Therapeutics for Skin Disease PDF

Therapeutics for Skin Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics 1  Learning Outcomes 1. Describe and give examples of the classes of m...

Therapeutics for Skin Dr Martin Hawes Senior Lecturer Veterinary Pharmacology and Therapeutics 1  Learning Outcomes 1. Describe and give examples of the classes of medications that might be employed to treat skin disease 2. Describe the mode of action of anti- inflammatory drugs 3. Describe a regime for long term dosing with corticosteroids 4. Explain the difference between various anti- inflammatories and considerations in selecting appropriate agents Friday, 08 November 2024 2  Drug therapies Infections and infestations Antimicrobials (antibiotics, antifungals, antiyeast) Ectoparasiticides Inflammation and allergies Glucocorticosteroids Cyclosporin Oclacitinib Lokivetmab Antihistamines Essential Fatty Acids Allergen-specific immunotherapy Others Emollients/moisturisers Keratolytic or keratoplastic Follicular flushing agents Friday, 08 November 2024 3  Infections and infestations Friday, 08 November 2024 4  Antibacterials Fusidic acid Friday, 08 November 2024 5  β-lactam antibiotics β-lactam antibiotics (penicillins, cephalosporins) Sounds familiar inhibit bacterial growth by interfering with the transpeptidation of bacterial wall synthesis – bactericidal, time dependent. Example: Superficial pyoderma – Rx minimum of 3 weeks including at least 7-10 days after resolution of clinical lesions Deep pyoderma – Rx at least 4-6 weeks including not less than 2 weeks after resolution of clinical lesions CLINICAL CURE vs BACTERIOLOGICAL CURE amoxicillin cefalexin Friday, 08 November 2024 6  Tetracyclines Sounds Tetracyclines (e.g. oxytetracycline, doxycycline) familiar inhibit protein synthesis in susceptible bacteria – bacteriostatic, time-dependent. Example: Foot rot in sheep and topical infections caused by organisms sensitive to oxytetracycline in cattle, sheep and pigs oxytetracycline Friday, 08 November 2024 7  Sulfonamides, DRIs and combination antibiotics Sulfonamides and dihydrofolate reductase Sounds familiar inhibitors (e.g. trimethoprim) interfere with the production of folic acid and thereby purine synthesis, usually combined (TMPS) - bactericidal, time-dependent. Example: Wound infections and open or drained abscesses in horses sulfadiazine + trimethoprim Friday, 08 November 2024 8  Lincosamide antibiotics Sounds Lincosamides inhibit protein synthesis familiar bacteriostatic, time-dependent. Example: Clindamycin - for treatment of infected wounds and abscesses and antimicrobial cover for dental procedures in dogs & cats Do not administer to rabbits, hamsters, guinea pigs, chinchillas, horses or ruminants because ingestion of clindamycin by these species may result in severe gastro- intestinal disturbance clindamycin Friday, 08 November 2024 9  Fusidic acid and Polymyxin B fusidic acid inhibits protein synthesis of bacteria - bacteriostatic, high concentrations may be bactericidal. Activity against Gram-positive bacteria, including Staphylococcus spp. (particularly S.pseudintermedius) polymyxin B binds to phospholipids in the bacterial cytoplasmic membrane and disrupts the membrane - bactericidal. Active against Gram-negative bacteria. fusidic acid + beclamethasone polymyxin B + miconazole + prednisolone Friday, 08 November 2024 10  Antifungals and antiyeasts - Topical Imidazoles (miconazole, ketoconazole, enilconazole) – inhibit ergosterol incorporation into cell membranes, cause increased cell wall permeability and leakage of cellular contents miconazole - antifungal and has activity against yeasts nystatin - broad spectrum antifungal, noted for its activity against Candida nystatin + prednisolone + miconazole + diethanolamine fusidate chlorhexidine + framycetin sulphate Microsporum canis Malassezia Friday, 08 November 2024 11  Antifungals - Oral Triazoles – same mode of action to miconazole - itraconazole is the systemic treatment of choice (cascade) Griseofulvin - exact antifungal MoA uncertain - absorbed over a prolonged period from the GI tract and deposited in keratin precursor cells. Concentrates in stratum corneum, nail and in hair thus preventing fungal invasion of newly forming cells. Used for ringworm in horses itraconazole Friday, 08 November 2024 12  Ectoparasiticides – general mechanisms Act on ectoparasite nervous system AChE inhibitors Na+ channel