antihistamines, anti-inflammation & glucocortoids

Anti-inflammatory, Antiallergic and Immunologic Drugs : 

Anti-inflammatory, Antiallergic and Immunologic Drugs Science 355

Chapter 69: 

Chapter 69 Antihistamines

Histamine: 

Histamine Endogenous compound Found in specialized cells Important role in: Allergic reaction (when H1 receptors stimulated) Regulation of gastric acid secretion (when H2 receptors stimulated)

Histamine: 

Histamine Distribution Present in practically all tissues Especially high in skin, lungs, and GI tract Low content in plasma

Histamine: 

Histamine Synthesis/storage Mast cells and basophils Produced by neurons Release Allergic Nonallergic

Slide 6: 

Fig. 69-1. Release of histamine by allergen-antibody interaction. (IgE = immunoglobulin E.)

H1 Receptors: 

H 1 Receptors Vasodilation Skin of the face and upper body Extensive – can cause hypotension Increased capillary permeability Edema Bronchoconstriction Not the cause of asthma attack CNS effects Role in cognition, memory, and sleep/waking cycles Other Itching, pain, secretion of mucus

H2 Receptors: 

H 2 Receptors Secretion of gastric acid Act directly on parietal cells to promote acid release Dominant role in acid release

Histamine Antagonists/Antihistamines: 

Histamine Antagonists/Antihistamines Act primarily on H 1 and H 2 receptors Used primarily for two pathologic states Allergic disorders Peptic ulcer disease

Mild Allergic Responses: 

Mild Allergic Responses Caused largely by histamine acting at H 1 receptors Rhinitis, itching, localized edema Hay fever, mild transfusion reactions, acute urticaria Usually responsive to antihistamine therapy

Severe Allergic Responses: 

Severe Allergic Responses Anaphylaxis Anaphylactic shock Bronchoconstriction, hypotension, edema of the glottis Histamine plays a minor role Leukotrienes are the principal mediators Antihistamines are of little use in treatment Epinephrine is the drug of choice for treatment (see Chapter 17)

Histamine Antagonists: 

Histamine Antagonists Antihistamines, histamine antagonists, and histamine blockers are used interchangeably. H 1 antagonists have similar antihistamine actions but differ significantly in side effects. No individual prototype selected. H 1 antagonists are divided into two major groups: First-generation H 1 antagonists (highly sedating) Second-generation H 1 antagonists

H1 Antagonists: 

H 1 Antagonists Mechanism of action Block the actions of histamine at H 1 receptors Do not block H 2 receptors Some bind to muscarinic receptors

H1 Antagonists: 

H 1 Antagonists Pharmacologic effects Peripheral effects Reduce localized flushing Reduce itching and pain Effects on the CNS Therapeutic dose – CNS depression Second-generation negligible CNS depression Overdose CNS stimulation Convulsions Very young children especially sensitive

H1 Antagonists: 

H 1 Antagonists Therapeutic uses Mild allergy Motion sickness Promethazine, dimenhydrinate Insomnia Common cold Anticholinergic properties, not H 1 blockade

H1 Antagonists: 

H 1 Antagonists Adverse effects Sedation Nonsedative CNS effects Dizziness, fatigue, coordination problems Gastrointestinal effects Can cause nausea, vomiting, loss of appetite, constipation Anticholinergic effects Weak atropine-like effects Cardiac dysrhythmias Rare

H1 Antagonists: 

H 1 Antagonists Drug interactions CNS depressants Acute toxicity Large margin of safety Widespread availability of drugs CNS and anticholinergic reactions

H1 Antagonists—First Generation: 

H 1 Antagonists—First Generation First generation (sedating) Brompheniramine (Brovex) Chlorpheniramine (Chlor-Trimeton) Clemastine (Tavist Allergy) Cyproheptadine (generic only) Dexchlorpheniramine (generic only) Diphenhydramine (Benadryl) Hydroxyzine (Vistaril) Phenindamine (Nolahist) Promethazine (Phenergan)

H1 Antagonists—Second Generation: 

H 1 Antagonists—Second Generation Second generation (nonsedating) Fexofenadine (Allegra) Cetirizine (Zyrtec) Loratadine (Claritin, Tavist ND, Alavert) Desloratadine (Clarinex) Azelastine (Astelin)

High-Risk Patients: 

High-Risk Patients Antihistamines contraindicated During third trimester of pregnancy Nursing mothers Newborn infants Use antihistamines with caution in: Young children The elderly Patients whose conditions may be aggravated by muscarinic blockade

Chapter 70: 

