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331 Cards in this Set
- Front
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H1 histamine receptor
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vasodilation, bronchoconstriction, increased capillary leakage
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H1 antihistamines
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end in "ine"
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epinephrine
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life-saving drug in systemic anaphylaxis;
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first generation vs. second generation H1 antagonists
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first gen have strong sedative effects; second not as strong
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Ethanolamines
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Carbinoxamine, Dimenhydrinate, Diphenhydramine, Doxylamine
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Ethylaminediamines
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pyrilamine, tripelennamine
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Piperazine derivs
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hydroxyzine, cyclizine, meclizine
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Alkylamines
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brompheniramine, chlorpheniramine
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promethazine
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a phenothiazine H1 antagonist; also an anti-emetic
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cyproheptadine
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H1 antag that also induces appetite; antagonist of histamine and serotonin
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terfenadine
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a second generation drug that was with drawn b/c it caused lethal arrhythmias
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fexofenadine (Allegra)
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carboxylated version of terfenadine; a piperidine second gen H1 blocker
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other second generation H1 antagonists
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loratadine (Claritin), cetrizine (Zyrtec), desloratadine (Clarinex);
all OTC; can still cause sedation but not as much as first gen. certirizine is the most sedating |
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kinetics of second generation H1 antagonists
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oral admin; peak 1-2 hours; metabolized by liver; can have duration of about 12-24 hrs
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mechanism of second gen
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carboxyl group makes them less lipid soluble (more polar); does not cross BBB --- no CNS penetration
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mechanism of H1 blockers
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resemble muscarininc and alpha adrenergic receptor blockers; some also block serotonin receptors; do not really affect H2 receptors
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CNS effects of H1 blockers
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sedation, anti motion sickness;
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Diphenhydramine
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used for atopic dermatitis; sedative, antipruritic;
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treatment of allergic rhinitis and chronic urticaria
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second generation drugs
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clinical uses of H1 blockers
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immediate allergies (hay fever, rhinitis, urticaria);
anti-tussive agents prophylaxis of motion sickness and vestibular disturbance nausea and vomiting during pregnancy |
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motion-sickness treatment
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scopolamine, diphenhydramine, promethazine;
piperazines - cyclizine and meclizine, but these have marked sedation |
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trt of nausea and vomiting during pregnancy
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Piperazine derivs used to be used, but withdrawn b/c of teratogenic effects
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adverse effects of H1 blockers
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sedation and antimuscarinic effects (dry mouth, blurred vision); orthostatic hypotension;
some adverse interactions with first gen drugs and other sedatives (benzodiazepines, alcohol) |
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adverse effects of H1 blockers cont'd.
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concomittant admin with macrolide, ketoconazole, itraconazole prolongs QT interval; lethal arrhythmias; not seen in Loratadine and acrivastine
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reditabs
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antoher formulation of loratadine
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Ethanolamines
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significant antimuscarinic activity; marked sedation;
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Diphenhydramine
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treats cough, anti-emetic, treats vomiting, vertigo; can treat drug-induced extrapyramidal symptoms; mild cases of Parkinson's;
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diphenhydramine vs. other antihistamines
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greater anticholinergic effects; antidyskinetic action;
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other uses of diphenhydramine
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relief from insect bites, minor burns, sunburn, minor abrasions; anesthetic effect; tolerance with prolonged use
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administration of diphenhydramine
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oral, topical, IV, IM
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Promethazine
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a phenothiazine; anticholinergic, sedative, antemetic, local anesthetic; used in cough and cold products
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Azelastine
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nasal spray; treats allergic rhinitis, sneezing, nasal pruritus; for patients who don't respond to fexofenadine
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mechanism of azelastine
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inhibits H1 receptor and inhibits release of histamine from mast cells;
inhibits leukotrienes |
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loratadine
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most widely-used second gen.; not associated with prolonged QT or torsades de pointes
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mechanism of loratadine
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binds preferentially at H1 receptors in periphery than in brain; taken once daily
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effects of loratadine
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anticholinergic, adrenergic blocker, antispasmodic, local anesthetic
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Desloratadine
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active metabolite of loratadine; relieves symptons of allergic rhinitis, perennial rhinitis;, and chronic idiopathic urticaria
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fexofenadine
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active metabolite of terfenadine; similar to loratadine
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Cetirizine
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active metabolite of hydroxyzine, but has higher affinity for H1 receptor; only antihistamine approved for infants as young as 6 months;
higher incidence of somnolence than fexofenadine and loratadine |
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mechanism
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blocks receptor as well as prevents release of mast cell mediators; oral admin
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Cyproheptadine
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also serotonin antag; increases appetite; useful for Cushing's syndrome, vascular headache, anorexia, anorgasmy caused by SSRI's
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Anti-asthmatic agents
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beta agonists, corticosteroids, mediator release inhibitors, muscarinic antagonists, methyl xanthine, anti-leukotriene agents, omalizumab, cetirizine, roflumilast, soluble IL-4 receptor
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asthma
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syndrome characterized by increased responsiveness of tracheobronchial tree to variety of stimuli
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mechanisms
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relaxation of broncial tone with beta agonists, theophylline, muscarinic antagonists, andn leukotriene antagonists;
constriction of bronchial tone via acetyl choline, leukotrienes, and adenosine |
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beta-2 agonists
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sympathomimetics that cause relaxation and dilation of bronchial smooth muscle by activiting adenylyl cyclase
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beta-2 agonist vs. epinephrine
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both are sympathomimetics, but beta-2 agonist is preferred b/c it has local effects only, rather than all effects of EPI
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short-acting sympathomimetics
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albuterol, metaproterenol, terbutaline;
used for acute episodes of bronchospasm |
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long-acting sympathomimetics
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salmeterol, formoterol;
used in prophylaxis |
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terbutaline administration
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inhalant, oral, parenteral
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albuterol administration
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inhalant, oral, oral sustained release
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salmeterol and formeterol administration
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inhalants
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toxicity of beta agonists
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skeletal muscle tremor; some cardiac effects (positive ionotropic effect); tachycardia arrhythmia with excessive use
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toxicity of short-acting mimetics
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tolerance; responsiveness to drug can be restored by corticosteroids
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isoetharine
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similar to isoproterenol;
short-acting beta 2 agonist metabolized by COMT (catechol-O-methyl transferase) |
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metaproterenol and terbutaline
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not metabolized by COMT, so they are long-acting; can be administered orally
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albuterol
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similar to metaproterenol; not metabolized by COMT; most appopriate choice for acute asthma attacks
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salmeterol
