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Questions and Answers
What is the primary infectious agent that causes tuberculosis?
What is the primary infectious agent that causes tuberculosis?
Mycobacterium tuberculosis
Which drug is activated on the surface of M.tuberculosis by katG enzyme?
Which drug is activated on the surface of M.tuberculosis by katG enzyme?
Pyrazinamide should be used with caution in patients with hyperuricaemia or gout.
Pyrazinamide should be used with caution in patients with hyperuricaemia or gout.
True
Ethambutol hydrochloride inhibits the incorporation of _______ into the mycobacterium cell wall.
Ethambutol hydrochloride inhibits the incorporation of _______ into the mycobacterium cell wall.
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What chemical group destroys the activity of sulphonamides when substituted for the sulphonamido function?
What chemical group destroys the activity of sulphonamides when substituted for the sulphonamido function?
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Match the drug with its mode of action:
Match the drug with its mode of action:
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Sulphonamides in combination: Trimethoprim with ____________.
Sulphonamides in combination: Trimethoprim with ____________.
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What type of groups bind to the basic centers of proteins according to the text?
What type of groups bind to the basic centers of proteins according to the text?
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Match the following sulphonamides with their properties and uses:
Match the following sulphonamides with their properties and uses:
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How are antibiotics different from antiseptics?
How are antibiotics different from antiseptics?
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What is the main structural difference between cephalosporins and penicillins?
What is the main structural difference between cephalosporins and penicillins?
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Match the following cephalosporins with their properties and uses:
Match the following cephalosporins with their properties and uses:
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Cephalosporin N is a derivative of 6-aminopenicillanic acid, and Cephalosporin C is a derivative of 7 amino-cephalosporanic acid. Cephalosporin C contains a side-chain derived from ___acid.
Cephalosporin N is a derivative of 6-aminopenicillanic acid, and Cephalosporin C is a derivative of 7 amino-cephalosporanic acid. Cephalosporin C contains a side-chain derived from ___acid.
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What is the purpose of monitoring therapeutic levels of cyclosporine and tacrolimus?
What is the purpose of monitoring therapeutic levels of cyclosporine and tacrolimus?
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Which adverse effect is more prominent with tacrolimus compared to cyclosporine?
Which adverse effect is more prominent with tacrolimus compared to cyclosporine?
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__________ is a macrolide antibiotic produced by bacteria Streptomyces tsukubaensis.
__________ is a macrolide antibiotic produced by bacteria Streptomyces tsukubaensis.
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Sirolimus is a calcineurin inhibitor.
Sirolimus is a calcineurin inhibitor.
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Match the drug with its primary usage:
Match the drug with its primary usage:
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What is the mechanism of action of IL-2 receptor antagonists?
What is the mechanism of action of IL-2 receptor antagonists?
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What is the primary use of Type I interferons IFN-α and IFN-β?
What is the primary use of Type I interferons IFN-α and IFN-β?
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Loop diuretics inhibit reabsorption of ______ and ______ by inhibiting the Na+ —K+ —2Cl– symport.
Loop diuretics inhibit reabsorption of ______ and ______ by inhibiting the Na+ —K+ —2Cl– symport.
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Match the following diuretics with their site of action:
Match the following diuretics with their site of action:
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What is the structure-activity relationship of ethacrynic acid?
What is the structure-activity relationship of ethacrynic acid?
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What is the effect of thiazides on Ca++ reabsorption in the distal convoluted tubule?
What is the effect of thiazides on Ca++ reabsorption in the distal convoluted tubule?
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What is the mechanism of action of thiazides?
What is the mechanism of action of thiazides?
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What is the effect of thiazides on NaCl reabsorption in the distal convoluted tubule?
What is the effect of thiazides on NaCl reabsorption in the distal convoluted tubule?
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What is the structure-activity relationship of thiazides?
What is the structure-activity relationship of thiazides?
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What is the mechanism of action of amiloride and triamterene?