Chapter 70 Cyclooxygenase Inhibitors: Nonsteroidal Anti-inflammatory Drugs and Acetaminophen

Cyclooxygenase Inhibitors: 

Cyclooxygenase Inhibitors Uses Suppress inflammation Relieve pain Reduce fever Adverse effects Gastric ulceration Bleeding Renal impairment

Classification of Cyclooxygenase Inhibitors: 

Classification of Cyclooxygenase Inhibitors Drugs with anti-inflammatory properties NSAIDs: nonsteroidal anti-inflammatory drugs Aspirin, celecoxib, ibuprofen, and naproxen Drugs without anti-inflammatory properties Acetaminophen

First-Generation NSAIDs: 

First-Generation NSAIDs Inhibit COX-1 and COX-2 Used to treat inflammatory disorders (rheumatoid arthritis, osteoarthritis, bursitis) Alleviate mild to moderate pain Suppress fever Relieve dysmenorrhea Suppress inflammation but have risk of serious harm

Cox 1 & Cox 2: 

Cox 1 & Cox 2

Aspirin: 

Aspirin Nonselective inhibitor of cyclooxygenase Therapeutic uses Analgesic, antipyretic, anti-inflammatory Suppression of platelet aggregation Protects in thrombotic disorders Dysmenorrhea Cancer prevention Prevention of Alzheimer ’ s disease

Aspirin: 

Aspirin Adverse effects Gastrointestinal effects Bleeding Renal impairment Salicylism Reye ’ s syndrome Pregnancy Anemia, postpartum hemorrhage, may prolong labor Hypersensitivity reaction

Aspirin: 

Aspirin Drug interactions Anticoagulants: warfarin and heparin Glucocorticoids Alcohol Ibuprofen ACE inhibitors and ARBS Acute poisonings

Nonaspirin First-Generation NSAIDs: 

Nonaspirin First-Generation NSAIDs Aspirin-like drug with fewer GI, renal, and hemorrhagic effects than aspirin 20+ nonaspirin NSAIDs available (all similar, but for unknown reasons, patients tend to do better on one drug or another Inhibit COX-1 and COX-2 – inhibition is reversible (unlike with aspirin) Principal indications – rheumatoid arthritis and osteoarthritis Do not protect against MI and stroke See Table 70-5

First-Generation NSAIDs : 

First-Generation NSAIDs Ibuprofen (Advil, Motrin) Fenoprofen Flurbiprofen Ketoprofen Naproxen Naproxen plus lansoprazole Oxaprozin Diclofenac Diclofenac plus misoprostol Diflunisal Etodolac Indomethacin Ketorolac Mefenamic acid Meclofenamate Nabumetone Piroxicam Sulindac Tolmetin Meloxicam

Second-Generation NSAIDs: 

Second-Generation NSAIDs Just as effective as traditional NSAIDs at suppressing inflammation and pain Somewhat lower risk for GI side effects Can impair renal function and cause hypertension and edema Increase the risk for MI and stroke 2005, two coxibs withdrawn from use: rofecoxib (Vioxx) and valdecoxib (Bextra) Use of celecoxib has sharply declined

Celecoxib (Celebrex): 

Celecoxib (Celebrex) Second-generation COX-2 inhibitor—fewer adverse effects than first-generation drugs Because of cardiovascular risks, last-choice drug for long-term management of pain Uses Osteoarthritis Rheumatoid arthritis Acute pain Dysmenorrhea Familial adenomatous polyposis

Celecoxib (Celebrex): 

Celecoxib (Celebrex) Adverse effects Dyspepsia Abdominal pain Renal toxicity Sulfonamide allergy Cardiovascular impact (stroke, MI, and other serious events) Use in pregnancy

Celecoxib (Celebrex): 

Celecoxib (Celebrex) Drug interactions Warfarin May decrease diuretic effect of furosemide May decrease antihypertensive effect of ACE inhibitors May increase levels of lithium Levels of celecoxib may be increased by fluconazole

Acetaminophen (Tylenol): 

Acetaminophen (Tylenol) Therapeutic uses Analgesic, antipyretic Does not have any anti-inflammatory or antirheumatic actions Not associated with Reye ’ s syndrome Action Inhibits prostaglandin synthesis in central nervous system

Slide 43: 

Fig. 70-2. Metabolism of acetaminophen.