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highly selective beta-2-agonist; long-term use; prevention of bronchospasm in adults with reversible COPD; should not be used for acute attacks
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salmeterol:fluticasone (Advair) combination
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combo of corticosteroid and beta agonist; inhalant; not suitable for acute attacks
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pirbuterol
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inhalant only
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bitolterol
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pro-drug; used for acute, chronic, and exercise-induced asthma; duration of action about 5-8 hrs
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Catecholamines (also sympathomimetics)
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epinephrine, isoproterenol
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mechanism of catecholamines
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EPI activates alpha and beta receptors;
alpha - relieves mucosal edema and congestion of upper airway; |
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EPI
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used for acute bronchospasm, resiratory manifestations of anaphylaxis, severe asthma exacerbation, and status asthmaticus
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isoproterenol
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non-selective beta agonist; adverse cardiac effects
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aerosol corticosteroids
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hydrocortisone, mometasone, flunisolide, triamcinolone, beclomethasone, fluticasone, budesonide, betamethasone, prednisolone
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mechanism of corticosteroids
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inhibit leukotrienes, prostaglandins, and thromboxanes, reduc bronchiole contraction, vascular permeability, and mucus secretion in airways
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prednisone vs. prednisolone
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prednisone is converted to predinsolone in the liver
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effects of corticosteroids on immune system
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reduce inflammatory and immune components of asthma, inhibit activity of mast cells, eosinophils, neutrophils, macrophages, lymphocytes
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adverse effects of corticosteroids
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inhalation of corticosteroids can cause changes in the oropharyngeal microflora, leading to infections such as oral candidiasis
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anticholinergic drugs
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similar effects as beta-adrenergic agonists; cholinergic and adrenergic are opposites
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ipratropium (Atrovent)
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oral-inhalational and nasal spray; only approved anticholinergic for bronchodilation; similar to atropine
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mechanism of ipratropium
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synthetic quaternary antimuscarinic agent; competitve antagonist of muscarinic cholinergic receptors;
decreases formation of cGMP, decreasing contractility of smooth muscle |
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adverse effects of ipratropium
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xerostomia; but not known to cause tremor or arrhythmias like the beta agonists do
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bronchoconstriction reflex
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mediated by vagus nerve;
stimuli: allergens, cold, emotions; impulse travels via vagus to initiate efferent action of vagal fibers to release ACh, causing constriction, mucus production, and degranulation of mast cells; also coughing |
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benefits of ipratropium over beta agonists
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beta agonists are more portent for reversing acute bronchospasm, but ipratropium is more potent and less toxic for patients with COPD, especially those with psychogenic exacerbations
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tiotropium (Handihaler)
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used for COPD, not asthma;
similar to ipratropium but administered only once daily (ipratropium must be taken up to 4 times per day) |
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mechanism of tiotropium
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acetylcholine antagonist (blocks M1, M2, and M3 receptors);
bronchodilation, bronchoprotection |
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administration of tiotropium
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dry powder via oral inhalation;
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methyl xanthines
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aminophylline, theophylline, dyphylline, oxtriphylline, pentoxifylline;
NOT THEOBROMINE OR CAFFEINE |
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effects of methyl xanthines
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relaxation of bronchial smooth muscle and pulmonary blood vessels; anti-inflammatory and immunomodulatory
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mechanism of methyl xanthines
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inhibition of type III and type IV phosphodiesterase, increasing cAMP, and causing relaxation; at clinical doses, however, inhibition is not great
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adensoine receptor mechanism of methyl xanthines
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binding to adenosine receptors, inactivating them;
A1 receptor stimulation causes inhibition of cAMP, while A2 stimulation causes increased cAMP; theophylline inhibitis both -- non-bronchodilatory effect of methylxanthines; questionable mechanism |
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physiological effects of methyl xanthines
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increased respiratory strength, endurance, and cetnral ventilatory drive; bronchodilation
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adverse CNS effects of methyl xanthines
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headache, anxiety, restlessness, insomnia, tremor, convulsions
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adverse GI effects of methyl xanthines
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nausea, diarrhea, vomiting, gastroesoph. reflux, anorexia, abdominal pain
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adverse cardiovascular effects of methyl xanthines
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large overdoses cause arrhtymias, palpitations, supraventricular tachycardia, ventricular arrhythmia, and hypotention
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adverse renal effects of methyl xanthines
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diuresis
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drug interactions that increase theophylline levels
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beta blockers, mexiletine, Ca channel blockers, quinolones, cimetidine, ranitidine, erythromycin, corticosteroids, ephedrine, flu virus vaccine and in liver failure, renal failure, CHF, and pneumonia
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drug interactions that decrease theophylline levels
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barbiturates, beta agonists, rifampin, phenytoin, cigarette smoking
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theophylline:aminophylline combo
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used for the trt of acute exacerbations of reversible airway obstruction including status asthmaticus for patietns who do not respond to first-line therapies and have not receive theophylline in the previous 24 hrs
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inhibitors of mast cell degranulation (mast cell stabilizers)
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cromolyn sodium, nedocromil; OTC
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cromolyn sodium
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synthetic compound; no bronchodilator activity, but inhibits antigen-induced bronchospasm; also used orally for inflammatory bowel disease, systemic mastocytosis, ulcerative colitis
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solutions of cromolyn sodium
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ophthalmic for allergic conjunctivitis; nasal for allergic rhinitis
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mechanism of cromolyn sodium
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inhibition of mast cell degranulation by inhibting the calcium influx caused by the IgE Ab-Ag complex; prevent release of histamine and slow-reacting substance of anaphylaxis; ineffective for trt of acute attack - extremely prophylactic
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nedocromil
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more potent than cromolyn sodium
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clinical use of cromolyn
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asthma in children; prophylactic against mild to moderate asthma as well as antigen and exercise-induced bronchoconstriction; reduce need for bronchodilators and severity of symptoms
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leukotriene antagonists, lipoxygenase inhibitors
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zileuton, zafirlukast, montelukast
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Zileuton
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oral; inhibits first enzyme in LOX pathway, preventing formation of leukotrienes and subsequent inflammatory response; reduces nasal congestion in allergic rhinitis; good for patients exposed to cold, dry air
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adverse symptoms of zileuton
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flu-like symptoms, headache; increases liver enzymes, therefore contraindicated in patients with liver disease and elevated transaminase
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zafirlukast
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leukotriene receptor antagonist; effective in controlling persistent asthma symptoms in adults and children over 5; can be used in combo iwth corticosteroids or beta agonists
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limitations of zafirlukast
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not used for management of acute exacerbations of bronchospasm
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mechanism of zafirlukast
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inhibits binding of leukotrienes D4 and E4; oral administration, can also be inhaled
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metabolism of zafirlukast
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done by cytochrome P450 CYP2C9; may inhibit activity of cytochrome isoenzymes CYP3A4 and CYP2C9
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montelukast (Singulair)
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available in chewable form for children; oral; does not inhibit the CYP3A4 and CYP2C9; approved for children as young as 12 months
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mechanism of montelukast
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selective antagonist of LTD4 at the receptor CysLT1; metabolized by liver, but does not inhibit cytochrome P450 isoenzymes
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Omalizumab (Xolair)
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very expensive!
