Antifungals/Antihistamines Flashcards
What are major differences between fungi and bacteria?
- cell membrane has ergosterol in fungi
2. cell wall contains beta-glucan in fungi
Superficial fungal infection
Cutaneous surfaces (common), subcutaneous, mucous membrane surfaces
Systemic fungal infection
Internal organs (cause pneumonia and can disseminate), difficult to treat, often life-threatening
What are fungal infections harder to treat than bacterial?
Fungal organisms grow slowly, infections often occur in poorly perfused tissues, and usually requires prolonged treatment
Systemic drugs for systemic infections
Azoles
Amphotericin B
Oral systemic drugs for mucocutaneous infections
Terbinafine
Griseofulvin
Topical drugs
Topical azoles
Topical amphotericin B
Nystatin
Topical terbinafine
Griseofulvin mechanism
Deposits in newly forming skin where it binds to keratin, protecting skin from new infection (prevents microtubule function)
Griseofulvin clinical use
Tinea capitis and glabrous (nonhairy) skin (e.g. nail)
Griseofulvin side effects
- Incidence of serious reactions is low
- GI upset (diarrhea, epigastric distress, bleeding, nausea, vomiting)
- Hepatotoxicity (rare)
- Photosensitivity
- Drug-drug interactions
Drug-drug interaction of griseofulvin
-Induces hepatic CYP450 enzymes, thereby increasing the rate of metabolism of other drugs (substrates of CYPs) such as warfarin, anti-epileptics (e.g., phenytoin), theophylline, oral contraceptives (OCPs), etc.
Terbinafine mechanism
- inhibits enzyme squalene epoxidase (fungal enzyme), further inhibiting ergosterol synthesis
- membrane damage and leaky
- accumulation of squalene which is toxic to fungal cells
Terbinafine clinical use
- Fungicidal
- oral or topical
- DOC for tinea unguium (nail) and capitis
- oral
- high cure rate
- prolonged therapy
- more effective than griseofulvin or azoles
Terbinafine side effects
- Well tolerated with rare side effects
- Low incidence of GI distress, headache, rash, hepatotoxicity, neutropenia, hypersensitivity
- Pregnancy Category B (no evidence of drug risks in humans) - recommended therapy for onychomycosis be postponed until after pregnancy
- no significant drug-drug interactions
Systemic azoles
Ketoconazole (older), fluconazole, itraconazole, voriconazole
Topical azoles
Clotrimazole, miconazole, ketoconazole
Azoles MOA
- Azoles inhibit the synthesis of erogsterol from lanosterol via inhibition of 14-a-demethylase, a CYP450 enzyme (CYP51A1)
- Decreasing ergosterol leads to membrane damage and leaky, also leads to accumulation of squalene
- Some azoles also inhibit other human CYP450 enzymes thus causing side effects
Azoles clinical use and general side effects
Clinical use:
-Used in both superficial and systemic infections. Broad spectrum of action including Candida spp., Cryptococcus neoformans, endemic mycoses (blastomycosis, coccidioidomycosis, histoplasmosis), dermatophytes, even Aspergillus infections.
Side effects:
-Relatively nontoxic. Can cause minor GI upset, abnormalities in liver enzymes, hepatitis
-Prone to drug-drug interactions because they inhibit human CYP450 enzymes
Ketoconazole clinical use
- Dermatophytosis, mucocutaneous candidiasis, tinea versicolor, seborrheic dermatitis (topical use)
- Not for systemic use (due to its narrow therapeutic index and side effects)
- Has been largely replaced by fluconazole and itraconazole for antifungal treatment, except using in Cushing’s syndrome (off-label use)
Off-label use of ketoconazole
- “Off-label use” means use the drug for a condition other than that for which it has been officially approved.
- Ketoconazole inhibits adrenal steroidogenesis (mechanism discussed in next slide), thus is used in
- Cushing’s syndrome (decrease glucocorticoid production)
- Prostate cancer (decrease androgen production)
Ketoconazole side effects
- Potent CYP450 inhibition
- Inhibits adrenal steroidogenesis causing adrenal insufficiency (related symptoms: gynecomastia, impotence, decreased libido, abnormal menstruation)
- Hepatotoxicity
How does ketoconazole inhibit adrenal steroidogenesis? (MOA)
- Inhibits CYP450 enzymes critical in adrenal steroid synthesis
- Binds to steroid receptors as an antagonist
Compared to ketoconazole, other azoles…
- Have same mechanism
- Used more frequently with better activity, less toxicity
- Less effect on CYP450
Clinical use of fluconazole
Cryptococcal meningitis (good CSF penetration), mucocutaneous candidiasis
Clinical use of itraconazole
Dimorphic fungi including Histoplasma, Blastomyces, Coccidioides immitis, Sporothrix
Clinical use of voriconazole
Candida spp., dimorphic fungi, Aspergillus spp.
Polyenes MOA
preferentially bind to ergosterol (unique to fungi), forming pores in membrane, causing leaky membranes and disrupting osmotic integrity (Polyenes form Pores)
Amphotericin B clinical use
- Broad spectrum activity
- DOC for most severe and/or life-threatening infections, systemic fungal infections (severe fungal pneumonia, severe cryptococcal meningitis (intrathecally for fungal meningitis), severe or rapidly progressing histoplasmosis, blastomycosis, coccidioidomycosis)
- Topical use for Candida albicans infection (ineffective against dermatophytosis)
Amphotericin B immediate toxicity side effects
- Shake and Bake (fever/chills), muscle spasms, vomiting, headache, hypotension
- prevention: slow infusion or decrease dose
- Treated by drugs [e.g, antipyretics (reduce fever), antihistamine (reduce allergy), meperidine (reduce pain), corticosteroids (reduce allergy and pain)
Amphotericin B cumulative toxicity side effects
- Renal toxicity (caused by: constriction of afferent arterioles and renal tubular damage caused by disruption of membrane permeability)
- Can cause renal tubular acidosis and renal wasting of K and Mg
Nystatin clinical use
- Topical only
- cutaneous, mucocutaneous, and oral infections normally caused by Candida spp.
