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pharmacology exam 3 > antihistamines and antifungals > Flashcards

antihistamines and antifungals Flashcards

1
Q

what tissues are histamine released

A

 MAST CELL POOL: -Stored in granules within mast cells & basophils
- Inflammatory response, allergy, anaphylactic shock
 Non-mast cell pool: GI, CNS, dermis, other tissues
- Constant production, rapid turnover

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2
Q

histamine receptors H1

A

-H1 receptor: high affinity (activated at low dose of histamine)
H1 activation will cause:
- Smooth muscle contraction:
Bronchioles > GI tract > urinary tract
-bronchoconstriction important (asthma attacks)
- Smooth muscle relaxation:
 Vasodilation of arterioles, capillaries

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3
Q

H2 receptor

A

 Lower histamine affinity, but longer duration
-HCL secretion from parietal cells
-H2 receptor blockers(iminidine): decrease HCL, ulcers. now we use omeprazole works better.

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4
Q

H3/ H4 receptors

A

 Located on CNS neurons, modulate NT release
 Limited veterinary relevance (for now)
H4 receptor:
 Allergic / inflammatory response?
 Limited veterinary relevance

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5
Q

Histamine role in allergic reactions

A

-Typically local cutaneous (i.e., dermal) response
 Foreign antigen cross-links with IgE on dermal mast cells
 This activation of mast cells causes degranulation
 Histamine release–> leads to cardinal signs of inflammation.

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6
Q

hitamine cardinal signs of inflammation

A

-redness: from vasodilation
-swelling: capillary dilation (edema)
-pain (stimulate nerve endings)
-heat (fever) loss of function

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7
Q

Histamine role in anaphylaxis

A

-Anaphylaxis can occur with severe, systemic histamine
release and widespread activation of H1 receptors:
 Hypotension: Vasodilation, ↓ peripheral resistance
 Bronchoconstriction
: Bronchiole smooth muscle contraction

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8
Q

Histamine & Neurons

A

 Histamine is a neurotransmitter within the CNS
 Peripheral release of histamine can stimulate sensory
neurons
 Recognized as pruritus, pain

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9
Q

H1-blocking antihistamines pharmacodynamics

A

-Usually called “reversible, competitive inhibition”
 Compete with histamine for H1 receptor binding site
-But may really stabilize H1 receptor in non-active state
- Either way, prevents histamine/H1 receptor activation
H1 blockers: No impact on H2 receptors
-hepatic metabolism results in active metabolites.

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10
Q

1st generation H1 antihistamines

A

 Varying degrees of anticholinergic effect:
 Can cause sedation (low doses) OR CNS excitement (usually at higher doses
-drowsy antihistamines (diphenhydramine=benadryl)

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11
Q

Pyrilamine

A

-H1 blockers
 Vet formulations available in Canada (Antihist)
 Injectable and oral formulations (both include ephedrine)

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12
Q

 Diphenhydramine

A

-H1 antihistamine blocker
-trade name (Benadryl®)
 No vet-approved formulations in Canada
 Human drugs commonly prescribed by vets, or used at
home by owners

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13
Q

 Dimenhydrinate

A

–trade name (Gravol®, Dramamine®)
-H1 blocker histamine
 No vet-approved formulations in Canada
 Human drugs commonly prescribed by vets, or used at
home by owners

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14
Q

Trimeprazine

A

-H1 blocking antihistamine
 “Anti-pruritic”
 Found in Vanectyl-P (very old oral formulation for treating skin
allergies in animals, also containing prednisolone)

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15
Q

H1-blocking antihistamines
2nd generation: more selective for peripheral H1 receptors and longer 1/2 life

A

No vet formulations available, but lots of human ones!
 Cetirizine (Zyrtec®, part of piperazine class)
 Loratidine (Claritin®)

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16
Q

clinical uses of H1 blocking antihistamines on allergic reaction

A
  • Modulate allergic reaction, but
    won’t stop allergen exposure or histamine release
    -work better if given BEFORE allergen contact and histamine release.
    -limited efficacy when used for atopic dermatitis (dogs/cats)
  • May ↓ pruritus for short time. but from sedation with antihistamine/ anticholinergic effects (decreasing scratching)
17
Q

other uses for H1-antagonists (antihistamines)

A
  • Adjunctive therapy for anaphylaxis, insect bite, etc. But does NOT replace sympathomimetics (epi)!
  • Adjunctive therapy for dogs with mast cell tumours: Help prevent pruritus due to degranulation (histamine release)
  • Antidote for “extrapyramidal reactions” caused by phenothiazine tranquilizers
    -doesnt work great for bronchoconstriction
18
Q

Antihistamines & “anticholinergic” effects

A

 1st gen H1-blocking antihistamines can also inhibit muscarinic receptors (i.e., parasympatholLYTIC signs)
-can produce similar (weaker) effects as anticholinergic like atropine: dry mouth, tachycardia, ileus, mydrisis
-CNS depression (sedation) or excitement