monoclonal antibody (ends in "ab") against IgE, first biologic therapy for the use of trt of asthma |
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mechanism of omalizumab
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prevents binding of IgE to the Fc receptor
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administration of omalizumab
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approved for patients 12 and over; subcutaneous injection;
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action of omalizumab in early phase of allergic response
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prevents binding of IgE to mast cells, inhibiting degranulation of mast cells
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action of omalizumab in late phase of allergic response
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binds to IgE and prevents it from bidning its Fc receptor on monocytes, eosinophils, dendritic cells, and platelets
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soluble IL-4 receptor
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investigational; this receptor is a cytokine antagonist that inhibits IL-4, which normally stimulates production of IgE
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Roflumilast
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investigational; trt of COPD and asthma by inhibiting PDE4 to maintain higher levels of cAMP, allowing bronchodilation
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Antimicrobials
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penicillins, cephalosporins, other cell wall synthesis inhibitors, cell wall disrupting agents
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beta lactams
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penicillins, cephalosporins, carbapenems, monobactams
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other cell wall synthesis inhibitors
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vancomycin, bacitracin, cycloserine, polymyxins, fosfomycin
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beta-lactamase inhibitors
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clavulanic acid, sulbactam, tazobactam
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cephalosporins
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beta lactams that have a 6-membered ring rather than the 4-membered ring of other beta lactams
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Penicillins
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three classes: natural (penicillin G), antistaphylococcal, and extended spectrum
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mechanism of penicillins
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inhibit cross-linking step in synthesis of bacterial cell wall; bactericidal; do not act on mycobacteria, fungi protozoa, or viruses b/c these orgnaisms lack a peptidoglycan cell wall
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mechanism of penicillins cont'd.
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bind to penicillin-binding proteins, which are enzymes involved in cell wall synth; this blocks cross-linking;
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action of penicillin on gram-positive vs. gram-negative bacteria
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penicillins get thru the cell wall easily in gram-pos bacteria, but porins are necessary for entry into the gram-negative bacteria
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penicillin G (benzylpenicillin)
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natural penicillin; used for trt of gram pos cocci, bacilli, gram neg cocci, and spirochetes as well as oral anaerobes;
susceptible to beta lactamase, unstable at acidic pH (of gastric env) |
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uses of penicillin G
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trt of gas gangrene due to clostridium; dphtheria, anthrax, actinomycosis, listeria; also highly active against Treponema pallidum
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use of penicillin G to treat enterococci
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requires aminoglycoside;
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procain penicillin G, and benzathine penicillin G
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repository form of penicillin that has duration of action 12-24 hrs; used for beta hemolytic streptococcal infection
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Penicillin V
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more stable in acidic environment than penicillin G; oral; poor bioavailability so only useful for minor infections; narrow spectrum; high minimal lethal concentration, not good choice for bacteremia
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characteristics of both penicillin G and V
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should be administered at least 1 hr before meals or 2-3 hrs after; probenecid prolongs duration of penicillin in body; 99% of drug eliminited by the kidney
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prophylactic uses of penicillins
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streptococcal infections, recurrence of rheumatic fever, gonorrheal ophthalmia in neonates, surgical procedures in patients with valvular disease, dental extractions, tonsillectomy, intestinal and genitourinary operations
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antistaphylococcal penicillins (gram-positive cocci)
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also anti-strep; these drugs are resistant to strep and staph beta lactamases; inactive against enterococci, anaerobic bacteria, gram-neg cocci and rods;
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examples of antistaph and strep penicillins
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methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin
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methicillin
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nephrotoxic; rarely used; poor oral absorption
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oxacillin
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oral; 8 times as potent as methicillin; given IV for serious systemic staphylococcal infections
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nafcillin
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any route of administration; can casue neutropenia; given IV for serious systemic staphylococcal infection
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dicloxacillin
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highly resistant to penicillinase (beta lactamase); very effective via oral admin
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extended spectrum penicillins
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effective against gram-negative bacteria; ampicillin and amoxicillin; carbenicillin, ticarcillin, piperacillin, azlocillin, mezlocillin (these are antipseudomonal penicillins)
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ampicillin
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drug of choice for aerobic and facultative anaerobic gram positive bacilli Listeria;
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amoxicillin
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given orally only; used prophylactically for patients with abnormal heart valves undergoing oral surgery; acid stable; not resistant to penicillinase; used along with beta lactamase inhibitors to prevent hydrolysis of amox.;