- swish for oral
- topical for diaper rash or vaginal
Nystatin side effects
Not absorbed from GI tract, skin, or vagina, thus has little toxicity
Primary DOC for tinea unguium; alternative?
Terbinafine; itraconazole, fluconazole
Primary DOC for tinea capitis? Alternative?
Terbinafine or griseofulvin; itraconazole, fluconazole
Primary DOC for tinea corporis, tinea cruris, tinea pedis? Alternative?
Topical azoles (clotrimazole, miconazole); terbinafine, fluconazole, itraconazole
DOC for tinea versicolor
Topical azoles (lesions have a tendency to recur), fluconazole or itraconazole (for recurrences), or selenium sulfide shampoo
Urticaria (hives, welts, or wheals)
Episodic inflammatory, allergic reaction in a localized area of skin; majority of cases are acute, not chronic; possible mechanisms: IgE mediated, non-IgE-mediated, autoimmune, idiopathic; vascular reaction in the upper dermis (pruritic, edematous, erythematous lesions)
H1 receptor
- Gq
- Found on: smooth muscle, endothelium, and CNS
- Activation: (mediated through C-nerve fibers)
- Vasodilation
- Separation of endothelial cells
- Itching (pruritus)
- Bronchoconstriction
- Primary receptor involved in allergic rhinitis symptoms and motion sickness
Antihistamines 1st gen
Diphenhydramine (oral, topical, parenteral)
Dimenhydrinate (oral)
Promethazine (oral)
Antihistamines 2nd gen
Fexofenadine
Loratadine
Cetirizine
ALL ORAL
Topical steroids
Clobetasol (super high potency)
Betamethasone (super high, high, low potency)
Hydrocortisone (low-medium potency)
Antihistamines
- Inverse agonists (not an antagonist)
- Block the physiological effects of histamine by selectively acting on receptors to prevent histamine from stimulating the receptor and inducing the common effects observed during an allergic reaction:
- redness, edema, itching
- allergy headache
- breathing difficulty
- Anticholinergic
- Drying effect that reduces nasal, salivary, and lacrimal gland secretions (runny nose, tearing, and itching eyes)
Antihistamine clinical usage
Allergic reactions Allergic rhinitis, hay fever, common cold Allergic conjunctivitis Angioedema (allergic) Antiemetic Insect bite reactions Sedation (1st generation) Urticaria
1st gen characteristics
- Older, traditional antihistamines
- Work both peripherally and centrally
- Lipid soluble - CNS penetration and effects
- Sedation and performance impairment is a primary concern with 1st generation
- Have anticholinergic effects, making them more effective than nonsedating agents in some cases
1st gen adverse effects
Sedation/drowsiness (gives effect of BAC of .05-.1)
Potential benefit of sedation in 1st gens
- decrease central itch perception
- helps patients sleep
Anticholinergic effects of 1st gens
Dry mouth Difficulty urinating Constipation Glaucoma exacerbation Tachycardia Blurred vision Confusion, etc.
2nd gen characteristics
- developed to eliminate unwanted side effects (less lipophilic, does not readily cross BBB)
- similar relief with few side effects
- work peripherally (fewer CNS side effects)
- longer duration of action (better compliance)
- shown to improve quality of life
2nd gen side effects
- Drowsiness (less)
- fatigue
- dry mouth
Topical steroids MOA
Anti-inflammatory
- Suppress production of
- Cytokines
- Prostaglandins
- Leukotrienes
- decrease release of proinflammatory mediators
- Stabilizes lysosomal membranes
- Prevents catabolic enzyme release from neutrophils
- Causes vasoconstriction and decreases capillary permeability
Super high potency used…
- for severe dermatoses over nonfacial/nonintertriginous areas
- e.g., psoriasis, severe atopic dermatitis, severe contact dermatitis
- Especially useful over areas that tend to resist topical steroid penetration due to the thick stratum corneum (e.g., palms, etc.)
Medium to high potency
Appropriate for mild to moderate nonfacial/nonintertriginous dermatoses
Low to medium potency
- Trunk, arms, legs
- Consider when large areas are treated
- Possible systemic absorption
Low potency
- Thin-skinned, sensitive areas
- Axillae, groin, perianal, breast folds, face, eyelids
Absorption depends on nature of lesions
High: atopic and exfoliative dermatitis
Low: hyperkeratinized and plaque forming lesions
Occlusion can enhance topical corticosteroid potency by as much as….
100-fold
Topical steroids adverse effects
Skin atrophy, striae Telangiectasia, purpura Perioral dermatitis, rosacea Tachyphylaxis or rebound Hypopigmentation Systemic absorption (uncommon) Contact dermatitis - reaction to preservatives and additives is also common with prolonged use
Minimizing risks of topical steroids
Avoid high potency steroids on flexures, face, or genitals
Be cautious when using steroids on face
Avoid high potency steroids in children
Avoid use of occlusion for long periods
Skin atrophy can have visible…
telangiectasia, hypopigmentation, and prominence of underlying veins