What is the mechanism of action of amiloride and triamterene?
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What is the effect of amiloride and triamterene on K+ and H+ secretion?
What is the effect of amiloride and triamterene on K+ and H+ secretion?
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What is the primary function of aldosterone in the kidneys?
What is the primary function of aldosterone in the kidneys?
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Which class of diuretics inhibits the action of carbonic anhydrase?
Which class of diuretics inhibits the action of carbonic anhydrase?
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Loop diuretics are considered the most potent type of diuretics.
Loop diuretics are considered the most potent type of diuretics.
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_______ is the only available aldosterone antagonist.
_______ is the only available aldosterone antagonist.
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Match the diuretic class with its site of action:
Match the diuretic class with its site of action:
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Which type of diuretic is commonly used to treat hypertension and other conditions?
Which type of diuretic is commonly used to treat hypertension and other conditions?
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Patients with congestive heart failure who are taking cardiac glycosides like digitalis are not at risk of developing hypokalemia.
Patients with congestive heart failure who are taking cardiac glycosides like digitalis are not at risk of developing hypokalemia.
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What electrolyte imbalance can diuretics lead to, which is characterized by low potassium levels?
What electrolyte imbalance can diuretics lead to, which is characterized by low potassium levels?
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Diuretics can affect electrolyte balance, leading to abnormalities such as hypokalemia, hyponatremia, hypomagnesemia, and ____(high potassium) in some cases.
Diuretics can affect electrolyte balance, leading to abnormalities such as hypokalemia, hyponatremia, hypomagnesemia, and ____(high potassium) in some cases.
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Match the diuretic type with the correct examples:
Match the diuretic type with the correct examples:
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Study Notes
Antimicrobials
- Antimicrobials reduce the possibility of infection and sepsis
- Antibiotics are derived from moulds or synthesized, absorbed into the body to kill or prevent bacterial growth
- Antibiotics can be administered parenterally, orally, or topically
- Antiseptics are applied to the skin, not absorbed, and reduce infection possibility
- Disinfectants destroy microorganisms on non-living objects
- Antifungal agents kill or inhibit fungal growth, administered intravenously, orally, or topically
Cephalosporins
- Isolated from Cephalosporium acremonium in 1948
- β-Lactam antibiotics with similar structure to penicillins, but with a dihydrothiazine ring
- More acid-stable than penicillins, with a similar mechanism of action
- Inhibit bacterial cell wall peptidoglycan unit cross-linking by inhibiting transpeptidase enzyme
Classification of Cephalosporins
- Classified based on chemical structure, clinical pharmacology, antibacterial spectrum, or penicillinase resistance
- Orally administered: cephalexin, cephradine, and cefaclor
- Parentrally administered: cephalothin, cephapirin, cephacetrile, and cefazedone
- Resistant to β-lactamase and parentrally administered: cefuroxime, cefamandole, cefoxitin
Generations of Cephalosporins
- First-generation: highest activity against gram-positive bacteria, lowest activity against gram-negative bacteria
- Second-generation: more active against gram-negative bacteria, less active against gram-positive bacteria
- Third-generation: less active against gram-positive organisms, but with a much expanded spectrum of activity against gram-negative organisms
- Fourth-generation: cefepime and cefpirome, with a broad spectrum of activity
- Fifth-generation: ceftobiprole, with anti-pseudomonal activity and less susceptible to resistance