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ampicillin and amoxicillin combos with beta lactamase inhibitors
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Augmentin - amox-clavulanic acid;
Unasyn - ampicillin-sublactam, used for trt of intra-abdominal and gynecological infections; Zosyn - piperacillin-tazobactam |
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carbenicillin and ticarcillin
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similar to ampicillin; effective against indole-positive Proteus and Pseudomonas
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ureido-penicillins
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azlocillin, mezlocillin, piperacillin; effective against Klebsiella pneumoniae, a facultative gram-neg rod
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piperacillin
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most potent ureido-penicillin; can cause platelet dysfunction
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kinetics of all penicillins
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cross placental barrier, but no teratogenic effects; penetration of CSF occurs only with inflammation
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adverse effects of penicillins
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hypersensitivity, skin rashes, Steven-Johnson syndrome; highest incidence with ampicillin; diarrhea, interstitial nephritis, neurotoxicity, seizures, platelet dysfunction; fever; anaphylaxis
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cephalosporins
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have 6-membered sulfur containing ring adjoining the beta lactam ring, making them highly resistant to pellicinase
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cephalosporinase
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a beta lactamase expressed by some bacteria; most cephalosporins are resistant to it
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organisms not susceptible to cephalosporins
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methicillin-resistant Staph aureus, Listeria monocytogenes, Clostridium difficile, Enterococci
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kinetics of cephalosporins
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administered parenterally and orally; most do not penetrate CNS; most excreted in urine; excretion blocked by probenecid; all are active against gram-pos cocci and many gram-pos bacilli
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applications of cephalosporins
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S. aureus infections of the skin, osteomyelitis, endocarditis; drug of choice in Klebsiella pneumoniae and Pneumonococcal pneumoniae caused by S. pyogenes
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parenteral cephalosporins
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used for Gonococcal disease, respiratory and urinary gram-neg bacterial infections
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prophylactic use of cephalosporins
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used in perioperative infections
|
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first generation cephalosporins
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cefazolin, cefadroxil, cephalexin, cephradine, cephalothin, cephapirin;
substitutes for penicillin G |
|
PEcK drugs
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first gen cephalosporins - active against Proteus, E.coli, and Klebsiella
|
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specifics about PEcK drugs
|
not active against enterococci or pseudomonas aeruginosa; excretion via kidneys;
|
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cefazolin
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drug of choice in surgical prophylaxis; only first gen cephalosporin used parenterally; alternative to anti-Staph. penicillins and in patients allergic to penicillin
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Second generation cephalosporins
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Cefaclor, cefamandole, cefmetazole, cefprozil, cefoxitin, cefonicid, cefotetan, cefuroxime, loracarbef;
active against more gram-neg organisms than first gen |
|
HENPEck drugs
|
second gen cephalosporins; active against: Haemophilus influenzae, Enterobacter aerogenes, Neisseria, and PEcK
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specifics about second gen cephalosporins
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not recommended against enterobacter; not active against enterococci or pseudomonas aeruginosa
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Cefaclor
|
second gen cephalosporin that is highly susceptible to beta-lactamase; use has diminished
|
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third generation cephalosporins
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broad-spectrum drugs; expanded gram-neg coverage; some can cross BBB (therefore can treat meningitis);
includes: cefdinir, cefixime, cefoperazone, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, ceftibuten, cefditoren, cefpodoxime |
|
first-line drugs for N. gonorrhoeae
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ceftriaxone and cefixime (3rd gen)
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cephalosporins active against P. aeruginosa
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ceftazidime and cefoperazone (3rd gen)
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cephalosporins against Bacteroides fragilis (gram neg anaerobic rod)
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ceftizoxime, moxalactam (3rd gen)
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cephalosporins excreted through biliary tract (not kidney)
|
cefoperazone and ceftriaxone (3rd gen)
|
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trt of meningitis
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3rd gen cephalosporins; meningitis caused by highly penicillin-resistant strains of pneumococci may not respond; rifampin or vancomycin may be necessary
|
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third gen vs. first gen cephalosporins
|
for gram-pos cocci, first gen is better; for gram-neg bacilli, 3rd gen is better
|
|
fourth generation cephalosporins
|
cefepime and cefpirome (cefpirome not in US)
|
|
cefepime
|
more resistance to hydrolysis by the chromosomal beta-lactamase of Enterobacter than are 3rd gen drugs; active against P. aeruginosa, Enterobacteriaceae, S. aureus, S. pneumoniae, Hemophilus, Neisseria
|
|
oral cephalosporins
|
first gen - cefadroxil, cephalexin, cephradine;
second gen - cefaclor, cefprozil, cefuroxime; third gen - cefdinir, cefixime, cefpodoxime, ceftibuten |
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adverse effects of cephalosporins
|
disulfiram-like symptoms with those that contain MTTZ (not 3rd gen), superinfection, renal damage, local tissue reactions, bleeding due to vit K effects
|
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carbapenems
|
synthetic beta lactams; imipenem, meropenem
|
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imipenem
|
metabolized to potentially nephrotoxic compounds in renal tubules by dehydropeptidase; cilastatin inhibits this enzyme and is therefore compounded with imipenem
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imipenem/cilastatin
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broaest spectrum of all beta lactams; cannot be used against methicillin-resistant bacteria
|
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meropenem
|
slightly greater activity than imipenem agaisnt gram-neg aerobes, less activity against gram-pos.
