Effects: Sodium retention, fluid retention, steroid myopathy, loss of muscle mass; osteoporosis, aseptic necrosis of femoral and humeral heads, peptic ulcer with possible perforation and hemorrhage, Impaired wound healing.

Used for: 1) diagnosis of Cushing's syndrome (adrenocortical hyperfunction) & 2) in the differential diagnosis of depressive psychiatric states.

In normal patients, the administration of a supraphysiologic dose of glucocorticoid results in suppression of ACTH and cortisol secretion. In Cushing's syndrome of whatever cause, there is a failure of this suppression when low doses of the synthetic glucocorticoid dexamethasone are given. In Cushing's disease there is typically a bilateral adrenal hyperplasia secondary to an ACTH-secreting pituitary adenoma, resulting in glucocorticoid hypersecretion, which can produce protein loss, poor wound healing, mental depression, etc. In patients with Cushing's disease, an appropriate high dose of dexamethasone will produce a >50% reduction in morning cortisol levels. Note: dexamethasone would not suppress glucocorticoid release from adrenal tumors, hence it is a useful diagnostic test for distinguishing between the two disorders.

Histamine

Mechanisms of action

Drug Class: Autacoid (Greek “self-remedy”)

Mechanism of Action: Histamine stimulates H1-H4 receptors.

1)Nervous system: H1 & presynaptic H3 receptors.

2) Cardiovascular: H1 & H2 receptors.

3) Bronchioles: H1.

4) Gastric mucosa: H2 receptors.

5) Triple response of Lewis: mostly H1, some H2 and H3.

Histamine

Post-receptor mechanisms

• H1: increased IP3 & DAG (Gq)
• H2: increased cAMP (Gs)
• H3: decreased cAMP & Cai (Gi)
• H4: decreased cAMP & Cai (Gi)

Betazole

• Brompheniramine (Brovex, Dimetane)
• Chlorpheniramine (Chlor-Trimeton)
• Diphenhydramine (Benadryl)
• Hydroxyzine (Atarax, Vistaril)
• Promethazine (Phenergan)
  
  
  These cross the BBB and cause drowsiness

• Fexofenadine (allegra)
• Loratadine (claritin)
  
  
  These do NOT cross the BBB

• Cromolyn Sodium (Intal, Nasalcrom)
• Nedocromil Sodium (Tilade)

Nedocromil

Trade Name: Tilade ®

Drug Class: an inhaled anti-inflammatory agent

Pharmacology:

essentially identical to cromolyn_sodium

Cromolyn Sodium

Trade Names: generic, Intal, Nasalcrom ®

Drug Class: an inhaled anti-inflammatory agent

Mechanism of Action:

1) inhibits both antigen- and exercise-induced asthma, and chronic use (four times daily) slightly reduces the overall level of bronchial reactivity.

Note: cromolyn and nedocromil sodium have no effect on airway smooth muscle tone, and are ineffective in reversing asthmatic bronchospasm.

2) The cellular mechanism is thought to be an alteration in the function of delayed chloride channels in the cell membrane (stabilizes cell membrane) that inhibits cellular activation and degranulation in eosinophils & specific mast cells in the lung.

Indications:

Prophylaxis for inhibiting asthma caused by allergens or exercise

Contraindications:

known hypersensitivity

Pharmacokinetics:

The Intal Inhaler (cromolyn sodium inhalation aerosol) is a metered dose aerosol unit for oral inhalation containing micronized cromolyn sodium

Side Effects:

1) throat irritation

2) bronchospasm

Brompheniramine

Trade Names: Brovex, Dimetane ®

Drug Class: H1 Antagonist (alkylamine subtype)

Mechanism of Action: Competitive H1 receptor antagonist

Indications: allergic rhinitis (nasal congestion), hay fever and urticaria, control of itching related to angioedema

Side Effects: slight sedation & anticholinergic side effects

Notes: In bronchial asthma, which involves several mediators, H1 antagonists are largely ineffective.

Chlorpheniramine

Trade Names: generic, Chlor-Trimeton ®

Drug Class: H1 Antagonist (alkylamine subtype)

Mechanism of Action: Competitive H1 receptor antagonist

Indications: (same as brompheniramine) Provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies.

