Nutrition and Skin Disease Flashcards
(163 cards)
1
Q
G.Pig protein deficits: CS
A
produces generalized alopecia
2
Q
Rat Protein deficits: CS
A
alopecia, exfoliative dermatitis, and depigmentation of the haircoat
3
Q
Copper
A
- Necessary for the enzymes that convert L-tyrosine to melanin and by follicular cells in the conversion of prekeratin to keratin
- Catalyst in hemoglobin formation, cardiac function, cellular respiration, connective tissue development, pigmentation, bone formation, myelin formation, and immune function
4
Q
What metals can interfere with the absorption of copper?
A
- Zinc, cadmium, iron and lead can interfere with the absorption of copper.
- Zinc may inhibit copper absorption by its action on intestinal metallothioneins, which sequester copper in the intestinal epithelial cells & make copper unavailable for use elsewhere in the body
5
Q
Deficiency (hypocuprosis) - Cats and Dogs
A
- Feline – poor reproductive performance, early foetal loss, fetal deformities, cannibalism, coat hypopigmentation, kinked tails & inverted carpi
- Canine – hair depigmentation & hyperextension of the distal fore-limbs
6
Q
Bovine Cu Deficiency
A
- Occurs due to a primary dietary deficiency; secondary to molybdenum poisoning
- Clinical signs include stunted growth, diarrhea, infertility, anemia, bone disorders, heart failure, a rough brittle, faded hair coat and varying degrees of itching and hair licking, black hairs often turn red or gray, especially around the eyes, producing a “spectacled” appearance
- Salt licks containing 0.5 to 1% copper sulfate are reported to be effective for prevention
- Copper toxicity – jaundice, hemoglobinuria, and methemoglobinemia was produced in calves fed rations containing 500ppm copper sulfate for several months or given 12 gm orally
7
Q
Ovine Cu Deficiency
A
- Loss of crimp in wool – becomes straight and steely in appearance.
- Tensile strength of the wool is reduced & the elastic properties are abnormal
- The physical properties of wool, including crimp, are dependent on the presence of disulfide groups that provide the cross-linkages of keratin and on the alignment of long-chain keratin fibrillae in the fiber – both of these are adversely affected in copper deficiency
- Also can access activity of erythrocyte superoxide dismutase (Cu containing enzyme) < 2 IU/mg Hb
- Treatment for sheep CUSO4
8
Q
Equine Cu Deficiency
A
Equine – causes a loss of black pigment; affected horses develop a coarse harsh hair quality and a russet-brown hue to the darker areas of the coat
In horses, alopecia and browning of the hair around the eyes gives the animal a “spectacled” appearance, but these signs are not as prominent in the horse as in cattle and may easily be missed.
• Dx with blood & liver assays for copper
• A more serious tendency to arterial rupture and chronic anemia associated with copper deficiency
9
Q
Rodent Cu Deficiency
A
Hamsters – alopecia and depigmentation
Rabbits – alopecia and a depigmented haircoat
10
Q
Cobalt
A
- Cobalamin - Vitamin B12, is the largest and most complex B vitamin
- Only one to contain a metal ion, cobalt.
- Vitamin B12 is important in one-carbon metabolism and is a hydrogen acceptor coenzyme in several metabolic reactions, most important is the reduction of ribonucleotides to deoxyribonucleotides – gene synthesis
- An essential trace element in ruminant nutrition that is stored in the body in limited amounts & must be continually present in the feed.
- Deficiency
- Bovine/Ovine – signs appear after 6 months on deficient pasture and include severe reduction in growth and lactation, tender broken wool, rough faded hair coat
- Tests for colbalt or vitamin B12 are diagnostically the most valuable.
- Therapy cobalt sulfate orally
11
Q
Iodine
A
- Essential component necessary constituent of thyroxine (T4) and triiodothyronine (T3)
- Iodine requirement is influenced by physiologic state and diet
- Lactating animals require more because about 10% of the iodine intake is normally excreted in the milk
- Excess calcium, goitrogens, and potassium increase the need for iodine
- Goitrogens: peas, peanuts, soybeans and flaxseed
- Include thiocyanates, perchlorates, rubidium salts & arsenic
- Interfere with thyroidal iodine uptake
- Deficiency
- Results in goitrous neonates has been reported in cattle, sheep, swine, goats, and horses
- Clinical signs in newborns include generalized alopecia and myxedematous skin – animals are usually alive at birth but usually die within a few hours
- Horses often have deformities such as contracted tendons and fused joints (arthrogryposis)
- Dermatohistopath – epidermal atrophy, sebaceous gland hypoplasia, diffuse mucinous degeneration and scarce hair follicles that are hypoplastic
- Necropsy thyroid glands are enlarged and may be hemorrhagic
- Supplementation an organic iodide
- Iodine toxicity – In large animals includes coughing, seromucoid nasal discharge, excessive lacrimation, and generalized scaling of the skin.
- Iodism can develop during the treatment of fungal and other infections with potassium or sodium iodide in horses
- The earliest signs include lacrimation, and a scrufy, dry coat quality
- Chroinc excessive iodine fed to adult horses (often in the form of seaweed powder supplements, etc.) may be responsible for sparse, short hair coat
12
Q
Vitamin D Terms
A
Ergocalciferol: vitamin D2 – occurs in plants
Cholecalciferol: vitamin D3 – occurs in animals
25-Hydroxycholecalciferol : calcifediol
1,25-Dihydroxycholecalciferol: calcitriol (vitamin D2)
13
Q
Vitamin D General Role
A
Calcium metabolism : enhances intestinal absorption and mobilization, as well as retention and bone deposition of calcium and phosphorus
Haematopoiesis
Cell differentiation
Regulation of insulin secretion
14
Q
Biosynthesis and Metabolism of Vitamin D:
A
• Two naturally occurring pro-vitamin Ds:
o Ergosterol common sterol found in fungi & lower forms of life vitamin D2
o 7-dehydrochoeserol found in plants and animals vitamin D3
• Upon ultraviolet irradiation of pro-vitamin D3 the bond between carbons 9 & 10 is cleaved to form previtamin D3
• Previtamin D3 is biologically inert and requires temperature-dependent isomerization to form cholecalciferol (vitamin D3)
• The photosynthesized vitamin D3 in skin then enters the circulation and binds to vitamin D-binding protein (DBP)
• The biosynthesis of vitamin D3 is a regulated process in which UVB is the primary regulator
• Vitamin D3 itself is quite photolabile so that unless it is quickly absorbed into circulation, it is transformed into inactive 5,6- trans cholecalciferol, supersterol I and supersterol II.
• DBP-bound vitamin D3 in circulation is also biologically inert and requires activation.