blockers Nicotinic ACh receptor antagonists GABA and Cl- channel inhibitors Inhibit insect growth and development Ectoparasite repellent Friday, 08 November 2024 13  Ectoparasiticides Sounds Macrocytic lactones familiar Open glutamate-chloride channels selamectin, ivermectin, moxidectin Phenylpyrazole insecticides and acaracides fipronil – inhibits the GABA complex. Binds to chloride channels resulting in uncontrolled CNS activity and death DO NOT USE IN RABBITS – can cause seizure & death fipronil selamectin Friday, 08 November 2024 14  Ectoparasiticides imidacloprid and nitenpyram belong to the neonicotinoid group of insecticides. High affinity for post-synaptic nicotinic ACh receptors – results in paralysis and death of fleas & larvae Good safety, virtually no effect on mammalian CNS Pyrethroids (permethrin/cypermethrin/flumethrin) – many mechanisms proposed - act on sodium channels causing initial excitement then paralysis and death DO NOT USE IN CATS – neurotoxic, can be fatal imidacloprid cypermethrin nitenpyram Friday, 08 November 2024 15  Ectoparasiticides amitraz – formamidine insecticide/acaracide, octopamine receptor agonist - increases nervous activity in synapses – rapid detachment/death of parasites Used to treat mites, esp. demodicosis. Weekly wash until 2 negative skin scraps/hair plucks 2 weeks apart. Prepare outside, use in well-ventilated area, wear gloves AEs – acts as alpha-2-adrenoceptor agonist (like xylazine) in mammals - sedation and bradycardia can be reversed with alpha-2-adrenoreceptor antagonist, atipamezole amitraz Friday, 08 November 2024 16  Ectoparasiticides Insect growth regulators (e.g. methoprene) affect developing stages (eggs, pupae and larvae) of insects and arthropods, not the adult parasite Effective control not achieved until several weeks after use, so mainly formulated as a combination with adulticides Adulticide fipronil + + Insect growth regulator methoprene combination Friday, 08 November 2024 17  Bewildering number of products Multiple products on the market - be aware as clients will ask Bottom line – follow practice policy Friday, 08 November 2024 18  Allergy and inflammation Friday, 08 November 2024 19  Complexity of inflammation Inflammation is extremely complex - multiple inflammatory mediators involved Taken from Weidinger et al, 2018 Nature Reviews Disease Primers: Atopic Dermatitis Friday, 08 November 2024 20  Glucocorticoids Highly effective anti-inflammatory drugs, frequently used, cheap prednisolone and dexamethasone most commonly used Marked effects on multiple body systems – so wide range of adverse effects Immediate: Polyuria, polydipsia, polyphagia, restlessness Chronic: Weight gain, UTIs, iatrogenic hyperadrenocortism ‘Anti-inflammatory’ dose and ‘Immunosuppressive dose’ Aim to induce remission with high dose once daily therapy then maintain remission on lowest every other day dose Stopping chronic therapy – 20-25% decrease in dose every 4-6 weeks Friday, 08 November 2024 21  Calcineurin inhibitors ciclosprin has more targeted T-cell suppression than glucocorticoids with efficacy comparable to glucocorticoids for pruritus – Inhibits activation of T-lymphocytes on antigenic stimulation by impairing the production of IL-2 and other T- cell derived cytokines. – May take 2-4 weeks for improvement to occur – AEs – transient vomiting & diarrhoea, gingival hyperplasia, hirsutism, muscle weakness/cramps ciclosporin Friday, 08 November 2024 22  Oclacitinib (Apoquel ) oclacitinib is a Janus kinase (JAK) inhibitor - inhibits variety of cytokines dependent on JAK enzyme activity – including proinflammatory cytokines which have a role in allergic responses/pruritis May also exert effects on other cytokines (e.g. those involved in host defence or haematopoiesis) with the potential for unwanted effects AEs – diarrhoea, vomiting, anorexia, new (sub)cutaneous lumps, lethargy, polydipsia oclacitinib Taken from Schwartz et al, 2017 Nature Reviews Drug Discovery, 16, pp. 843–62 Friday, 08 November 2024 23  Lokivetmab (Cytopoint ) lokivetmab is a caninised monoclonal antibody for treatment of atopic dermatitis in dogs Specifically targets the inflammatory cytokine canine interleukin-31 (IL-31) Watch the Cytopoint video on Surrey Learn Friday, 08 November 2024 24  Other anti-inflammatory therapies Antihistamines (e.g. chlorphenamine, promethazine, cetirizine) antagonise histamine binding to cellular receptors (specifically, the H1-receptors), which are present on nerve endings, smooth muscles, and glandular cells Variable efficacy (up to 30%?) Theoretically most effective when initiated prior to allergen exposure – possibly more effective for seasonal disease Lack of response to one does not rule out good response to another - try different types (for 10-14 days each) Essential fatty acids (omega-3 [fish oils] & omega-6 [plant-derived oils] may interact in arachidonic acid cascade and have weak anti-inflammatory effect Steroid-sparing (?) Give for at least 8-10 weeks Allergen-specific immunotherapy (allergy shots) chlorphenamine Refer to additional reading on Surrey Learn Friday, 08 November 2024 25  Key Points LO - Describe and give examples of the classes of medications that might be employed to treat skin disease Antibacterials that are widely used for skin disease include cephalexin, amoxicillin/clavulanate, clindamycin, fucidic acid and polymyxin B Topical antifungals include miconazole and nystatin. Itraconazole is the systemic antifungal of choice. These drugs also have activity against yeasts Adult ectoparasiticides act through a variety of mechanisms including glutamate-chloride channels (macrocytic lactones e.g. selamectin, ivermectin, moxidectin); GABA (fipronil, alfoxalaner); nicotinic ACh receptors (imidacloprid); sodium channels (permethrin); octopamine receptor (amitraz) Insect growth regulators (e.g. methoprene) affect developing stages (eggs, larvae and pupae) of insects and arthropods, not the adult Friday, 08 November 2024 26  Key Points LO - Describe and give examples of the classes of medications that might be employed to treat skin disease - explain the difference between various anti-inflammatories and considerations in selecting appropriate agents Pruritus can be difficult to manage. Reaching an agreed, shared plan with clients is key to success. Glucocorticoids and oclacitinib for short term treatment of pruritus and inflammation related to allergic dermatitis Glucocorticoids, oclacitinib, ciclosporin and lokivetmab are all options for the (long term) treatment of atopic dermatitis. Choice of therapy should take into account the signalment of the animal, possible comorbidities, concurrent drug use and safety profile of the therapy (and cost) Adjunctive therapies (e.g. essential fatty acids, antihistamines) can help reduce steroid and cost of expensive therapies Friday, 08 November 2024 27  Key Points LO - Describe the mode of action of anti-inflammatory drugs Glucocorticoids (e.g. prednisolone, dexamethasone) bind to specific cytoplasmic receptors which then enter the nucleus and alter transcription of DNA. This leads to alterations in cellular metabolism resulting in wide-spread anti-inflammatory, immunosuppressive and antifibrotic effects Calcineurin inhibitors (e.g. ciclosporin, Atopica ) inhibit activation of T-lymphocytes on antigenic stimulation by impairing the production of IL-2 and other T-cell derived cytokines oclacitinib (Apoquel ) is a Janus kinase (JAK) inhibitor. It inhibits a variety of cytokines dependent on JAK enzyme activity, including proinflammatory cytokines which have a role in allergic responses/pruritis Friday, 08 November 2024 28  Key Points LO - Describe the mode of action of anti-inflammatory drugs lokivetmab (Cytopoint ) is a caninised monoclonal antibody for treatment of atopic dermatitis in dogs which specifically targets interleukin-31 (IL-31) Antihistamines (e.g. chlorphenamine) antagonise histamine binding to H1-receptors, which are present on nerve endings, smooth muscles, and glandular cells Essential fatty acids (omega-3 [fish oils] & omega-6 [plant- derived oils] may interact in arachidonic acid cascade and have weak anti-inflammatory effect Friday, 08 November 2024 29  Key Points LO – Describe a regime for long term dosing with corticosteroids Long-term administration of glucocorticoid therapy is associated with the suppression of the hypothalamic-pituitary axis (HPA), causing adrenal atrophy. The risk of iatrogenic hyperadrenocorticism can be reduced by inducing remission with high dose once daily therapy, then maintaining remission on the lowest every other day dose, combining steroid with ‘steroid-sparing’ therapy Withdrawal from chronic therapy should be carried out slowly over several weeks – a suitable regimen would be to reduce the dose by 20-25% every 4-6 weeks. Friday, 08 November 2024 30