19
Q

Types of Fungal Infections

A
  • Superficial mycoses: Affect the skin, hair and nails
  • Systemic (invasive) mycoses:
    – Involve the internal organs
    – Primary vs. opportunistic
    – Prolonged duration of therapy typically required (months)
20
Q

appetite stimulant in cats

A

mirtazapine

21
Q

systemic antifungals

A
  • Amphotericin B
  • Azole antifungals:
    – Ketoconazole
    – Itraconazole
    – Fluconazole
22
Q

topical antifungals

A
  • Azole antifungals:
    – Miconazole, Clotrimazole
  • Terbinafine
    -ionophores, chlorhexidine.
23
Q

targets for antifungal therapy

A

-cell membrane: Fungi use principally ergosterol not cholesterol. this is the target
-DNA Synthesis: arresting DNA synthesis
-Cell Wall: Unlike mammalian cells, fungi
have a cell wall with chitin, so chitin inhibitors

24
Q

Amphotericin B

A

-systemic antifungal for severe cases
-IV
-Mechanism: binds to sterols in fungal cell membrane, Alters membrane permeability
* Broad anti-fungal spectrum, but no effect on bacteria/rickettsia.
-* Mammalian cells do contain sterols (cholesterol)= highly toxic (more in cats)

25
Q

Amphotericin B: Clinical Use

A
  • Used for invasive fungal infections in dogs, cats, and horses:
    – Aspergillosis, Blastomycosis, Cryptococcous, Candida (not 1st choice drug)
    -nephrotoxic (↓ GFR) reversible at first but irreversible with more use.
    AE-anorexia, vomiting, anemia.
26
Q

systemic azole antifungals types

A
  • Ketoconazole
  • Itraconazole( Itrafungol in cats) used EX in dogs
    -fluconazole
  • Most systemic (oral / injectable) azole antifungals
    are NOT currently licensed for veterinary use
  • Human formulations are used
  • Exception = Itrafungol (cats)
27
Q

“Azole” Mechanism of Action

A

-systemic antifungals
 Binds to cytochrome P450 enzyme complex
 Inhibits the synthesis of ergosterol
 End result: damaged fungal cell membrane
-azoles can also impact normal function of
mammalian CYP enzymes too: cannot convert to cholesterol which is needed for cell membrane and steroid hormones.
-lots of drug interactions

28
Q

“Azole” – General PK/PD

A

-systemic antifungals
* Possibly concentration-independent fungistatic agents, need time for drug [ ] to disrupt not a higher dose.
* Goal of dosing: Maintain 1 – 2x MIC of fungal species for the entire dosing interval. dose frequently takes weeks-months

29
Q

“Azole” Antifungal Resistance

A

-systemic antifungals
-Fungal species can develop resistance to azoles over time:
* Failure of drug accumulation in the pathogen
– ↓ drug influx, or ↑ drug efflux. reduces intake of the drug.
* Changes in drug interaction with target enzymes in ergosterol synthesis pathway

30
Q

Ketoconazole

A

-topical or systemic antifungal
* Formulations = oral tablets &
suspensions, topical creams/shampoos
– All human products
* Veterinary uses: To treat mycotic infections due to:
– yeast (Malassezia)
– systemic fungi
* Coccidioidomycosis
* Blastomycosis
* Histoplasmosis
* Cryptococcosis
– dermatophytes

31
Q

Ketoconazole Adverse Events

A
  • Hepatic toxicity (esp. cats)
    – Dose-dependent
    – Monitor liver enzymes
    – Watch for drug interactions!
  • GI: nausea, vomiting, anorexia
    – dose-dependent
    – ↓ adverse events if administered with food
32
Q

Itraconazole

A

-systemic antifungal (1st choice)
* Itrafungol oral solution licensed for use in cats (treatment of feline dermatophytosis caused by Microsporum canis)
-compounded is bad, human products for oral and solutions. $$ but safer.
PK:
* ↑ F when given with food
* High VD, accumulates in hair/skin

33
Q

Itraconazole Clinical uses

A
  • Itrafungol label: skin fungal infections in cats“activity against dermatophytes (Trichophyton spp., Microsporum spp.), yeasts
    (Candida spp., Malassezia spp.), various dimorphic fungi, zygomycetes and eumycetes (e.g., Aspergillus spp.)
  • Common extralabel uses:
    – Systemic fungal diseases:
  • Blastomycosis (dogs)
  • Cryptococcus (cats)
    – Horses: gutteral pouch mycosis, nasal aspergillosis, fungal keratitis
34
Q

fluconazole

A

-no vet formulations, human only
-PK: good oral F, penetrates into tissues and CROSSES BBB**
-limited hepatic metabolism, mostly in urine, better for animals with liver disease*
-$$$ but safe
Narrower antifungal spectrum than keto/itraconazole:
* Good activity against Candida, Cryptococcus, Coccidioides
– e.g., fungal meningitis

35
Q

-Miconazole (surolan) & Clotrimazole (otomax)

A

-topical antifungals
-topical azoles
* Licensed for topical use against superficial
skin/ear mycotic infections in small animals
– Products often include an antibiotic & steroid
* Systemic use leads to:
– rapid hepatic enzyme induction (↑ drug clearance)
– serious adverse events

pharmacology exam 3 (4 decks)

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