|
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adverse effects of carbapenems
|
leads to seizures when there are excessive levels in patients with renal impairment
|
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monobactams
|
aztreonam - free beta lactam ring; specific for enterobacteria; active against gram-neg rods (Pseudomonas, Serratia marcescens); not active against gram-pos coci and anaerobic bacteria
|
|
administration of monobactams
|
IV or IM (100% bioavailability with IM)
|
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aztreonam
|
monobactam; low allergic reactions - penicillin alternative for gram-neg infections; can be substituted for aminoglycosides (beta lactamase inhibitors) to trt UTI and RTI;
also treats osteomyelitis, gonorrhea, gynecologic and intra-abdominal infections |
|
vancomycin
|
oral and parenteral; used as reserve, or rescue, drug;
useful against methicillin-resistant staph infections; used to trt sepsis, endocarditis |
|
oral admin of vancomycin
|
to treat pseudomembranous colitis caused by Clostridium difficile
|
|
restrictions for vancomycin
|
used to treat only serious infections by beta-lactam resistant gram-pos. bacteria
|
|
action of vancomycin
|
inhibits cell wall phospholipid synth and peptidoglycan polymerization
|
|
vancomycin + aminoglycosides
|
for enterococcal infections
|
|
adverse effects of vancomycin
|
ototoxicity, nephrotoxicity -- risk of these increased when used with aminoglycosides;
"red man" or "red neck" syndrome -- due to release of histamine |
|
fosfomycin
|
inhibits early stage of cell wall synthesis; analogue of PEP; single-dose, oral; trts UTI in women who are pregnant
|
|
bacitracin
|
nephrotoxic if administered systemically; proteinuria, hematuria, nitrogen retention; used only topically! - local effects only; usually combined with polymyxin and neomycin
|
|
polymyxin B and polymyxin E
|
active against gram-neg bacteria - restricted to trting these infections; only polymyxin B in US
|
|
action of polymyxins
|
detergent action; they are amphipathic and interact with phospholipids to disrupt cell membrane
|
|
resistance to polymyxins
|
proteus and neisseria
|
|
toxicity of polymyxins
|
nephrotoxicity and neurotoxicity, therefore not used for systemic admin
|
|
use of polymyxins
|
treatment of corneal ulcers, external otitis
|
|
cycloserine
|
only cell wall synthesis inhibitor that can treat tuberculosis; adverse effects: CNS toxicity, headache, tremors, psychosis, convulsions
|
|
Protein synthesis inhibitors
|
tetracyclines, macrolides and ketolides, aminoglycosides, spectinomycin, chloramphenicol, clindamycin
|
|
tetracyclines
|
end in "cycline"; 4 fused 6-membered rings; isolated from Streptomyces; synthetic derivs: methacycline, doxycycline, minocycline
|
|
activity of tetracyclines
|
wide range; little activity against fungi; bacteriostatic; useful against chancroid (H. ducreyi), Legionella pneumophilia, H. pylori, Y. pestis and Francisell tularensis; effective against Rickettsiae and anearobic organisms
|
|
tetracycline againest spirochetes
|
Borrelia (Lyme disease), T. pallidum (syphilis), Chlamydia, mycoplasma
|
|
effect of tetracycline on intestinal flora
|
occasionally produces colitis by toxin from C. difficile
|
|
mechanism of tetracycline
|
bind 30S ribosome so that protein synth does not occur in bacteria
|
|
kinetics of tetracycline
|
minocycline - absorbed well, enters brain in absence of inflammation therefore useful for eradication of meningococcal carrier-state; absorption of tetracyclines is inhibited by divalent and trivalent ions (Mg2+, Ca2+, Al3+) -- cannot be taken with milk
|
|
short-acting tetracyclines
|
chlortetracycline, oxytetracycline, tetracycline
|
|
intermediate-acting
|
demeclocycline, metachycline
|
|
long-acting
|
doxycycline, minocycline
|
|
resistance to tetracyclines
|
Vibrio cholera, gonococci
|
|
clinical uses of tetracyclines
|
drugs of choice for Mycoplasma pneumoniae, Chlamydiae, Rickettsiae, Spirochetes, H. pylori, protozoal infection, brucella infections
|
|
demeclocycline
|
inhibits action of ADH in renal tubule; useful for trt of inappropriate secretion of ADH
|
|
adverse effects of tetracycline
|
brown coloration of fetal teeth if mother takes it; photosensitization with demeclocycline and doxycycline
|
|
Macrolides and Ketolides
|
Erythromycin, Clarithromycin, Azithromycin, Dirithromycin
|
|
mechanism of macrolides and ketolides
|
bind 50S ribosome; aminoacyl translocation is blocked; cells are more permeable to the non-ionized form of the drug, so the drugs have increased activity at alkaline pH
|
|
erythromycin
|
bacteriostatic normally, but bacteriocidal at high conc; not useful for atypical infections; useful to patients who are resistant to penicillin and have Staph. aureus infection; not active against aerobic enteric gram-neg bacilli
|
|
Clarithromycin
|
more potent against strains of Staph and Strep that are resistant to erythromycin; active against M. catarrhalis (flora of upper resp tract), Chlamydia, Borrelia, M. pneumoniae
|
|
Azithromycin
|
less active than erythro against gram-pos (Strep and Enterococci); more active against H. influenzae and Campylobacter
|
|
activity against Mycobacterium avium
|
clarithromycin and azithromycin --- good for atypical infections
|
|
resistance to macrolides
|
gram-negative rods: esterases
gram-positive bacteria: methylase |
|
kinetics of macrolides
|
sensitive to acid env; erythromycin is esterified to improve stability; azithromycin - extensive tissue distribution and high conc in cells; other
|
|
clinical uses of azithromycin
|
trt of Chlamydia during pregnancy; single does; atypical mycobacterial infections in AIDS patients (also clarithromycin)
|
|
aminoglycosides
|
amikacin, gentamycin, neomycin, netilmicin, streptomycin, tobramycin, kanamycin, paromomycin
|
|
use of aminoglycosides
|
trt infections caused by aerobic gram-neg bacteria; bactericidal; ototoxicity and nephrotoxicity are major limitations
|
|
mechanism of aminoglycocides
|
transported across bacterial membrane in energy-dependent phase I that can be blocked by anaerobic conditions; in an anaerobic atmosphere, these drugs are less effective;
bind to polysomes and act on 30S subunit to block the formation of translation initiation complex, cause misreading of the mRNA, and disrupt polysomes; |