Structure-Activity Relationship (SAR) of Cephalosporins
- 7-Acylamino substitution: addition of amino group and hydrogen at α and α1 position produces a basic compound, increasing stability and activity
- Substitutions on the aromatic ring: increase lipophilicity, providing higher gram-positive activity and generally lower gram-negative activity
- Modification at C-3 position: affects pharmacokinetics and pharmacodynamics
Degradation of Cephalosporins
- In strong acid solutions
- In the presence of β-lactamase
- In the presence of acylase
Anti-TB Drugs
- First-line drugs: isoniazid, streptomycin, rifampicin, ethambutol, and pyrazinamide
- Second-line drugs: ethionamide, p-amino salicylic acid, ofloxacin, ciprofloxacin, cycloserine, amikacin, kanamycin, viomycin, and capreomycin
Isoniazid
- Prodrug, activated by katG enzyme to isonicotinic acid
- Inhibits bacterial cell wall mycolic acid, making M.tuberculosis susceptible to reactive oxygen radicals
- Bacteriostatic or bactericidal, depending on concentration and susceptibility of the organism
Pyrazinamide
- Prodrug, activated by M.tuberculosis amidase enzyme to pyrazine carboxylic acid
- Bactericidal, effective in low pH environments
- Used to treat tuberculosis and meningitis
Ethambutol
- Bacteriostatic, inhibits incorporation of mycolic acid into the mycobacterium cell wall
- Used in combination with other antitubercular drugs
Rifampicin
- Bactericidal, inhibits DNA-dependent RNA polymerase of mycobacteria
- Used in combination with other antitubercular drugs
Streptomycin
- Aminoglycoside, inhibits protein synthesis
- Used in combination with other antitubercular drugs to treat pulmonary infections
Ethionamide
- Inhibits mycolic acid synthesis
- Used as an antitubercular drug
Para-amino-salicylic acid
- Inhibits bacterial folate metabolism
- Bacteriostatic, highly specific for M.tuberculosis
- Used to treat tuberculosis### Antibacterial Sulphonamides
- Para amino benzene sulphonamide (sulphanilamide) is the first effective chemotherapeutic agent used to prevent and treat bacterial infections in humans.
- Sulphonamides are bacteriostatic antibiotics with a wide spectrum of action against most gram-positive bacteria and many gram-negative organisms.
Structure-Activity Relationship (SAR) of Sulphonamides
- Sulphanilamide skeleton is the minimum structural requirement for antibacterial activity.
- Amino and sulphonyl groups on the benzene ring are essential and should be in the 1 and 4 positions.
- The N-4 amino group could be modified to be prodrugs, which are converted to free amino function in vivo.
- Sulphur atom should be directly linked to the benzene ring.
- Replacement of the –SO2NH group by –CONH reduces the activity.
- Heterocyclic substituents lead to highly potent derivatives.
Classification of Sulphonamides
- Based on the site of action:
- Sulphonamides for general infections (e.g. Sulphanilamide, Sulphapyridine, Sulphadiazine, Sulphamethoxazole).
- Sulphonamides for urinary tract infections (e.g. Sulphaisoxazole, Sulphathiazole).
- Sulphonamides for intestinal infections (e.g. Phthalylsulphathiazole, Succinyl sulphathiazole, Sulphasalazine).
- Sulphonamides for local infections (e.g. Sulfacetamide, Mafenide, Silver sulphadiazine).
- Sulphonamides for dermatitis (e.g. Dapsone, Solapsone).
- Sulphonamides in combination (e.g. Trimethoprim with Sulphamethoxazole).
- Based on pharmacokinetic properties:
- Poorly absorbed sulphonamides (locally acting sulphonamides, e.g. Sulphasalazine, Phthalylsulphathiazole, Sulphaguanidine, Salicylazo sulphapyridine, Succinyl sulphathiazole).
- Rapidly absorbed and rapidly excreted sulphonamides (systemic sulphonamides, e.g. Sulphamethoxazole, Sulphaisoxazole, Sulphadiazine, Sulphadimidine, Sulphafurazole, Sulphasomidine, Sulphamethiazole, Sulphacetamide, Sulphachlorpyridazine).
- Topically used sulphonamides (e.g. Sulphacetamide, Mafenide, Sulphathiazole, Silver sulphadiazine).
- Based on duration of action:
- Extra long-acting sulphonamides (e.g. Sulphasalazine, Sulphaclomide, Sulphalene).
- Long-acting sulphonamides (e.g. Sulphadoxine, Sulphadimethoxine, Sulphamethoxy pyridazine, Sulphamethoxydiazine, Sulphaphenazole, Sulphamethoxine).