• In the liver, vitamin D3, is hydroxylated at the C-25 position by a cytochrome P-450 enzyme system to 25(OH) D3 the major circulating form of vitamin D.
• This metabolite is hydroxylated again in the kidney at the C-1 position to form 1,25(OH)2D3 (calcitriol) which stimulates absorption of calcium from the intestine..
• Calcitriol production is stimulated by:
o Parathyroid hormone
o Hypophosphotaemia
• Calcitriol production is inhibited by:
o Hyperphosphotemia
o 1,25(OH)2D3 (calcitriol)
15
Q
Although the _____ is clearly the major source of 1,25(OH)2D3 production, 1-hydroxylase activity has been observed elsewhere such as cultured keratinocytes and bone cells
A
kidney
16
Q
_____ is responsible for calcium and phosphorus regulation and inhibits the proliferation and maturation of both normal and tumor cells that possess its receptor
A
Calcitriol
17
Q
What are the non-calcemic effects of calcitriol?
A
o Enhances IL-1 production
o Inhibits gamma-globulin synthesis
o Reduced antigen presentation to Langerhans cells
o Enhances thyrotropin secretion
o Stimulates calcium binding protein activity
o Inhibits tumor proliferation activity
o Produces maturation of both tumor and normal cultured cells
18
Q
When exposed to calcitriol human keratinocytes in culture show ______ proliferation and increased _______ in a concentration-dependent manner
A
proliferation
terminal differentiation
- Epidermal particulate & soluble transglutaminase activity was enhanced in a dose dependent manner
- Transglutaminase activity is stimulated by increasing the intracellular free Ca concentrations by non-genomic actions
- Calcitriol used on cultured keratinocytes decreased EGF receptors
19
Q
What is the biologic activity of calcitriol on melanogenesis and hair growth?
A
• Reported to stimulate melanogenesis and tyrosinase activity
• May have effects on hair follicle development and maturation during embroyogenesis
Indications
• Calcitriol used in Cockers with primary seborrhea at 10ng/kg q24 hrs
• Over 60% experienced significant improvement; all dogs showed decreased cell proliferation
• As it can decrease PTH, Ca and phosphorus levels should be checked weekly, as an accidental overdose can be fatal
• Topical analogs are used to treat psorasis in humans
• Calcitriol used in human keratinocyte cultures has shown the ability to down regulate TH1 response associated with immune-mediated disease.
20
Q
What are the primary functions of Zn?
A
• Some of the primary functions include: o Nucleic acid metabolism o Protein synthesis o Carbohydrate metabolism o Senses – smell and taste acuity o Immuno-competence – a decrease results in lymphopenia; decreases in T-cell response to mitogens, neutrophil chemotaxis, Mφ phagocytosis, Mφ killing & an increased susceptibility to pyoderma o Skin and wound healing o Cell replication and differentiation o Growth o Reproduction o Interacts with hormone production: testosterone, adrenal corticosteroids and insulin• Zn homeostasis is controlled through absorption (primarily through the duodenum, jejunum and ileum) and excretion
21
Q
Decreased zinc absorption occurs due to:
A
o Phytates (present in proteins of plant origin such as soy) o high dietary levels of Calcium o Copper o Iron o Cadmium o Phosphate o Chromium o EFA deficiency
The antagonistic effects of calcium are greatest when phytate is also present, resulting in the formation of a highly insoluble complex of calcium, phytate and zinc
22
Q
Enhanced zinc absorption occurs with:
A
o Ligands such as EDTA, Citrate, picolinate,
o Amino acids (histidine, glutamate)
o EFA supplementation
23
Q
Describe zinc metabolism
A
• The liver is the primary organ involved in zinc metabolism.
• Zinc in plasma is bound to protein in two forms:
o Firmly bound zinc that appears to bind to globulin (approximately 33% of total plasma zinc)
o Loosely bound zinc complexed with albumin (66% of total plasma zinc)
• Storage is limited except in bone
• Stores increase only slightly as dietary zinc increases
• Zinc concentration in bone has been used as a measure of zinc absorption and/or zinc status in young growing animals
• Plasma zinc is only a reliable index
• Eliminated primarily through the feces as unabsorbed & endogenous zinc (pancreatic juice, bile, and other digestive secretions)
24
Q
What is the relationship between zn and skin?
A
• Contains approximately 20% of the total body zinc stores
• Epidermis containing 6 times more than the dermis
• Concentrations tend to be greater in tissues with high epithelial proliferation rates, which may suggest that zinc is involved in the keratinization process of the skin
• Highest concentrations of zinc are observed in areas of pressure keratinization (footpads) and in parakeratotic sites (planum nasale)
• Dermatological diseases associated with epidermal hyperproliferation such as zinc responsive dermatosis may greatly increase utilization of the body’s zinc stores
Deficiency
• Primary due to inadequate amounts in the diet
• Secondary due chelating agents mentioned above that affect zinc absorption and requirements
• Reported in horses, cattle, sheep and goats.
• Feline - in kittens thin hair coat, slow hair growth, seborrhea sicca, ulceration of the buccal margins
• Chinchilla – alopecia
• Rats – exfoliative dermatitis, alopecia, and depigmentation of the haircoat
• Rabbit – alopecia, scaling, and depigmented haircoat
• Mouse – exfoliative dermatitis, alopecia and depigmentation of the haircoat
• Recent work indicates that Zn deficiency is rare in dogs; and has been documented in Bull terriers, however, a recent prospective study of 28 Bull terriers with lethal acrodermatitis could not document statistically significant differences of Zn levels between the affected dogs and the controls (McEwan NA, McNeil PE, et al. JSAP 2000 41: 501-507)
25
Equine zn deficiency
• Equine develops within a short time as reserves are low
o Generalized alopecia with extensive surface scaling and flaking giving the appearance of severe dandruff.
o Initially thighs and ventral abdominal wall.
o Severe and prolonged deficiencies result in generalized exudation and flaking with extensive and severe loss of hair.