Side Effects: slight sedation & anticholinergic side effects

Notes: a common component of OTC “cold” medication

Diphenhydramine

Trade Names: generic, Benadryl ®

Drug Class: H1 Antagonist (ethanolamine subtype)

Mechanism of Action: Competitive H1 receptor antagonist

Indications:

1) Antihistaminic: For allergic conjunctivitis due to foods; mild, uncomplicated allergic skin manifestations of urticaria and angioedema; adjunctive to epinephrine and other standard measures in treatment of anaphylactic reactions - after the acute manifestations have been controlled.

2) Motion sickness: For active and prophylactic treatment of motion sickness.

3) Antiparkinsonism: For parkinsonism (including drug-induced) in the elderly unable to tolerate more potent agents.

4) Local anesthesia: in patients allergic to conventional local anesthetics.

5) Sedation: used as a mild sedative in Tylenol PM ®.

Contraindications: should not be used in nursing mothers, newborn or premature infants, or patients with history of drug hypersensitivity to similar antihistamines.

Pharmacokinetics: A single oral dose is quickly absorbed with maximum activity occurring in approximately one hour. The duration of activity following an average dose of diphenhydramine HCl is from four to six hours. Little, if any, is excreted unchanged in the urine; most appears as the degradation products of metabolic transformation in the liver, which are almost completely excreted within 24 hours.

Side Effects:

1) Marked sedation; disturbed coordination.

2) Antihistamine overdosage reactions may vary from central nervous system depression to stimulation.

3) Stimulation is particularly likely in children.

4) Atropine-like signs and symptoms, dry mouth; fixed, dilated pupils; flushing, and gastrointestinal symptomsmay also occur.

Major drug interactions: has additive effects with alcohol and other CNS depressants (hypnotics, sedatives, tranquilizers, etc). MAO inhibitors prolong and intensify the anticholinergic (drying) effects of antihistamines.

Notes: the salt of diphenhydramine is dimenhydrinate (Dramamine ®), which is commonly used to treat motion sickness. Diphenhydramine is more potent than procaine as a local anesthetic.

Hydroxyzine

Trade Names: generic, Atarax, Vistaril ®

Drug Class: H1 Antagonist (piperazine subtype)

Mechanism of Action:

1) H1 competitive receptor antagonist

2) Bronchodilator activity, and analgesic effects

3) An anti-emetic

Indications:

1) management of histamine-mediated pruritus due to allergic conditions such as chronic urticaria and atopic and contact dermatoses

2) for symptomatic relief of anxiety and tension associated with psychoneurosis and as an adjunct in organic disease states in which anxiety is manifested

3) anxiety withdrawal symptoms in alcoholics or patients with delirium tremers (injection)

4) to reduce nausea & vomiting (injection)

Contraindications:

contraindicated in early pregnancy (fetal anomolies in rats and mice)

Pharmacokinetics:

1) oral (liquid, tablet or capsule) or i.m. injection routes of administration

2) rapidly absorbed from the gastrointestinal tract and its clinical effects are usually noted within 15 to 30 minutes after oral administration

3) IM injection should only be given in the upper deltoid region of the arm, and only if it is well developed (do not administer to the lower or mid-third of the arm)

4) In adults it can be given in the upper outer quadrant of the buttock or mid-lateral thigh

Warnings:

Hydoxyzine should NOT be administered subcutaneously, intra-arterially or intravenously

Pregnancy:

Hydroxyzine is contraindicated in early pregnancy (overall Pregnancy Risk Category C)

Side Effects:

marked sedation, dry mouth

Major drug interactions:

As a sedative when used as premedication and following general anesthesia, hydroxyzine may potentiate meperidine (Demerol®) and barbiturates, so their use in pre-anesthetic adjunctive therapy should be modified on an individual basis

Promethazine

Trade Names: generic, (previously marketed as Phenergan ®) (available by prescription in US, available OTC outside the US. Also sold as a combination with other drugs)

Mechanism of Action:

1) a phenothiazine (antipsychotic) derivative with very weak dopamine receptor antagonism, that also blocks H1 receptors.

2) It produces clinically useful anti-emetic and sedative effects.

Pharmacokinetics:

1) well absorbed orally; also available as a rectal suppository

2) Clinical effects begin within 20 minutes after oral administration and typically last 4-6 hrs, but may persist for up to 12 hrs.