- Intermediate-acting sulphonamides (e.g. Sulphasomizole, Sulphamethoxazole).
- Short-acting sulphonamides (e.g. Sulphamethiazole, Sulphaisoxazole).
- Based on chemical structure:
- N-substituted sulphonamides (e.g. Sulphadiazine, Sulphacetamide, Sulphadimidine).
- N-4 substituted sulphonamides (prodrugs, e.g. Prontosil).
- Both N-1 and N-4 substituted sulphonamides (e.g. Succinyl sulphathiazole, Phthalylsulphathiazole).
Specific Sulphonamides
- Sulphacetamide: used to treat bacterial infections of the urinary tract, exists as a white crystalline powder, bitter in taste.
- Sulphasalazine: used to treat ulcerative colitis, exists as a bright yellow or brownish-yellow fine powder.
- Sulphadiazine: used to treat canceroids and rheumatic fever, exists as a white or yellowish-white crystalline powder or crystals.
- Sulphadimidine: used to treat bacterial infections, exists as a white crystalline powder with a bitter taste.
- Sulphamerazine: used as an antibacterial agent, exists as a white or almost white crystalline powder.
- Trimethoprim: used as a dihydrofolate reductase inhibitor, effective against chloroquine and pyrimethamine-resistant strains of Plasmodium falsiparum.
Immunosuppressant Drugs
- Inhibitors of cytokine (IL-2) production or action:
- Calcineurin inhibitors (e.g. Cyclosporine, Tacrolimus).
- Sirolimus (rapamycin).
- Inhibitors of cytokine gene expression:
- Corticosteroids (e.g. Prednisone, Prednisolone, Methylprednisolone, Dexamethasone).
- Cytotoxic drugs:
- Inhibitors of purine or pyrimidine synthesis (antimetabolites, e.g. Myclophenolate Mofetil, Leflunomide, Azathioprine, Methotrexate).
- Alkylating agents (e.g. Cyclophosphamide).
- Immunosuppressive antibodies:
- Antilymphocyte globulins (ALG).
- Antithymocyte globulins (ATG).
- Rho (D) immunoglobulin.
- Muromonab-CD3.
- Basiliximab.
- Daclizumab.
Cyclosporine
- A fungal polypeptide composed of 11 amino acids.
- Mechanism of action: inhibits interleukin-2 production, decreases proliferation and differentiation of T cells.
- Pharmacokinetics: given orally or i.v., slowly and incompletely absorbed, peak levels reached after 1-4 hours, elimination half-life 24 hours.
- Therapeutic uses: organ transplantation, autoimmune disorders, graft-versus-host disease.
- Adverse effects: nephrotoxicity, hypertension, hyperkalemia, liver dysfunction, hyperglycemia, viral infections, lymphoma, hirsutism, neurotoxicity.
Tacrolimus (FK506)
- A macrolide antibiotic, chemically not related to cyclosporine.
- Mechanism of action: similar to cyclosporine, inhibits calcineurin.
- Kinetics: given orally or i.v., variable and incomplete absorption, half-life 9-12 hours.
- Uses: similar to cyclosporine, organ and stem cell transplantation, prevention of rejection of liver and kidney transplants.
- Toxic effects: nephrotoxicity, neurotoxicity, hyperglycemia, GIT disturbances, hypertension, anaphylaxis.
Sirolimus (Rapamycin)
- A macrolide antibiotic, not a calcineurin inhibitor.
- Mechanism of action: inhibits the response of T cells to IL-2, blocks activation of T- and B-cells.
- Pharmacokinetics: given orally, reduced by fat meal, extensively bound to plasma proteins, metabolized by CYP3A4, excreted in feces.
- Uses: synergistic action with cyclosporine, solid organ allografts, hematopoietic stem cell transplant recipients.