Daily dietary supplementation with zinc methionine
26
Food animal zn deficiency
• Bovine, Ovine, Caprine – signs of deficiency are similar in all three species; although the sequence of clinical signs is not consistent and include:
o Low levels of ALP
o Decreased feed consumption and growth rate
o Depraved appetite (wool eating)
o Wool break
o Listlessness
o Shivering
o Testicular atrophy
o Stiff or swollen joints, bowing of the hind legs
o Decreased resistance to infections
o Nasal and oral mucosae become inflamed and submucosal hemorrhages and horny overgrowth are seen on the lips and dental pads
o Wound healing is prolonged
o Suggested that low Zn levels predispose to infectious pododermatitis in cattle and sheep
Goats: pruritic crusting dermatitis that is most severe on the face and feet
27
“Itching Tail Root Eczema”
• Syndrome in young non-lactating cattle and in dairy cows during the dry period
• Occurs when high Ca & low Zn and Cu ratios
• Results in pruritus over tailhead (licking and biting), twitching of the tails, crusting & excoriation of the tailhead, decreased appetites, fertility and milk production
• Treatment with ZnCl or ZnO resulted in clinical remission
• Histopath:
o Marked parakeratosis
o Epidermal hyperplasia
o Superficial perivascular accumulation of mononuclear cell and eosinophils
o Some animals show only orthokeratotic hyperkeratoisis or alternating parakeratotic & orthokeratotic hyperkeratosis.
• Scanning EM of wool fibers defects, including irregular or absent cortical scale pattern, separation of cortical cells and breaking, fraying and distortion of fibers
Therapy – zinc levels in plasma and hair are unreliable; best indicator is response to zinc therapy
• IM injections may be preferred due to oral absorption
• ZnO or metallic zinc powder had been shown to be effective and quick acti
28
Zinc-Responsive Dermatosis: Humans
• Reported in:
o Dogs Cats Cattle Sheep Goats Llamas Pigs, Rats, Humans
Humans
• Described as acrodermatitis enteropathica
• Autosomal recessive
• Triad of dermatitis, diarrhea and alopecia
• Paraonychia, pustular dermatitis with acral and mucocutanoeus junction distribution
29
Zinc-Responsive Dermatosis: Bovine
* Lethal Trait A46
* Autosomal recessive
* European Friesian & Black Pied Cattle
* Intestinal malabsorption of Zn.
* Onset of lesions occurs at 4-8 weeks of age
* Erythema, crust, alopecia, on the face, distal limbs, and mucocutaneous junctions.
* Other clinical signs include conjunctivitis, rhinitis and diarrhea
* Fatal if left untreated.
* Histopathology: hyperplastic superficial perivascular dermatitis w/ marked diffuse parakeratosis.
* Also: Hypoplasia and lymphocyte depletion of thymus, lymph nodes, and spleen
* Treatment: ZnO PO q.24 hrs or ZnSO4
30
Zinc-Responsive Dermatosis Syndrome 1: Canine
• Siberian Huskies & Alaskan Malamutes
o Other breeds like the Bull Terrier may be affected
• Siberian Huskies and chrondrodysplastic Alaskan Malamutes have a genetic defect
• Malamutes: decreased capability for zinc absorption from the intestine exists
• Skin lesions develop despite well-balanced diets with sufficient zinc
• Early in adulthood (1 to 3 years of age) and progress at a variable rate
• Age of onset can range from 6 months to 10.5 years with 41% of dogs developing lesions before 2 years old
• Most September through January. (Northern hemisphere – autumn/winter)
Clinical signs:
• Over one-half of the dogs have lesional pruritus & pruritus in “normal” skin can be the hallmark of a pending relapse during maintenance
• Early erythema is followed by alopecia, crusting, scaling, and underlying suppuration around the mouth, chin, eyes, and ears can be present.
• Other body openings and the scrotum, prepuce and vulva may be affected
• Lesions are often unilateral initially but become symmetrical as the disease progresses
• Although the coat is dull, there is excess sebum production
• Thick crusts may appear in the elbows and other pressure points
• The skin may be inelastic and the legs stiff, as a result of hardened crusts.
• Footpads may become hyperkeratotic and claw disease, especially onycholmalacia, may be observed
• Chronic lesions may be hyperpigmented
• Clinical signs may be precipitated or intensified by stress, illness, and estrus
• A decreased sense of smell (hyposmia) and taste (hypogeusia) may be evident
• Secondary bacterial and Malassezia infections are common, especially when there is pruritus - resulting from breakdown of the normal epithelial barrier as well as the paucity of zinc which leads to impaired immunocompetence
31
Zinc-Responsive Dermatosis Syndrome 2: Canine
* Rapidly growing puppies or young adult dogs that are fed zinc deficient diets, diets high in phytates or minerals discussed above
* Many breeds may be abnormal, but Great Danes, Doberman pinschers, Beagles, German Shepherds, German Shorthaired Pointers, Labs, Rhodesian ridgebacks and Standard Poodles
* Generic dog food disease may be a variant of syndrome 2.
* Severity of clinical signs within a litter are variable & may range from unaffected to depression, anorexia, stunted growth, pyrexia, and lymphadenopathy
* Dermatologic lesions: hyperkeratotic plaques over areas of repeated trauma, footpads & nasal planum may be affected, and any thickened area may have deep fissures.
* Secondary infection of the crusts & an associated lymphadenopathy
* Severely affected dogs can resemble canine distemper.
* Diagnosis for both syndromes is made from the history, physical examination, skin biopsies and response to Zn supplementation.
* Histopath – superficial perivascular dermatitis, with marked diffuse and follicular pararkeratotic hyperkeratosis is suggestive of Zn responsive dermatosis.
* Papillomatosis and mild diffuse spongiosis are also common. Eosinophils and lymphocytes are often prominent in the perivascular cellular infiltrate. Intraepidermal pustular dermatitis and suppurative folliculitis reflect secondary bacterial infection
* Extracutaneous histological lesions – include irregular epithelial hyperplasia and dysplasia of the buccal mucosa as well as a marked absence of lymphocytes in the thymus and T-cell regions of the lymph nodes and spleen – all of these changes indicate alteration in lymphocyte (T-cell) development or migration.
* DDX: dermatophytosis, demodicosis, PF, SLE, mucocutaneous pyoderma, SND
32
Zinc-Responsive Dermatosis: Llamas
• Idiopathic Hyperkeratosis (zinc-responsive dermatosis)
• Common disorder; Usually recognized first in 1 to 2 year old llamas but age of onset is variable
• Both sexes affected, although males may be over-represented.
• Disease has developed in spite of the fact that dietary zinc concentration appear to be adequate
• Lesions are most common over the ventral abdomen, inguinal region, medial thighs, and axilla
• Initially papular, progressing to raised alopecic plaques with a dry adherent scale
• Larger areas of involvement often give the skin a diffusely thickened appearance & feel
• Lesions do not appear inflammatory
• As the disease progresses there may be involvement of the face (especially bridge of the nose) & distal extremities.
• Lesions usually are asymptomatic although on occasion mild pruritus may be noted.
• No systemic symptoms.
• Histopathology: Marked epithelial and follicular orthokeratotic hyperkeratosis
o A mild to moderate perivascular dermatitis, characterized by increases in lymphocytes, macrophages, and eosinophils.