3) Undergoes hepatic metabolism to a mixture of metabolites

Indications:

1) allergy

2) prevention/treatment of motion sickness

3) nausea & vomiting, sedation

4) pre- and post-operative use (sedation, anti-emetic)

5) sedation in both children & adults.

Side Effects: drowsiness, dry mouth, respiratory depression, neuroleptic malignant syndrome

Warnings:

1) Should not be used in pediatric patients <2 yrs old due to risk of fatal respiratory depression.

2) When given (accidentally) by intra-arterial injection it has caused several cases of gangrene & limb amputation (by an unclear mechanism).

Fexofenadine

Trade Name: Allegra ®

Drug Class: H1 Antagonist (piperidine subtype)

Mechanism of Action: antihistamine with selective peripheral H1-receptor antagonist activity.

Indications:

1) relief of symptoms associated with seasonal allergic rhinitis in adults and children 6 years of age and older. Symptoms treated effectively include sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes.

2) treatment of uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 years of age and older. It significantly reduces pruritus and the number of wheals.

Contraindications: known hypersensitivity to fexofenadine

Pharmacokinetics: Approximately 5% of fexofenadine gets metabolized. It's half-life is ~14 hours in healthy patients, becoming longer in patients with renal failure.

Side Effects: second generation H1 blockers are less lipid soluble, have less complete distribution into the CNS, and have little or no sedative or stimulant actions, and far fewer autonomic effects.

Major drug interactions: Despite it's minimal metabolism, co-administration of fexofenadine with ketoconazole or erythromycin can result in increased plasma levels of fexofenadine. Fexofenadine is the metabolite of terfenadine (Seldane ®) which was taken off the market due to it's ability to induce cardiac arrhythmias (torsade de pointes). Fexofenadine does not have the same effect on the heart.

Loratadine

Trade Names: Claritin ®

Drug Class: H1 Antagonist (tricyclic subtype)

Mechanism of Action: a long-acting tricyclic antihistamine with selective peripheral histamine H1-receptor antagonistic activity

Indications: relief of nasal and non-nasal symptoms of seasonal allergic rhinitis and for the treatment of chronic idiopathic urticaria in patients 6 years of age or older.

Contraindications: known hypersensitivity

Pharmacokinetics: Loratidine is metabolized by cytochrome P450 3A4 (CYP3A4) and, to a lesser extent, by cytochrome P450 2D6 (CYP2D6) to form a metabolite (descarboethoxyloratidine) that is also active. The elimination half-life for normal adult subjects is 8 hours (range = 3 to 20 hours) for loratadine and 28 hours (range = 8.8 to 92 hours) for descarboethoxyloratadine.

Side Effects: few

Major drug interactions: cimetidine, erythromycin and ketoconazole can increase loratidine plasma levels, but this is not commonly associated with clinically significant side effects

• Cimetidine (Tagamet )
• Famotidine (Pepcid, Pepcid AC)
• Nizatidine (Axid, Axid AR)
• Ranitidine (Zantac, Zantac 75)

Cimetidine

Trade Names: generic, Tagamet ®

Drug Class: H2 Antagonist

Mechanism of Action:

1) Competitive antagonist at the H2 receptor.

2)Blocks H2 receptors in parietal cells which supresses basal and meal-stimulated acid secretion in a dose-dependent manner

3) Cimetidine also inhibits gastric acid secretion stimulated by food, histamine, pentagastrin, caffeine and insulin.

Indications:

1) Short-Term Treatment of Active Duodenal Ulcer

2) Maintenance Therapy for Duodenal Ulcer Patients at Reduced Dosage after Healing of Active Ulcer

3) Short-Term Treatment of Active Benign Gastric Ulcer

4) Erosive Gastroesophageal Reflux Disease (GERD) (Oral Solution Only)

5) Prevention of Upper Gastrointestinal Bleeding in Critically Ill Patients (Injection Only)

6) The Treatment of Pathological Hypersecretory Conditions: (i.e., Zollinger-Ellison Syndrome).

Contraindications:

known drug hypersensitivity, inhibitor of CYP-450 ( CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4)

Pharmacokinetics:

Undergoes 1st pass hepatic metabolism, resulting in a bioavailability of ~50%. The remainder is secreted into the urine via kidney tubules unchanged. Half life is 2 hrs. Dose reduction is required in patients with moderate to severe renal (and possibly hepatic) insufficiency. In the elderly there is a decline of up to 50% in drug clearance and reduction in Vd.