- Toxic effects: hyperlipidaemia, thrombocytopenia, leukopenia, hepatotoxicity, hypertension, GIT dysfunction.Here are the study notes for the text:
Glucocorticoids
- Lead to decreased eicosanoid production and cyclooxygenase expression
- Decrease production of inflammatory mediators, such as prostaglandins, leukotrienes, histamine, platelet-activating factor, and bradykinin
- Inhibit gene transcription of many inflammatory genes
- Suppress cell-mediated immunity, decreasing production of cytokines (IL-1, IL-2, interferon, TNF) and T lymphocyte proliferation
- Suppress humoral immunity, reducing both B cell clone expansion and antibody synthesis
Kinetics
- Can be administered orally, parenterally, topically, and by inhalation (for asthma)
- Dynamics include:
- Anti-inflammatory and immunosuppressive effects
- Suppression of response to infection
- Metabolic effects
Indications
- Solid organ allografts and hematopoietic stem cell transplantation
- Autoimmune diseases, such as refractory rheumatoid arthritis, systemic lupus erythematosus, and asthma
- Acute or chronic rejection of solid organ allografts
Adverse Effects
- Adrenal suppression
- Osteoporosis
- Hypercholesterolemia
- Hyperglycemia
- Hypertension
- Cataract
- Infection
Cytotoxic Drugs
- Antimetabolites:
- Leflunomide
- Azathioprine
- Mycophenolate mofetil
- Methotrexate
- Alkylating agents:
- Cyclophosphamide
Azathioprine
- Derivative of mercaptopurine
- Prodrug
- Inhibits de novo synthesis of purines required for lymphocyte proliferation
- Prevents clonal expansion of both B and T lymphocytes
- Pharmacokinetics:
- Orally or intravenously administered
- Widely distributed but does not cross the blood-brain barrier
- Metabolized in the liver to thiouric acid
- Excreted primarily in urine
- Drug interactions:
- Co-administration with allopurinol may lead to toxicity due to inhibition of xanthine oxidase
- Uses:
- Acute glomerulonephritis
- Systemic lupus erythematosus
- Rheumatoid arthritis
- Crohn's disease
- Autoimmune hemolytic anemia
- Adverse effects:
- Bone marrow depression
- Leukopenia
- Thrombocytopenia
- Gastrointestinal toxicity
- Hepatic dysfunction
- Increased risk of infections
Mycophenolate Mofetil
- Semisynthetic derivative of mycophenolic acid
- Prodrug
- Inhibits de novo synthesis of purines
- Inhibits inosine monophosphate dehydrogenase, crucial for purine synthesis
- Pharmacokinetics:
- Given orally, intravenously, or intramuscularly
- Rapidly and completely absorbed after oral administration
- Undergoes first-pass metabolism to give the active moiety, mycophenolic acid
- Extensively bound to plasma protein
- Metabolized in the liver by glucuronidation
- Excreted in urine as glucuronide conjugate
- Clinical uses:
- In solid organ transplantation
- In hematopoietic stem cell transplant patients
- In autoimmune disorders, such as rheumatoid arthritis and dermatologic disorders
- Adverse effects:
- Gastrointestinal toxicity
- Leukopenia
- Neutropenia
- Lymphoma
Leflunomide
- Antimetabolite immunosuppressant
- Inhibits pyrimidine synthesis
- Can be given orally
- Prodrug
- Active metabolite undergoes enterohepatic circulation
- Has a long duration of action
- Approved only for rheumatoid arthritis
- Adverse effects:
- Elevation of liver enzymes
- Renal impairment
- Teratogenicity
- Cardiovascular effects (tachycardia)
Methotrexate
- Folic acid antagonist
- Can be given orally or parenterally
- Excreted in urine
- Inhibits dihydrofolate reductase required for folic acid activation
- Inhibits DNA, RNA, and protein synthesis
- Interferes with T-cell replication
- Used in treatment of many neoplastic disorders, including acute lymphoblastic leukemia