Acetaminophen (Tylenol): 

Acetaminophen (Tylenol) Adverse effects Very few at normal doses Hepatotoxicity With overdose or in patients with liver failure Overdose – hepatic necrosis S/S of hepatic failure, coma, death Early symptoms: N/V, diarrhea, sweating, abdominal pain Treatment for overdose: acetylcysteine (Mucomyst)

Acetaminophen (Tylenol): 

Acetaminophen (Tylenol) Drug interactions Alcohol Warfarin

AHA Statement on COX Inhibitors: 

AHA Statement on COX Inhibitors Most COX inhibitors – especially COX-2 inhibitors – increase the risk for MI and stroke AHA recommends a stepped-care approach Four basic steps

Chapter 71: 

Chapter 71 Glucocorticoids in Nonendocrine Diseases

Glucocorticoid Drugs: 

Glucocorticoid Drugs Also known as corticosteroids and nearly identical to steroids produced by the adrenal cortex Physiologic effects (low doses) Modulation of glucose metabolism in adrenocortical insufficiency Pharmacologic effects (high doses) Suppression of inflammation

Glucocorticoids in Nonendocrine Diseases: 

Glucocorticoids in Nonendocrine Diseases Glucocorticoid physiology Metabolic effects Cardiovascular effects Effects during stress Effects on water and electrolytes Respiratory system in neonates

Slide 50: 

Fig. 71-1. Feedback regulation of glucocorticoid synthesis and secretion. (ACTH = adrenocorticotropic hormone, CNS = central nervous system, CRH = corticotropin-releasing hormone.)

Pharmacology of the Glucocorticoids: 

Pharmacology of the Glucocorticoids Molecular mechanisms of action different from those of other drugs Glucocorticoid receptors are inside the cell. Glucocorticoids modulate the production of regulatory proteins versus signaling pathways.

Pharmacology of the Glucocorticoids: 

Pharmacology of the Glucocorticoids Effects on metabolism and electrolytes Anti-inflammatory and immunosuppressant effects Therapeutic uses in nonendocrine disorders Rheumatoid arthritis Systemic lupus erythematosus Inflammatory bowel disease Miscellaneous inflammatory disorders

Pharmacology of the Glucocorticoids: 

Pharmacology of the Glucocorticoids Therapeutic uses in nonendocrine disorders (continued ) Allergic conditions Asthma Dermatologic disorders Neoplasms Suppression of allograft rejection Prevention of respiratory distress syndrome

Pharmacology of the Glucocorticoids: 

Pharmacology of the Glucocorticoids Adverse effects Adrenal insufficiency Osteoporosis and resultant fractures Infection Glucose intolerance Myopathy Fluid and electrolyte disturbances Growth retardation Psychologic disturbances

Pharmacology of the Glucocorticoids: 

Pharmacology of the Glucocorticoids Adverse effects ( continued) Cataracts and glaucoma Peptic ulcer disease Iatrogenic Cushing ’ s syndrome Use in pregnancy and lactation Drug interactions Interactions related to potassium loss Nonsteroidal anti-inflammatory drugs Insulin and oral hypoglycemics Vaccines

Pharmacology of the Glucocorticoids: 

Pharmacology of the Glucocorticoids Contraindications Patients with systemic fungal infections Those receiving live virus vaccines Use with caution in pediatric patients and pregnancy/breast-feeding

Slide 58: 

Fig. 71-1. Feedback regulation of glucocorticoid synthesis and secretion. (ACTH = adrenocorticotropic hormone, CNS = central nervous system, CRH = corticotropin-releasing hormone.)

Pharmacology of the Glucocorticoids: 

Pharmacology of the Glucocorticoids Adrenal suppression Why it can develop Adrenal suppression and physiologic stress Glucocorticoid withdrawal Taper the dosage over 7 days Switch from multiple doses to single doses Taper the dosage to 50% of physiologic values Monitor for signs of insufficiency

Glucocorticoid Routes of Administration: 

Glucocorticoid Routes of Administration Oral, parenteral (IV, IM, subQ), and topical Individual glucocorticoids differ in 3 ways Biologic half-life Mineralocorticoid potency Glucocorticoid potency

Glucocorticoid Dosage: 

Glucocorticoid Dosage Highly individualized Determined empirically (trial and error) No immediate threat – start low and slow Immediate threat – start high; decrease as possible Long-time use – smallest effective amount Prolonged treatment with high doses only if disorder is life-threatening or has potential to cause permanent disability Increase in times of stress Wean gradually Alternate-day therapy

Chapter 68: 

Chapter 68 Immunosuppressants

Immunosuppressants: 

Immunosuppressants Inhibit immune response Uses Prevention of organ rejection Treatment of autoimmune diseases Toxicity Increased risk of infection Increased risk of neoplasms

Slide 66: 

Fig. 68-1. Sites of action of immunosuppressant drugs.