• Treatment: daily supplementation with zinc sulfate, may discontinue alfalfa hay as high in Ca
33
Treatment of Canine Zn Responsive Dermatosis
* For syndrome II – inspect and correct any inadequacy in the diet, including base diet, water and any supplements or treats. Dietary adjustments can resolve the skin lesions in 2 to 6 weeks.
* In syndrome I, Zn supplementation is necessary and approximately 25% of dogs can have the Zn supplementation stopped without an immediate relapse in the condition
* Oral Zn supplementation –vomiting is the main adverse reaction.
* Zn sulfate tablets should be crushed and mixed with food to enhance absorption and decrease gastric irritation
* Zn gluconate –Zn methionine –
* In syndrome I, Zn administration is typically lifelong; in syndrome II the supplement can be withdrawn when the skin has returned to normal and the diet has been corrected. If no response is seen within 4 weeks after initiating therapy, the dosage should be increased by 50%.
* In dogs that do not improve with oral supplementation – IV administration of sterile zinc sulfate transient panting and cardiac arrhythmias have been observed as an adverse effect of IV Zn supplementation
* Low dose corticosteriods – may be indicated in dogs that do not respond to zinc alone. GC’s are known to increase zinc absorption for the GI tract by induction of metallothionein, but they may also have some direct anti-inflammatory effect on the skin
* Other options – tetracycline and lincomycin; topical therapy with warm water soaks and antibacterial or antiseborrheic shampoos may aid in controlling infections and crust removal.
* EFA supplementation
34
Lethal Acrodermatitis of Bull Terriers
* Inherited autosomal recessive trait that strongly resembles severe zinc deficiency
* Does not respond to oral zinc supplementation.
* Metabolic disease of bull terriers
* In 28 cases, all dogs had difficulty eating, were stunted in comparison with littermates, and had splayed digits giving the appearance of large, flat feet.
* Early skin changes consisted of erythema and tightly adherent scale and crust involving primarily the feet, distal limbs, elbows, hocks and muzzle, other body areas including the trunk and tail were occasionally involved
* Other clinical findings include nasal discharge 7/28, skeletal deformities 5/28, systolic murmurs 3/28, and abnormal ocular changes 2/28
* In general, dogs that survived 6 months of age or older developed severe skin disease with marked pad hyperkeratosis nail disease and paronychia.
* Plasma zinc levels in 22 dogs were not statistically different when compared to dogs with atopic dermatitis
* Malassezia & Candida organisms could be found
* Histopath – most prominent feature diffuse, marked parakeratotic hyperkeratosis.
* Mild to moderate acanthosis together with superficial perivascular dermatitis were also common.
* Laminar pallor of the upper epidermis due to hydropic changes of keratinocytes was an additional finding noted in some biopsy specimens
35
Generic Dog Food Skin Disease
*** stupid but just in case....***
• Developed bilateral symmetrical scaling & crusting dermatoses within 1 month after consuming the diet
• Lesions: bridge of the nose, mucocutaneous junctions, pressure points, & distal extremities.
• Well-demarcated, older lesions had erythematous borders with scales, crusts, and variable hyperpigmentation and lichenification.
• A few had pustules, papules, focal erosions and alopecia
• Most had fever, depression, lymphadenopathy, and pitting edema of dependent areas
• Histopath – hyperplastic superficial perivascular dermatitis with diffuse parakeratotic hyperkeratosis, prominent focal keratinocyte apoptosis and a mixed dermal cellular infiltrate
36
Swine Parakeratosis
• Pathogenesis is unknown, but is related to zinc and EFA deficiency;
• Exacerbated by high levels of dietary calcium, phytates and other mineral and chelator agents
• The condition occurs only extremely rarely in animals with access to pasture grass
• Temporary, nutrition related metabolic disorder of rapidly growing pigs
• Occurs in housed feeder pigs 7-20 weeks of age; no sex or bred predisposition
• Clinical signs: 1st erythematous macules & papules on the ventral abdomen and medial thighs;
Then spread and evolution to hard, dry crusts, especially on the distal limbs, face, ears, tail, and ventrum
No pruritus, no seborrhea; secondary skin infections are common (especially hock abscesses).
Reduced appetite, growth rate and feed utilization; occasionally diarrhea & vomiting
• Histopathology: hyperplastic superficial perivascular dermatitis, parakeratotic hyperkeratosis; edema in superficial dermatitis, perivascular accumulation of mononuclear cells and eosinophils
• Diagnosis: history, herd status, PE, histopath, decreased ALP
• Therapy and prevention: supplementation with Zn salts
• Evolution: self-limiting disease: spontaneous recovery in 10-45 days depending on severity
37
Structure of Lipids
The basic subunits of lipids are hydrocarbon molecules linked by covalent bonds
Most dietary and body fats consist of free fatty acids, long aliphatic carbon chains with a terminal methyl (CH3) group at one end and a carboxyl (COOH) group at the other.
Fatty acids may be saturated or unsaturated.
38
Saturated fatty acids
Saturated fatty acids are straight carbon chains without double bonds
39
Unsaturated fatty acids
Unsaturated fatty acids have one or more double bonds
**Saturated and monounsaturated fatty acids can be derived directly from the diet or synthesized de novo by mammals
40
The majority of fatty acid biosynthesis occurs in the _____(organ)
Liver
41
Polyunsaturated Fatty Acid Biochemistry
PUFA’s are unsaturated fatty acids with two or more double bonds.
• A shorthand identification system commonly used identifies the:
o Number of carbon atoms
o Number of double bonds
o Position of the first double bond counting from the terminal (“omega” or “n”) methyl end of the molecule
E.g. LA (18:2n-6) is an 18 carbon molecule with two double bonds, with the first double bond located between the sixth and seventh carbon.
42
PUFAs determined to be essential for normal growth and health are:
* LA – linoleic acid
* AA – arachidonic acid
* EPA – eicosapentaenoic acid
* DHA – docosahexaenoic acid
43
Establishing double bonds in fatty acids requires microsomal _____,
desaturase enzymesMammals can introduce double bonds starting at C9-10
If a double bond is not present in the -9 position, the other desaturase enzymes cannot work.
Consequently, mammals are unable to synthesize LA or ALA, but can make AA from LA and EPA from ALA
Cats lack -6-DES, have limited -5-DES activity, unable to synthesize AA, and therefore must be obtained directly from the diet.
44
Define essential fatty acid (EFA)
An EFA is a PUFA that cannot be synthesized by animals but is required for normal physiologic function.
• LA is the key EFA because without LA and AA animals will die
• AA and EPA are essential constituents of cell membranes and CNS tissue
• LA and ALA the precursors to the required AA and EPA cannot be made de novo and must be derived from dietary sources.