Side Effects:

1) H2 blockers are extremely safe drugs, with side effects in less than 3% of patients (headaches, diarrhea, fatigue).

2) Mental status changes may occur with i.v. administration in elderly.

3) Endocrine effects: cimetidine inhibits the binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol & increases serum prolactin levels. With chronic use may cause gynecomastia or impotence in men & galactorrhea in women. These effects are specific for cimetidine.

Major drug interactions:

1) Cimetidine inhibits multiple forms of cytochrome P450 (CYP1A2, CYP2C9, CYP2D6 & CYP3A4). Hence the half-lives of drugs metabolized by these pathways may be prolonged. Examples: warfarin, theophylline, phenytoin, lidocaine, quinidine, propranolol, metoprolol, tricyclic antidepressants, benzodiazepines, calcium channel blockers, sulfonylureas, and ethanol.

2) Ranitidine binds 4-10 times less avidly to cytP450 than cimetidine.

3) H2 blockers also compete with drugs for renal tubular secretion via P-glycoprotein (e.g. procainamide).

Famotidine

Trade Names: generic, Pepcid, Pepcid AC ®

• Drug Class: H2 Antagonist
• Mechanism of Action: same as cimetidine
• Indications: same as cimetidine
• Contraindications: known hypersensitivity
• Pharmacokinetics: Famotidine undergoes minimal first-pass metabolism, but is incompletely absorbed. The bioavailability of oral doses is 40-45%. Famotidine is eliminated by renal (65-70%) and metabolic (30-35%) routes with elimination half-life of 2.5-3.5 hours. There is a close relationship between creatinine clearance values and the elimination half-life of famotidine.
• Side Effects: headache (5%), dizziness (1%).
• Major drug interactions: none of clinical significance (unllike cimetidine!)

Nizatidine

Trade Names: Axid, Axid AR ®

• Drug Class: H2 Antagonist
• Mechanism of Action: same as cimetidine
• Indications: same as cimetidine
• Contraindications: known hypersensitivity
• Pharmacokinetics: Bioavailability exceeds 70%. More than 90% of an oral dose of nizatidine is excreted in the urine within 12 hours. About 60% of an oral dose is excreted as unchanged drug. Eliminatrion half life is 1-2 hrs. Moderate to severe renal impairment significantly prolongs the half-life and decreases the clearance of nizatidine.
• Side Effects: few
• Major drug interactions: none of clinical significance (unllike cimetidine!)

Ranitidine

Trade Names: generic, Zantac, Zantac 75 ®

• Drug Class: H2 Antagonist
• Mechanism of Action: same as cimetidine
• Indications: same as cimetidine
• Contraindications: known hypersensitivity
• Pharmacokinetics: 50% absorbed after oral administration. The principal route of excretion is the urine, with approximately 30% of the orally administered dose collected in the urine as unchanged drug in 24 hours. Plasma half life is ~3 hrs in normal patients. Renal impairment prolongs the half-life and decreases the clearance of ranitidine.
• Side Effects: few
• Major drug interactions: none of clinical significance (unllike cimetidine!)

• Cimetidine (moderate: CYP 1A2, 2C19, 2D6, 3A4)
• Erythromycin & other Macrolides (major: 3A4, weak: 1A2, 2B6)
• Ciprofloxacin (strong: 1A2; weak: 3A4)
• Ketoconazole (strong: 1A2, 2C9, 3A4; moderate: 2A6, 2C19, 2D6)
• Fluoxetine (Prozac ®) (strong: 2D6; moderate: 1A2, 2C19; weak: 2B6, 2C9, 3A4)
  Grapefruit Juice

• Rifampin (strong: 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 3A4).
• Phenobarbital (barbiturates) (strong: 1A2, 2A6, 2B6, 2C8, 3A4)
• Carbamezepine (strong: 1A2, 2B6, 2C8, 2C9, 2C19, 3A4)
• Phenytoin (strong: 2B6, 2C8, 2C9, 2C19, 3A4)
• St. John's wort (induces: 3A4, 2C9, 1A2 & P-glycoprotein)

Used to treat Cushing's disease

Inhibitor of glucocorticoid receptors and progesterone receptors.

Also used as an abortifacient.