- Used in autoimmune disorders, such as rheumatoid arthritis, psoriasis, and Crohn's disease
- Adverse effects:
- Pulmonary fibrosis
- Nausea, vomiting, diarrhea
- Alopecia
- Bone marrow depression
- Teratogenicity
Cyclophosphamide
- Alkylating agent
- Destroys proliferating lymphoid cells
- Anticancer agent in lymphomas
- Effective in autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus
- Adverse effects:
- Alopecia
- Hemorrhagic cystitis
- Bone marrow suppression
- Gastrointestinal disorders
- Sterility
Antibodies
- Used as a quick and potent immunosuppressive therapy to prevent acute rejection reactions
- Types:
- Polyclonal antibodies:
- Antilymphocyte globulins (ALG)
- Antithymocyte globulins (ATG)
- Monoclonal antibodies:
- Rho (D) immunoglobulin
- Basiliximab
- Daclizumab
- Polyclonal antibodies:
Antilymphocyte Globulins (ALG) and Antithymocyte Globulins (ATG)
- Obtained by immunizing either horses or rabbits with human lymphoid cells
- Produces mixtures of polyclonal antibodies directed against a number of lymphocyte antigens
- Bind to the surface of circulating T lymphocytes, which are phagocytosed in the liver and spleen, giving lymphopenia and impaired T-cell responses and cellular immunity
- Kinetics:
- Given intramuscularly or slowly infused intravenously
- Half-life extends from 3-9 days
- Uses:
- Combined with cyclosporine for bone marrow transplantation
- To treat acute allograft rejection
- Steroid-resistant rejection
- Adverse effects:
- Antigenicity
- Anaphylactic and serum sickness reactions
- Leukopenia
- Thrombocytopenia
- Risk of viral infection
Muromonab-CD3
- Murine monoclonal antibody
- Prepared by hybridoma technology
- Directed against the glycoprotein CD3 antigen of human T cells
- Given intravenously
- Metabolized and excreted in the bile
- Mechanism of action:
- Binds to CD3 proteins on T lymphocytes
- Leads to transient activation and cytokine release
- Followed by disruption of T-lymphocyte function
- Decreased immune response
- Block killing by cytotoxic T cells
- Uses:
- Used for treatment of acute renal allograft rejection
- Steroid-resistant acute allograft rejection
- To deplete T cells from bone marrow donor prior to transplantation
- Adverse effects:
- Anaphylactic reactions
- Fever
- CNS effects (seizures)
- Infection
- Cytokine release syndrome
Basiliximab and Daclizumab
- Obtained by replacing murine amino acid sequences with human ones
- Have less antigenicity and longer half-lives than murine antibodies
- Mechanism of action:
- Interleukin-2 receptor antagonists
- Bind to CD25 (α-subunit chain of IL-2 receptor on activated lymphocytes)
- Block IL-2-stimulated T-cell replication and T-cell response system
- Given intravenously
- Half-life: Basiliximab (7 days), Daclizumab (20 days)
- Uses:
- Given with CsA and corticosteroids for prophylaxis of acute organ rejection in renal transplantation
- Adverse effects:
- Gastrointestinal disorders
Interferons
- Families:
- Type I IFNs (IFN-α, β): induced by viral infections
- Type II IFN (IFN-γ): produced by activated T lymphocytes
- Interferon types and uses:
- IFN-α:
- Hepatitis B and C infections
- Treatment of cancer (malignant melanoma)
- IFN-β:
- Multiple sclerosis
- IFN-γ:
- Treatment of chronic granulomatous diseases
- IFN-α:
Diuretics
- Increase the rate of urine flow
- Also increase excretion of Na+ and an accompanying anion (negatively charged ion) like Cl–
- Reduce extracellular fluid volume (decrease in edema) by decreasing total body NaCl content
- Classes of diuretics:
- Carbonic anhydrase inhibitors
- Osmotic di
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Description
Learn about antimicrobials, antibiotics, and their modes of action in preventing infection and sepsis.