45
Three families of unsaturated fatty acids are critical to the therapeutic importance of EFA’s
```
Plant derived (-linolenic) and fish oil derived (eicosapentaenoic acid) n-3 family
Plant derived n-6 family
De Novo (nonessential) fatty acid family (n-9 family)
```
46
List members of the n-3 family
* -linolenic acid (18:3n-3)
* Eicosapentaenoic acid (20:5n-3)
* Docosahexaenoic acid (22:6n-3)
* Green leafy vegetables
* EPA is a metabolic product of ALA; marine fish oil
47
List members of the n-6 family
* Linoleic acid (18:2n-6)
* -linolenic acid (18:3n-6)
* Arachidonic acid (20:4n-6)
* Vegetables; abundant in certain seed oils
* E.g. safflower or sunflower seed
* GLA, a -6-DES product of LA, may be derived from the seed oils of the borage, evening primrose, and black currant plants
48
De Novo (nonessential) fatty acid family (n-9 family)
* Palmitic acid (16:0)
* Oleic acid (18:1n-9)
* Synthesized de novo from acetyl coenzyme A by the liver and tissue microsomes
A number of fungal sources such as oil of javanicus produced from Mucor javanicus are also rich in EFA’s
49
What are the three main functions of EFAs?
1. Act as a structural component of cellular membranes (primarily AA)
2. Maintain the epidermal water barrier
3. Parent compounds for eicosanoids
50
Eicosanaoids include:
o Prostacyclins
o Prostaglandin (PG)
o Thromboxanes (TX) which are termed prostanoids
o Leukotrienes (LT)
o Lipoxins (LX)
o Hydroperoxy-eicosatetraenoic acids (HPETE)
o Hydroxyeicosatetraenoic acids, (hydroxy fatty acids or HETE)
51
Describe how EFAs are a structural component of cellular membranes
• Physical & functional properties of cell membranes are determined by their phospholipid f.a. composition
• Important implications for cell integrity, growth, inflammation & immunity
• Without PUFA’s membranes incorporate straight chain saturated fatty acids
o These membranes are less fluid and thus become unstable.
o The increased tissue permeability that results, leads to nutrient and water loss, alteration of normal membrane receptors, enzyme activity, and altered cytokine production
• AA is also an important regulator of epidermal proliferation
52
Describe how EFAs maintain the epidermal water barrier
• This function is dependent on the LA-containing lipids (ceramides) in the intercellular lamellar granules extruded from epidermal keratinocytes at the stratum granulosum-stratum corneum interface
53
How are EFAs parent compounds for eicosanoids?
* AA, EPA and GLA are precursors of eicosanoids. • Produced in response to physical and chemical insults such as trauma, thermal injury, ischemia, endotoxin release, antigen antibody interactions, increased intracellular calcium, cytokine production, or histamine release.
* Such stimuli result in the cleavage of the PUFAs through the action of phospholipase A2 (leukocytes) and phospholipase C (platelets).
* Eicosanoids are formed by subsequent oxygenation of the PUFAs by local cyclooxygenase and lipoxygenase enzymes.
* The release of AA from its membrane store is the rate-limiting step in eicosanoid synthesis.
* Its availability for eicosanoid synthesis requires its liberation by a phospholipase
54
The release of _____ from its membrane store is the rate-limiting step in eicosanoid synthesis.
AA - arachidonic acid
**Its availability for eicosanoid synthesis requires its liberation by a phospholipase
55
Eicosanoids derived from omega-6 fatty acids (DGLA or AA) are generally _______.; While, eicosanoids produced from omega-3 fatty acids (EPA) have _______.
Pro-inflammatory, pro-aggregatory, and immuno-active.
| Little or no inflammatory activity, and act to modulate platelet aggregation and immune-reactivity.
56
PGE2 is considered proinflammatory in the ____, but is protective of ______.
skin
| gastric mucosa
57
What is the pathogenesis of cutaneous inflammation?
• Inflammation begins with transient vasoconstriction
Followed by vasodilation
Increased blood flow
Increased vascular permeability
Extravasation of plasma into the injured tissue
• Damaged cells release interleukins, and other chemotactic factors:
Recruit leukocytes and mast cells
Release mediators - histamines, bradykinin, serotonin, liposomal enzymes, & eicosanoids
Further promote the inflammatory response or help bring it to an end.
58
What is PG role in inflammation?
PGs potentiate vascular dilation, leading to erythema, edema, pain and heat at the site
Series 2 prostaglandins:
• Vasodilation
• increased vascular permeability
• Pain/Hyperalgesia
• Extracellular signal for NFB
• Increased keratinocyte DNA synthesis – proliferation
• increased histamine release from mast cells
• Smooth muscle contraction
• Decreased CD8 lymphocyte activity promote antibody synthesis
• And some even inhibits platelet aggregation
59
What is LTs role in inflammation?
LTs (especially LTB4) are potent chemotactic factors and attract additional inflammatory cells to the area
Actions of LTB4:
• Chemotaxis for neutrophils and eosinophils
• Activation of neutrophils and eosinophils
• Adherence of neutrophils and eosinophils
• Increased keratinocyte proliferation
• Enhanced NK cell activity
• Hyperalgesia
• Increased vascular permeability
• Superoxide generation by neutrophils
LTC4, LTD4, LTE4: SLOW REACTING SUBSTANCE OF ANAPHYLAXIS
60
Fatty Acid Deficiency
* Uncommon to rare and is seen only in animals that are fed dry rations, commercial food that has been poorly preserved (storage, temperature, preservative problems), or homemade foods
* Can be seen in dogs that are fed high-quality reducing dog foods in which the fat content has been lowered
* Other causes are low fats in feeds and diets or destruction of fat in feed during storage (mostly due to rancidity in the absence of antioxidants like VE)
* Oxidation of fat during storage causes it to become rancid and the EFA as well as the vitamins D, E and biotin are destroyed
* Intestinal malabsorption, pancreatic disease and chronic hepatic disease are also causes of FA deficiency
* Documented in horses, cows, swine, dogs, cats, and rats
* Clinical signs: Renal & reproductive abnormalities, decreased growth rate, immunologic abnormalities, hypotricosis, alopecia, exudation, scaling, weak cutaneous blood vessels and increased tendency to bruise, decreased wound healing, sebaceous gland hypertrophy accompanied by increased sebum viscosity and increased transepidermal water loss
* There is an early decrease in lipid production with resultant fine scaling and loss of luster and sheen of the hair – the dry phase can last for months and can have associated hair loss and secondary bacterial infections
* Later the skin thickens, becomes greasy, especially in the ears, in the intertriginous areas, and between the toes; The dryness of the coat is replaced by greasiness and many become pruritic
* Histopath for all animals – orthokeratotic or parakeratotic hyperkeratosis, hypergranulosis, epidermal hyperplasia
* Consequences of the deficiency
* When LA and AA are absent, oleic acid (18:1n-9) or mead acid (20:3n-9) is incorporated into cell membranes as a substitute for the essential n-6 fatty acid
* Cellular membrane integrity is lost and clinical signs of EFA deficiency appear.