|
Kanamycin
|
should not be used against p. aeruginosa and Serratia
|
|
Gentamycin, Kanamycin, Tobramycin, Netilmycin, Amikacin
|
limited action against gram-positive; Strep. pneumoniae and Strep. pyogenes are highly resistant; genta and tobra active against most strains of staph aureus and staph epidermidis
|
|
ototoxicity with aminoglycosides
|
ototoxicity - can occur in children if used during pregnancy; increased by loop diuretics; most vestibular toxic are gentamycin and streptomycin;
|
|
nephrotoxicity with aminoglycosides
|
mostly by neomycin, tobramycin, and gentamycin; potentiated by amphotericin B, vancomycin, cephalothin, cisplatin and cyclosporine, loop diuretics
|
|
neuromuscular effects of aminoglycosides
|
respiratory paralysis - rare; mostly with neomycin
|
|
Spectinomycin
|
trt for gonorrhea in patients who are allergic to penicillin or gonococci are resistant to other medications; IM (painful)
|
|
Chloramphenicol
|
useful for meningococcal infection b/c it crosses BBB; binds 50S ribosome, inhibits transpeptidation (transfer of peptide to its amino acid acceptor)
|
|
action of chloramphenicol
|
broad spectrum; bacteriostatic; active against aerobic and anaerobic gram-pos and gram-neg.; alternative to beta lactams for meningitis
|
|
clinical uses of chloramphenicol
|
toxic, therefore not used systemically; back-up for severe salmonella infections, meningitis, rickettsia; commonly used topically
|
|
toxicity of chloramphenicol
|
inhibition of red cell maturation; Gray baby syndrome (lack of glucuronosyl transferase to eliminate drug); cyanosis, cardiovascular collapse with accumulation of drug
|
|
drug interactions with chloramphenicol
|
inhibits metabolism of phenytoin, coumarin, and tolbutamide
|
|
Clindamycin
|
a lincosamide; mechanism similar to macrolides, even though they are not chemically related
|
|
clinical uses of clindamycin
|
effective against gram-pos aerobe, as well as gram-pos and gram-neg anaerobes; used to trt infections caused by strains taht are resistant to less toxic antimicrobials; trt of sever infections of Bacteroides; prophylaxis of endocarditis in patients with valvular disease
|
|
clinical uses of clindamycin, cont'd
|
useful against P. carinii and T. gondii; prophylactic for endocarditis as a result of bacteremia due to dental procedures
|
|
adverse effects of clindamycin
|
GI irritation, rashes, hepatic dysfunction, superinfection b/c the drug eliminates intestinal microflora
|
|
drugs that cause inhibition of DNA synthesis
|
folate synthesis inhibitors, folate reduction inhibitors, quinolones
|
|
folate synthesis inhibitors
|
sulfonamides - "sulfa"
|
|
folate reduction inhibitors
|
pyrimethamine, trimethoprim, proguanil
|
|
folate synthesis and redcution inhibitors
|
Trimethoprim-Sulfamethoxazole (Co-trimoxazole); Pyrimethamine-Sulfadoxine
|
|
Sulfonamides
|
insoluble in water; wide range, treat gram-pos and gram-neg; many bacteria develop resistance;
|
|
mechanism of sulfonamides
|
antimetabolite; analogues of PABA and therefore prevent normal utilization of PABA by bacteria to synthesize folic acid
|
|
synergists of sulfonamide
|
trimethoprim (inhibitor of dihydrofolate reductase); combo of these 2 causes sequential block of folate synthesis and bactericidal action
|
|
resistance to sulfonamides
|
plasmid-mediated mutation, random mutation, increased capacity to inactivate drug, alternate pathways of folic acid synthesis, increased production of PABA, decreased uptake of drug due to reduction in permeabiity
|
|
short-acting sulfonamides
|
sulfisoxazole and sulfamethizole
|
|
intermediate acting sulfonamides
|
sulfamethoxazole, sulfadiazine
|
|
sulfisoxazole
|
rapidly absorbed and excreted; low renal toxicity, low incidence of crystalluria
|
|
sulfonamides for UTI antiseptic and analgesic
|
sulfisoxazole-phenazopyridine (orange-red urine);
sulfamethoxazole-phenazopyridine |
|
sulfonamides for trt of otitis media
|
sulfisoxazole acetyl + erythromycin
|
|
sulfamethoxazole
|
longer half-life than sulfisoxazole; crystalluria more common b/c drug is insoluble; used with trimethoprim as co-trimoxazole
|
|
sulfadiazine
|
crosses CSF
|
|
sulfasalazine
|
poorly absorbed; used for ulcerative colitis (preferred over corticosteroids), regional enteritis, but relapse is common; also used for granulomatous colitis
|
|
topical sulfonamides
|
sulfacetamide, silver sulfadiazine, combo of sulfabenzamide, sulfacetamide, and sulfathiazole;
mafenide; sulfadoxine |
|
sulfacetamide
|
used for opthlamic infections
|
|
silver sulfadiazine
|
prevention of infection in burns
|
|
triple combo (sulfabenzamide, sulfacetamide, sulfathiazole)
|
bacterial vaginosis caused by Hemophilus (Gardnerella) vaginalis
|
|
Mafenide
|
prevention of iinfection in burns; adverse: candida superinfection, intense pain, allergic rxn
|
|
sulfadoxine
|
long-acting; trt of plasmodium falciparum; used in combo with pyrimethamine
|
|
Oral trimethoprim
|
folate reduction inhibitor; used in acute uncomplicated UTI
|
|
oral trimethoprim-sulfamethoxazole
|
prevents folate synthesis and reduction; effective in P. carinii pneumonia, Shigellosis, Salmonella, UTI, ear infection, prostatitis, respiratory pathogens, Klebsiella; alternative to beta lactams for URI and community-acquired pneumonia; also used for methicillin-resistant Staph
|
|
IV trimethoprim-sulfamethoxazole
|
P. carinii in AIDS patients; gram-neg sepsis, shigellosis, typhoid fever, UTI
|
|
oral pyrimethamine-sulfadoxine
|
trt of Leishmaniasis (parasitic protozoa), toxoplasmosis (also protozoa); falciparum malaria (esp for Mefloquine-resistant strains); adverse: Steven-Johnson syndrome, so only used prophylactically in high-risk cases
|
|
Proguanil
|
folate reductase inhibitor; active metabolite: cycloguanil; used in combo with atovaquone to prevent and trt malaria
|
|
adverse rxns of sulfonamides and folate inhibitors
|
hemolytic anemia; Steven-Johnson
|
|
Quinolones
|
fluoroquinolones ("oxacin"); quinolones: Nalidixic acid and Cinoxacin
|
|
UTI antiseptics
|
methenamine, nitrofurantoin
|
|
mechanism of quinolones
|
acts on A subunit of DNA gyrase (topoisomerase II in euk), which prevents its strand-cutting function, inhibiting supercoiling; also inhibit topoisomerase IV; bactericidal
|
|
kinetics of quinolones
|