Calcineurin Inhibitors: 

Calcineurin Inhibitors Cyclosporine and tacrolimus – most effective immunosuppressants available Differ in structure, but share same mechanism Both inhibit calcineurin and thereby suppress production of interleukin-2 (IL-2)

Cyclosporine (Sandimmune): 

Cyclosporine (Sandimmune) Mechanism To suppress the production of interleukin-2, interferon gamma, and other cytokines Uses Drug of choice for organ rejection (kidney, liver, and heart) of an allogenic transplant Some autoimmune diseases

Cyclosporine (Sandimmune): 

Cyclosporine (Sandimmune) Adverse effects Nephrotoxicity Infection Hepatotoxicity Lymphoma Hypertension Tremor Hirsutism Leukopenia, gingival hyperplasia, gynecomastia, sinusitis, hyperkalemia Anaphylactic reactions

Cyclosporine (Sandimmune): 

Cyclosporine (Sandimmune) Drug and food interactions Drugs that can decrease cyclosporine levels Drugs that can increase cyclosporine levels Nephrotoxic drugs Grapefruit juice

Tacrolimus (Prograf): 

Tacrolimus (Prograf) An alternative to cyclosporine Somewhat more effective – but also more toxic Concurrent use with glucocorticoids Therapeutic use Prophylaxis of organ rejection (liver, kidney, or heart) Adverse effects Nephrotoxicity is the major concern Neurotoxicity GI effects Hypertension Hyperkalemia

Tacrolimus (Prograf): 

Tacrolimus (Prograf) Adverse effects (cont ’ d) Hyperglycemia Hirsutism Gum hyperplasia Anaphylaxis with IV administration Drug and food interactions Agents that inhibit CYP3A (an isozyme of cytochrome P450) Grapefruit juice NSAIDs should be avoided

Sirolimus (Rapamune): 

Sirolimus (Rapamune) Actions and therapeutic use Only for prevention of renal transplant rejection Use in conjunction with cyclosporine and glucocorticoids Adverse effects Increased risk of infection Raises levels of cholesterol and triglycerides Risk of renal injury Severe complications in the liver and lung Rash, acne, anemia, thrombocytopenia, joint pain, diarrhea, hypokalemia

Sirolimus (Rapamune): 

Sirolimus (Rapamune) Drug and food interactions Drugs that inhibit or induce CYP3A4 (the 3A4 isozyme of cytochrome P450) High-fat foods Grapefruit juice

Glucocorticoids: 

Glucocorticoids Used to widely suppress immune response Suppression of allograft rejection, treatment of asthma, rheumatoid arthritis, SLE, and multiple sclerosis Large doses used to prevent rejection Increased risk for infection, thinning of skin, bone dissolution with fractures, impaired growth in children, and suppression of hypothalamic-pituitary-adrenal axis

Cytotoxic Drugs: 

Cytotoxic Drugs Suppress immune response by killing B and T lymphocytes undergoing proliferation Nonspecific – toxic to all proliferating cells Adverse effects Bone marrow suppression Neutropenia Thrombocytopenia GI disturbances Reduced fertility Alopecia

Cytotoxic Drugs: 

Cytotoxic Drugs Azathioprine (Imuran) Suppresses cell-mediated and humoral immune responses Therapeutic uses Adjuvant treatment with transplants Autoimmune disorders Adverse effects Neutropenia Thrombocytopenia Mutagenic and teratogenic Neoplasms

Other Cytotoxic Drugs: 

Other Cytotoxic Drugs Cyclophosphamide (Cytoxan, Neosar) Anticancer drug Methotrexate (Rheumatrex, Trexall) Anticancer agent Autoimmune disorders Suppression of B and T lymphocytes Mycophenolate mofetil (CellCept, Myfortic) Approved for prophylaxis of organ rejection Acts on B and T lymphocytes to inhibit inosine monophosphate dehydrogenase Selective inhibition of B and T lymphocyte proliferation

Antibodies: 

Antibodies Muromonab-CD3 (Orthoclone OKT3) Monoclonal antibody Actions and uses Blocks all T-cell function Prevents acute rejection of transplants Depletes T cells prior to bone marrow transplant Adverse effects Fever Chills Dyspnea Chest pain Nausea and vomiting

Other Antibodies: 

Other Antibodies Basiliximab and daclizumab Monoclonal antibodies Blocks activation of T cells by IL-2 Prophylaxis of acute organ rejection Lymphocyte immune globulin (Atgam) Antithymocyte (Equine) Rho(D) immune globulin (RhIG)