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Flashcards in Antifungals/Antihistamines Deck (59):
1

What are major differences between fungi and bacteria?

1. cell membrane has ergosterol in fungi
2. cell wall contains beta-glucan in fungi

2

Superficial fungal infection

Cutaneous surfaces (common), subcutaneous, mucous membrane surfaces

3

Systemic fungal infection

Internal organs (cause pneumonia and can disseminate), difficult to treat, often life-threatening

4

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

5

Systemic drugs for systemic infections

Azoles
Amphotericin B

6

Oral systemic drugs for mucocutaneous infections

Terbinafine
Griseofulvin

7

Topical drugs

Topical azoles
Topical amphotericin B
Nystatin
Topical terbinafine

8

Griseofulvin mechanism

Deposits in newly forming skin where it binds to keratin, protecting skin from new infection (prevents microtubule function)

9

Griseofulvin clinical use

Tinea capitis and glabrous (nonhairy) skin (e.g. nail)

10

Griseofulvin side effects

-Incidence of serious reactions is low
-GI upset (diarrhea, epigastric distress, bleeding, nausea, vomiting)
-Hepatotoxicity (rare)
-Photosensitivity
-Drug-drug interactions

11

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.

12

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

13

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

14

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

15

Systemic azoles

Ketoconazole (older), fluconazole, itraconazole, voriconazole

16

Topical azoles

Clotrimazole, miconazole, ketoconazole

17

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

18

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

19

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)

20

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)

21

Ketoconazole side effects

-Potent CYP450 inhibition
-Inhibits adrenal steroidogenesis causing adrenal insufficiency (related symptoms: gynecomastia, impotence, decreased libido, abnormal menstruation)
-Hepatotoxicity

22

How does ketoconazole inhibit adrenal steroidogenesis? (MOA)

-Inhibits CYP450 enzymes critical in adrenal steroid synthesis
-Binds to steroid receptors as an antagonist

23

Compared to ketoconazole, other azoles...

-Have same mechanism
-Used more frequently with better activity, less toxicity
-Less effect on CYP450

24

Clinical use of fluconazole

Cryptococcal meningitis (good CSF penetration), mucocutaneous candidiasis

25

Clinical use of itraconazole

Dimorphic fungi including Histoplasma, Blastomyces, Coccidioides immitis, Sporothrix

26

Clinical use of voriconazole

Candida spp., dimorphic fungi, Aspergillus spp.

27

Polyenes MOA

preferentially bind to ergosterol (unique to fungi), forming pores in membrane, causing leaky membranes and disrupting osmotic integrity (Polyenes form Pores)

28

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)

29

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)

30

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

31

Nystatin clinical use

-Topical only
-cutaneous, mucocutaneous, and oral infections normally caused by Candida spp.
-swish for oral
-topical for diaper rash or vaginal

32

Nystatin side effects

Not absorbed from GI tract, skin, or vagina, thus has little toxicity

33

Primary DOC for tinea unguium; alternative?

Terbinafine; itraconazole, fluconazole

34

Primary DOC for tinea capitis? Alternative?

Terbinafine or griseofulvin; itraconazole, fluconazole

35

Primary DOC for tinea corporis, tinea cruris, tinea pedis? Alternative?

Topical azoles (clotrimazole, miconazole); terbinafine, fluconazole, itraconazole

36

DOC for tinea versicolor

Topical azoles (lesions have a tendency to recur), fluconazole or itraconazole (for recurrences), or selenium sulfide shampoo

37

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)

38

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

39

Antihistamines 1st gen

Diphenhydramine (oral, topical, parenteral)
Dimenhydrinate (oral)
Promethazine (oral)

40

Antihistamines 2nd gen

Fexofenadine
Loratadine
Cetirizine
ALL ORAL

41

Topical steroids

Clobetasol (super high potency)
Betamethasone (super high, high, low potency)
Hydrocortisone (low-medium potency)

42

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)

43

Antihistamine clinical usage

Allergic reactions
Allergic rhinitis, hay fever, common cold
Allergic conjunctivitis
Angioedema (allergic)
Antiemetic
Insect bite reactions
Sedation (1st generation)
Urticaria

44

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

45

1st gen adverse effects

Sedation/drowsiness (gives effect of BAC of .05-.1)

46

Potential benefit of sedation in 1st gens

-decrease central itch perception
-helps patients sleep

47

Anticholinergic effects of 1st gens

Dry mouth
Difficulty urinating
Constipation
Glaucoma exacerbation
Tachycardia
Blurred vision
Confusion, etc.

48

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

49

2nd gen side effects

-Drowsiness (less)
-fatigue
-dry mouth

50

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

51

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.)

52

Medium to high potency

Appropriate for mild to moderate nonfacial/nonintertriginous dermatoses

53

Low to medium potency

-Trunk, arms, legs
-Consider when large areas are treated
-Possible systemic absorption

54

Low potency

-Thin-skinned, sensitive areas
-Axillae, groin, perianal, breast folds, face, eyelids

55

Absorption depends on nature of lesions

High: atopic and exfoliative dermatitis
Low: hyperkeratinized and plaque forming lesions

56

Occlusion can enhance topical corticosteroid potency by as much as....

100-fold

57

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

58

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

59

Skin atrophy can have visible...

telangiectasia, hypopigmentation, and prominence of underlying veins