* A decrease in LA (thus AA) and its replacement by n-9 fatty acids also result in a decrease in epidermal prostaglandin E2 (PGE2), this decrease may play a role in epidermal hyperproliferation observed in EFA deficiency.
* Abnormal keratinization is thought to result from AA deficiency with a resultant PGE deficiency, which causes aberrations in the ratios of epidermal cAMP and cGMP and in DNA synthesis
* All abnormalities can be reversed by vegetable oil supplementation in large animals.
* Excessive fat supplementation is contraindicated in cases in which the FA deficiency is intentional, such as in the management of obesity, pancreatic disease, or hyperlipidemia disorders.
* In these cases, treatment with a balanced omega 6 & omega 3 FA supplements may be of some benefit.
* When dietary fat supplementation is impossible, topical application of EFAs may be of some benefit
* Studies in mice have shown that topically applied fats can correct the cutaneous changes of fatty acid deficiency
* FA deficiency responds gradually to supplementation
* Mild cases respond in 4 to 8 weeks, but severe cases can take up to 6 months.
* There is no specific test for fatty acid deficiency; the diagnosis is confirmed by response to treatment
61
Fatty acid requirement/deficiency CS in different species
* Swine – experimental deficiency produced with diets containing 0.06% fat (requirement 1% caloric intake must be linoleic acid) usual rations are not low enough in essential fatty acids to cause deficiency; other recommendations for swine are that fats = 1% total ration for swine
* Swine parakeratosis may be at least partially caused by fatty acid deficiency
* Dog food should have a minimum of 3% fat in canned food and 7 to 8% fat in dry food
* Cats usually have 35-40% of their calories provided by fat a much higher amount because they need a dense caloric formula
* Chinchilla – FA deficiency: generalized scaling, poor haircoat, reduced hair growth, & cutaneous ulcers
* G. Pig – generalized alopecia, scaling, and dermatitis
* Hamsters – generalized alopecia, scaling, and the production of profuse amounts of cerumen
* Mouse – exfoliative dermatitis
* Rat – exfoliative dermatitis and occasionally necrosis of the tail
62
What domain of DNA does retinoid acid bind to?
RA bind to regulator regions in DNA called hormone response elements and they activate gene transcription in a ligand dependent manner.
For RA this domain in termed RARE and for Vitamin D the domain is VDRE.
63
Retinoid acid MOA?
Vitamin A, in the retinoic acid form, plays an important role in gene transcription. Once retinol has been taken up by a cell, it can be oxidized to retinal (by retinol dehydrogenases) and then retinal can be oxidized to retinoic acid (by retinal oxidase). The conversion of retinal to retinoic acid is an irreversible step, meaning that the production of retinoic acid is tightly regulated, due to its activity as a ligand for nuclear receptors. Retinoic acid can bind to two different nuclear receptors to initiate (or inhibit) gene transcription: the retinoic acid receptors (RARs) or the retinoid "X" receptors (RXRs).
Once the retinoic acid binds to the receptors and dimerization has occurred, the receptors undergo a conformational change that causes co-repressors to dissociate from the receptors. Coactivators can then bind to the receptor complex, which may help to loosen the chromatin structure from the histones or may interact with the transcriptional machinery. The receptors can then bind to the response elements on the DNA and upregulate (or downregulate) the expression of target genes, such as cellular retinol-binding protein (CRBP) as well as the genes that encode for the receptors themselves
64
What are the two nuclear retinoid acid receptors required to initiate (or inhibit) gene transcription?
RAR and RXR must dimerize before they can bind to the DNA. RAR will form a heterodimer with RXR (RAR-RXR), but it does not readily form a homodimer (RAR-RAR). RXR, on the other hand, readily forms a homodimer (RXR-RXR) and will form heterodimers with many other nuclear receptors as well, including the thyroid hormone receptor (RXR-TR), the Vitamin D3 receptor (RXR-VDR), the peroxisome proliferator-activated receptor (RXR-PPAR) and the liver "X" receptor (RXR-LXR).
65
What is the different between RAR-RAR homodimer and RXR-RAR reterodimer?
The RAR-RXR heterodimer recognizes retinoid acid response elements (RAREs) on the DNA whereas the RXR-RXR homodimer recognizes retinoid "X" response elements (RXREs) on the DNA. The other RXR heterodimers will bind to various other response elements on the DNA.
66
What is AP1? What inhibits AP1 activity?
• AP-1 is a complex of the proto-oncoproteins Jun & Fos and is a powerful transcription factor that is induced by cytokines, growth factors, tumor promoters, and sunlight.
o Increased AP-1 activity increases transcription of cytokines like IL-2 & metalloproteases
o RA treatment inhibits the action of AP-1
o Reciprocally, elevated expression of either Jun or Fos component of AP-1 has the potential to prevent activation of RARE by RARs.
o A RAR-AP-1 is a nonproductive complex
67
RA MOA Summary
• Profound effects on cell proliferation and differentiation – especially keratinizing epithelia
• In general retinoids:
o Suppress differentiation of basal keratinocytes
o Promote keratinocyte proliferation in normal skin
o Downregulate hyperproliferative states in keratinocytes
• Delivery of synthetic retinoids to target tissue
o Unbound drug is available to enter cells and does not require receptor interaction
o Translocated to nucleus perhaps by CRABP and thus does not interfere with normal Vit A metabolism
68
Regulation of Vit D and RA responsive genes by RXR in skin
Because RXR heterodimerizes with either VDR or RAR to regulate gene transcription by binding to VDRE or RARE, it serves as a key protein in controlling the overall VD or retinoid response of a given biological system
69
Vitamin A deficiency leads to....