do not penetrate CNS, but good oral bioavailability to other tissues; renal elimination for ofloxacin, lomefloxacin, cinoxacin
|
|
non-renally eliminated quinolones
|
pefloxacin and nalidixic acid
|
|
pefloxacin
|
should not be used in patients with hepatic failure
|
|
antimicrobial spectrum for quinolones
|
E. coli, Salmonella, Shigella, Enterobacter, campylobacter, Neisseria --- see page C50
|
|
fluoroquinoloens for UTI
|
norfloxacin (approved in US for UTI ONLY); ciprofloxacin, ofloxacin, TMP-SMX (folate inhib)
|
|
fluoroquin for prostatitis
|
norfloxacin, cipro, ofloxacin; effective when TMP-SMX is not
|
|
fluoroquin for STD's
|
not active against T. pallidum; CI = pregnancy;
Chlamydia urethritis - ofloxacin; Gonorrhea - ofloxacin, cipro (single dose); Chancroid (due to H. ducreyi) - 3 days of cipro |
|
fluoroquinolones for GI and abdominal infections
|
traveler's diarrhea, Shigellosis - norfloxacin, cipro, ofloxacin;
cholera - norfloxacin; S. typhi enteric fever - cipro and ofloxacin |
|
fluoroquinolones for Respiratory tract infections
|
poor activity against strep pneumoniase and anaerobic bacteria -- beta lactams better;
Sparfloxacin (new) can act against these; good activity against H. influenzae, C. pneumoniae, legionella pneumophilia; useful for trt of P. aeruginosa and patients with CF |
|
fluoroquinolones for bone joint and soft tissue infections
|
cipro - shouldnt be given to children or pregnant women; also trts diabetic foot ulcers
|
|
treatment of TB (also M. avium complex in AIDS patients)
|
multi-drug regimen; Cipro + clarithromycin and amikacin, or with rifampin, ethambutol and clofazimine for MAC in HIV patients)
|
|
neutropenic cancer trt
|
quinolones prophylactically decrease gram-neg bacteremia
|
|
toxicity of fluoroquinolones
|
not recommended for young or pregnant patients due to cartilage erosion; tendonitis, joint swelling;
Sparfloxacin - arrhythmia, photosensitivity |
|
drugs used for trt of tuberculosis (antimycobacterial)
|
first-line: isoniazid, rifampin, ethambutol. pyrazinamide, streptomycin;
second-line: amikacin, cipro, ethionamide, p-aminosalicylic acid, capreomycin, cycloserine, viomycin, PAS, thiacetazone, kanamycine, clofazimine, clarithromycin, rifabutin, rifapentine, quinolones |
|
mycobacteria
|
aerobic bacilli, acid-fast (not gram-pos or gram-neg); mycolic acid
|
|
isoniazid
|
BEST; inhibits synth of enzymes needed for synth of mycolic acid; bacteriostatic; used in most drug regimes and in prophylaxis of skin test converters;
|
|
admin of isoniazid and its adverse effects
|
oral, IM;
hepatotoxicity, neurotoxicity; alleviated by pyridoxine; anemia, lupus-like syndrome, liver enzymes monitored in high-risk patients |
|
rifampin
|
second-most imp; bactericidal; blocks RNA synth by binding DNA-dep. RNA polymerase; used for TB and leprosy; prophylactic for INH-intolerant patients
|
|
kinetics
|
oral; goes to CNS; turns urin, sputum and saliva red-orange; eliminated in orange feces; adverse: GI upset; hepatits in alcoholics and elderly; proteinuria, impaired antibody response; CANNOT BE USED WITH PROTEASE INHIBITORS IN HIV PATIENTS
|
|
rifabutin
|
semisynthetic; active agianst some of the rifampin-resistant strains; active against MAI and non-tubuerculous mycobacteria
|
|
Ethambutol
|
bacteriostatic; unknown mechanism; oral, CNS; used for TB in combo regimen; adverse: Green blindness, retinal damage, peripheral neuritis, confusion
|
|
pyrazinamide
|
deriv of nicotinic acid; bactericidal; converted to active drug by the M. tuberculosis; similar to isoniazid, but specific for TB
|
|
streptomycin
|
used in combo trt for tuberculosis meningitis and organ tuberculosis; an aminoglycoside
|
|
Leprsy (Hansen's disease)
|
sulfones - dapsone, acedapsone;
clofazimine - binds DNA, skin discoloration |
|
Dapsone
|
inhibition of folic acid synth; eliminated in urine; alternative drug for P. carnii in AIDS patients;
adverse: GI, fever, rash, methemoglobinia; hemolysis in G6PDH deficiency |
|
acedapsone
|
repository form of dapsone
|
|
atypical mycobacterial infections
|
MAC, MAI, M. ulcerans, M. marinum, M. abscessus, M. haemophilum, M. xenopi
|
|
drugs for atypical myobacterial infections
|
antimycobacterials: ethambutol, rifampin, rifabutin;
other antibiotics: erythromycin, amikacin, azithromycin, clarithromycin, cipro |
|
opportunistic mycoses
|
fungal infections in patients who are immune-comproised
|
|
endemic mycoses
|
distributed evenly throughout world
|
|
amphotericin B
|
antifungal; amphipathic; interacts with ergosterol in fungal membrane to make it leaky to Na, K, H;
used for severe fungal infections; IV for fungal meningitis and systemic infections; bladder irrigation for Candida cystitis; cream for superficial Candida; |
|
adverse effects of amphotericin B
|
flushing, chills, fever, headache, anemia, whistling respiration, decreased renal function, azotemia (urea in blood); lipid formulations bind to mammalian membranes less readily -- reduce renal impairment caused by this drug, but costly
|
|
flucytosine
|
antifungal; converted to 5-fluorouracil and inhibits thymidylate synthase; fungistatic; used for systemic candidiasis, cryptococcal infection, combo with amphotericin B for cryptococcal meningitis; adverse: bone marrow suppression, GI effects
|
|
imidazoles and triazoles
|
antifungals; triazoles have less effect on human sterol synth and are more slowly metabolized than imid; inhibits 14-alpha demethylase necessary for synth of ergosterol; drugs end in "azole
|
|
clotrimazole
|
topical, oral trouche (lozenge) for oropharyngeal candidiasis (used often in AIDS pt)
|
|
miconazole (Monistat)
|
topical and parenteral; cutaneous candidiases and vulvovaginitis due to C. albicans; also oral candidiasis
|
|
itraconazole
|
oral and parenteral; suppressive therapy of histoplasmosis in HIV pts; similar to ketoconazole
|
|
fluconazole (Diflucan)
|
effective for immunocompromised pt; more specificity than ketoconazole; primary trt of cryptococcal meningitis in AIDS pt; trt of mucosal candidiases (orophar, esoph)
|
|
Ketoconozaole
|
only antifungal that is routinely used systemically; first antifungal agent avail for deep sytemic mycoses; drugs that increase gastric pH reduce absorpiton of ketoconazole; effective for deep-seated candidiasis; oral and pharyngeal cand. in AIDS pt.