Epidermal hyperkeratosis
Squamous metaplasia of MM
Keratinization disorders
Precancerous conditions
70
Vitamin A physiology
o Can’t be made by body, must be ingested through the diet
o Important for vision, repro, regulation of embryogenic development/morphogenesis, promotion of general growth, and immune modulation, epithelial differentiation and normal growth
o Precursor to Vit A = Carotenoid (synthesized by plants), which is ingested & oxidized into Vit A
• One molecule of beta carotene is converted into 2 molecules of retinal, then absorbed
• Vit A from meat, eggs, and milk: provide retinal esters hydrolyzed to retinol in intestines & stored in the liver as retinal palmitate
71
Describe the 3 generations of Vit A
1.Manipulate the polar end group and the polyene side chain and you get:
First generation retinoids: are non-aromatic
Tretinoin
Isotretinoin
Alitretinoin
2.Manipulate the cyclic end group w/substituted & non-substituted rings systems you get:
Second Generation retinoids: monoaromatic
Etretinate (Tegison)
Acitretin (Soriatane)
3.Manipulate cyclization of the polyene side chain you get:
Third generation retinoids: polyaromatic: interact selectively w/specific receptors
Include the arotinoids and selected other retinoids
Tazarotene (Tazorac)
Adapalene (Differin)
Bexarotene (Targretin)
72
What is the absorption and distribution of vitamin A?
o Oral bioavailability improved with food intake
o Transported by plasma proteins
o Accumulation in the liver
o Very little lipid deposition of isotretinoin and acitretin
o But etretinate is 50x’s more lipophilic than its metabolite acitretin
• Increased storage in fat, slowly released
• Can persist for at least several years in various fatty tissues like SQ
• Small amounts in breast milk so that infant receives 1.5% of the maternal dose therefore must be avoided during breast feeding.
73
What is the metabolism and excretion of vitamin A?
o Liver metabolism: involves oxidation & chain shortening to biologically inactive, water soluble products
o The oxidative metabolism is induced mainly by retinoids themselves and possibly also agents that induce CYP-450 3A4
o All are excreted in urine and feces
o T ½ vary:
• First gen Tretinoin: 40-60 minutes
• Third gen Bexarotene: 7-9 hours
• First gen Isotretinoin : 10-20 hours
• Second gen Acitretin: 50 hours
• Second gen Etretinate: 80-160 days
o Alcohol indirectly enhances the re-esterification (or “reverse metabolism”) of acitretin to etretinate (8 glasses of ethanol in 3 hours for an adult male)
• The levels of etretinate produced were similar to taking one 5 mg oral dose of etretinate.
• Since etretinate has the longest T ½ this finding led to recommendation that contraceptive use after cessation of acitretin be: 2 years: Europe & 3 years: US.
o Inability to detect plasma etretinate is a poor predictor of the absence of etretinate in the fat.
• When monitoring acitretin and etretinate levels, both should be quantified in the SQ tissue when plasma levels are negative.
74
Isotretinoin: MOA
o Activate nuclear receptors -and- Regulate gene transcription
• Inhibit sebaceous gland differentiation and proliferation
• Reduce size of seb glands
• Suppress sebum production
• Suppress skin DHT production
• Down regulate skin androgen receptors
• Normalization of follicular epithelial desquamation
• Inhibit neutrophil chemotaxis
Summary: anti-inflammatory, reduce impacted hyperkeratotic infundibula and comedones, decrease sebum production
75
Etretinate/Acitretin: MOA
o Activate nuclear receptors -and- Regulate gene transcription
• Probably inducing cellular differentiation, anti-proliferation, anti-inflammation, anti-keratinization
• Inhibit neutrophil chemotaxis
Summary: antipsoratic
76
Bexarotene: MOA
o Activate nuclear receptors -and- Regulate gene transcription
• Trans-activate retinoid X receptor: RXR-α,β,γ
• Regulate cellular differentiation and proliferation
Summary: differentiation/anti-proliferation of cutaneous T-cell lymphoma
77
How is Vitamin A transported?
In the serum: provided by a complex of retinol binding protein (RBP) and transthyretin (formerly known as pre-albumin)
At the cellular level:
• For retinol: retinol is released from the liver and bound to a surface receptor and translocated to the nucleus by cytosolic RBP (CRBP)
CRBP-I is responsible for cellular uptake of retinol from plasma, solubilizes and renders retinol non-toxic in the cytoplasm, and delivers it to the appropriate enzymes to form RA (biologically active form) or retinyl esters (storage form).
• For retinoic acid:
The physiologically active form (RA) is mainly in the all-trans-form (ATRA), some is 13-cis RA.
Albumin provides serum transport
It has a separate intracellular carrier = CRABP = cytosolic RA binding protein.
Transports RA to the cell nucleus
In high levels in epidermis & markedly elevated in lesional psoratic skin.
CRABP I modulates levels of RA in various tissues; decrease CRABP II (predominant form in human epidermis) with application of retinoids
Acitretin competes with RA for CRABP
CRABP levels decreased by 200% in non-lesional skin of psoratic patients treated with Acitretin, with little to no further increase within psoratic plaques
78
What protein is responsible for cellular uptake of retinol from plasma, solubilizes and renders retinol non-toxic in the cytoplasm, and delivers it to the appropriate enzymes to form RA (biologically active form) or retinyl esters (storage form).
CRBP-I (cellular retinol-binding protein)
79
What protein modulates levels of RA in various tissues; decrease CRABP II (predominant form in human epidermis) with application of retinoids.
CRABP I ( cellular RA-binding protein)
Acitretin competes with RA for CRABP
CRABP levels decreased by 200% in non-lesional skin of psoratic patients treated with Acitretin, with little to no further increase within psoratic plaques
80
Retinoids can induce both direct and indirect effect on gene transcription
Direct: mediated through retinoic acid response elements (RARE’s) in the promoter regions of target genes.
o RAR/RXR heterodimers can bind directly to RARE’s
o Multiple types of RARE’s allow for various physiobiologic and morphogenic effects.
• Indirect: Retinoids can down regulate genes that DO NOT have RARE’s, this inducing an indirect negative effect on gene transcription
81
Three types of retinoid ligands that bind to RAR’s and result in 3 different types of gene transcription regulation
Retinoids can be agonists of gene transcription
• Inverse agonists of gene transcription
• Neutral antagonists of gene transcription
82
RA immunologic and anti-inflammatory effects:
1. Etretinate can correct over expression of IL-6, IL-8, ICAM-I and ELAM-1
2. Correct HLA-DR abnormalities (an MHC molecule is called a human leukocyte antigen, HLA-DR belongs to the Class II set of MHC molecules)
3. Reduce the release of leukotrienes and HETE products
4. May inhibit Ig synthesis from B cells
5. Reduce lymphocyte proliferation by 20-30%
6. Decrease cytotoxic T lymph (CD8+s) induction
83
RA effects on protein kinases
Increase the level & activity of PKA (protein kinase A) (psoratic patients deficiency of PKA)
Promote an increase binding of cAMP to the RI-cAMP binding protein
84
RA anti-keratinizing effect
Modulate the expression of keratins in vitro.