|
|
tioconazole, terconazole, butoconazole
|
vaginal ointment, vaginal suppository, and vaginal cream, resp.
|
|
adverse effects of ketoconazole
|
prolongs QT interval, causing ventricular tachycardia, torsade de pointes, not recommended for pregnant or nursing women b/c of endocrinological abnormalities due to inhibition of steroid biosynth.
|
|
nystatin
|
similar to amphotericin B; topical, but foul taste; toxic parenterally; used for Candida infections of mucosa, skin, intestine, vagina
|
|
Griseofulvin
|
antifungal; fungistatic; disrupts mitotic spindle formation; binds keratin; systemic for diseases of skin, hair, nails;
|
|
ciclopirox
|
antifungal; cream and lotion, acts on cell membrane
|
|
tolnaftate and butenafine
|
for dermatophyte infections; topical
|
|
naftifine and terbinafine
|
inhibit squalene epoxidase
|
|
DNA viruses
|
enter host nucleus, transcribe viral DNA to mRNA using host RNA pol; makes viral proteins;
exception: poxvirus has its on RNA pol |
|
RNA viruses
|
host cell is usually not involved in RNA replication; rubella, rhabdoviruses, picornavirus, arenavirus, arbovirus, orthomyxovirus, paramyxoviruses, retrovirus
|
|
antiviral agents
|
inhibit replication of virus; do not usually eliminate non-replicating or latent viruses; must undergo phosphorylation to be effective
|
|
classes of antivirals
|
Anti-herpetic, anti-CMV agents; influenza A agents; RSV agents; Anti-retroviral - NRTI's, NNRTI's, protease inhibitors, fusion inhibitors
|
|
HSV 1 and HSV 2
|
HSV 1: disease of mouth, face, skin, esophagus, brain;
HSV 2: genitals, rectum, skin, hands, meninges |
|
Acyclovir
|
anti-herpetic;
guanine analogue; inhibits vDNA pol; trts HSV I and 2, varicella zoster, CMV (prophylaxis in transplant pt); topical, oral, IV |
|
idoxuridine and trifluridine
|
ant-herpetic;
inhibits DNA synth; topical trt of HSV I keratitis (trifluridine is more potent); ocular epithelial HSV and trifluridine for primary keratoconjunctivitis |
|
adverse effects of idoxuridine ad trifluridine
|
parenteral admin causes marrow death; pain, pruritis, edema of eyelids, inflammation
|
|
vidarabine
|
anti-herpetic;
adenosine analog; inhibits DNA pol; HSV encephalitis, neonatal herpes, herpes zoster, varicella zoster, HSV keratitis; less allergenic than idoxuridine; teratogenic |
|
ganciclovir
|
anti-herpetic;
inhibits DNA pol; must be phosphorylated; chronic suppression CMV retinitis in immunocomp pt. and acyclovir-resistant HSV; CMV prophylaxis in transplant pt; adverse: leukopenia, thrombocytopenia, CNS side effects |
|
Foscarnet
|
anti-herpetic; PHOSPHATE analogue (not base analogue); inhibits vRNA pol, DNA pol, HIV RT; admin IV for CMV retinitis in immunocomp pt; herpes in AIDS pt and HSV resistant to acyclovir and ganciclovir; adverse: nephrotoxicity, electrolyte disturbance
|
|
ribavirin
|
purine nucleoside analogue; must be phosphorylated; trt of influenza A and B, RSV (bronchitis, pneumonia); aerosol form approved for RSV bronchiolitis and pneumonia in hospitalized children;
IV for immune suppresed pt. and Lassa fever; adverse: myelosuppression, conjunctival irritation with aerosol |
|
cidofovir
|
anti-herpetic; HSV 1 and 2, CMV; phosphorylation not necessary
|
|
fomivirsen
|
inhibits CMV through antisense mechanism that inhibits protein synth; IV for CMV retinitis in AIDS pt
|
|
NRTI's
|
nucleoside reverse transcriptase inhibitors; anti-retroviral;
azidothymidine, zidovudine - thymine analogues; also Didanosine, Zalcitabine, Lamivudine, Stavudine; pg C77 |
|
abacavir
|
guanine analogue, NRTI; HIV
|
|
NNRTI's
|
nevirapine, delavirdine, efavirenz; bind RT at different site than do NRTI's; do not requre phosphorylation
|
|
retroviral protease ihibitors
|
ritonavir, saquinavir, indinavir, nelfinavir, amprenavir, atazanvir; inhibit cleavage of precursors to viral proteins and enzymes; used for HIV; CI for use with rifampin
|
|
amantadine and rimantadine
|
inhibit M2 protein of influenza A virus, inhibiting replication; also effective against influenza C; rimantadine: prophylaxis and trt in adults, but only prophylaxis in children;
amantidine also useful in trt of parkinsonism; adverse: neurotoxic effects |
|
zanamivir and oseltamivir
|
ihibit viral neuraminidase, essential for replication;
trt of influenza A and B; zanamivir: intranasal; oseltamivir: oral prodrug, activated by liver; decrease duration and intensity of flu |
|
Palivizumab
|
monoclonal antibody against F glycoprotein on RSV; IM; adverse: aminotransferase elevation
|
|
interferons (IFN)
|
cytokines; affect viral RNA and DNA synth;
IFN-alpha for hep B, C; Kaposi's sarcoma in HIV pt.; genital warts; herpes zoster in cancer pt. |