Tretinoin and isotretinoin down regulate K6 and 16
Etretinate and acitretin induce differentiation and reduce hyperplasia in psoriasis
85
RA anti-acne and sebum effects
Inhibit lipid synthesis
Isotretinoin can cause 80% decrease in DHT: is important for sebum production regulation
Other first generations and second and third generations do not alter lipids
86
RA effects on apoptosis
Regulates expression of Bcl-2 and tissue transglutaminase and caspase proteolytic activity.
87
RA anti-tumor and anti-proliferative effects
Tazarotene normalizes EGF-R expression (overexpressed in psoriasis)
88
RA effects on Intercellular matrix components:
Inhibit proliferation of fibroblasts
Decrease collagen type I and III synthesis
Explains why retinoids at high doses interfere with wound healing
89
What are retinoids effects on cell membranes?
o At lower doses, retinoids appear to stabilize cell membranes
o At higher doses they have a detergent – like effect that leads to labilization of lysosomal membranes, with enzyme release and toxicity.
90
How does retinoic acid interferes with cornification?
* During terminal differentiation, Retinoic acid interferes with cornification by suppressing the expression of epidermal transglutaminase I (crucial to the cross-linking and formation of the CCE), and cholesterol sulfate
* RA decreases the total keratin content of keratinocytes and changes keratin expression patterns
91
What are the anti-proliferative effects of retinoid acid?
The antiproliferative effects of retinoids may be their ability to block the cell cycle in the G-1 phase and thus inhibit the ornithine decarboxylase induction necessary for cell cycle progression
92
Adverse effects of RA
Teratogenic (CNS, craniofacial and thymic malformation, cardiac)
Ocular = reduce night vision, dry eye, S. aureus infection
Bone = DISH, osteophyte formation, osteoporosis, premature epiphyseal closure
Lipids = elevated cholesterol or triglycerides
GI = IBD, pancreatitis 2° to increase triglycerides)
Hepatic = toxic hepatitis, transaminase elevations
Endocrine = hypothyroid, DM (controversial)
Hematologic = leukopenia, agranulocytosis
Nuerologic = depression (suicidal ideation)
Muscle = myopathy
Minor adverse effects that are relatively common:
• Cutaneous: xerosis, palmoplantar and digital desquamation, retinoid dermatitis, photosensitivity, pyogenic granulomas, sticky sensation, S. aureus infections
• Hair: telogen effluvium, abnormal hair texture and dryness
• Nails: softening, fragility, paronychia, onycholysis
• Ocular: dry eye, visual blurring, photophobia, blepharoconjuctivitis
• Oral: cheilitis (esp lower lip) dry mouth, sore mouth and tongue
• Nasal: dry mucosa, decreased mucus secretion, epistaxis
• Musculoskeletal: arthralgia, myalgia, fatigue, tendinitis
• Neurologic: headache, mild depression
• GI: nausea, diarrhea, abdominal pain
Contraindications: Pregnancy, Nursing mother, Leukopenia, Hypothyroid w/Bexarotene, Increased cholesterol or triglyceride elevation, Hepatic dysfunction, Renal dysfunction
93
What drugs may INCREASE SERUM LEVELS OF RETINOIDS (thus increasing toxicity)
* Vit A
* Tetracycline, doxycycline, minocycline
* Gemfibrozil
* Macrolides, azoles, other CYP-450 3A4 inhibitors may increase retinoid drug levels
94
What drugs may DECREASE SERUM LEVELS of RETINOIDS via CYP-450 3A4 induction
* Antituberculosis drugs (rifampin, rifabutin)
| * Anticonvulsants (phenytoin, phenobarb, carbamazepine)
95
RETINOIDS may INCREASE drug levels and therefore toxicity of the following drugs
CSA
96
RETINOIDS may DECREASE drug levels of the following:
Progestin-only contraceptives
97
Describe the pharmacology of Tretinoin
Tretinoin and all-trans-retinol are naturally occurring retinoids so the human body has the binding proteins and enzymatic machinery in place to properly metabolize the retinoids.
Adapalene and tazarotene are not naturally occurring so metabolic pathways are more difficult to predict
98
What are the two different enzyme systems in keratinocytes that direct esterification and hydrolysis of retinyl esters?
1. Acyl CoA: retinol acyltransferase (ARAT), more important for topically applied retinol
2. Lecithin: retinol acyltransferase (LRAT), more important for endogenously supplied all-trans-retinol
99
Synthetic Retinoids: Vit A activity
• Retinol, retinoic acid, retinal derivatives or analogs
• More than 1500 synthetic retinoids have been developed and evaluated
• Different synthetic drugs may have profoundly different pharmacologic effects, side effects, and disease indications
• Different types of receptors, dimmers, response elements, and intermediary proteins means that physiology is mediated by many pathways.
• Non-selective retinoids that activate multiple pathways are likely to be associated w/ high incidence of adverse effects.
• Naturally occurring Vitamin A is an alcohol = all-trans-retinol. Oxidized to retinal and retinoic acid.
• Two most used in Vet Med
o Isotretinoin (Accutane) is a natural metabolite of retinol
o Etretinate (Tegison) is a synthetic retinoid
No longer available but many studies in vet med had used it.
Has been replaced by acitretin: less toxic, shorter half life (2 days vs 80-160 days)
• Function
100
Vit A function
o Enter cell and are transported to nuclei, interact with specific gene regulatory receptors.
o Natural Vit A works at the cellular level by binding first to cell membrane then transferring through the cellular cytoplasm by specific proteins
o Nuclear receptor families help transfer retinoid through the nucleus
o RAR = retinoic acid receptors
o RXR = retinoid X receptors
o Each has three members for a minimum of six different nuclear receptors.
o Can function as homodimer, heterodimer, or with other nuclear receptors such as those for Vit D3 and thyroid hormone
o Nuclear receptor and retinoid complex bind with target genes and alter gene transcription
• Another mechanism is by suppression of other nuclear transcription factors, which results in less production of other proteins. May be mechanism responsible for anti-inflammatory effects and described earlier as an indirect effect
101
Vit Sensitivity
* Depends on relative and absolute levels of cellular and nuclear binding proteins present in target cell
* Once genetic changes are made, the cells may alter growth and differentiation by altering expression of growth factors, keratins, and transglutaminases. Also down regulation of nitrites and TNF-α.
102
Vit A effects
```
• Variable
o Anti-proliferative
o Anti-inflammatory
o Immunomodulatory
o Regulate proliferation, growth, & differentiation of epithelial cells: major benefit in derm
```
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Isotretinoin
o 1-3 mg/kg q24h
o Give with food
o Toxicity less of a problem in dog/cat than human
o Dog: conjunctivitis, hyperactivity, pruritus, pedal and MC junction erythema, stiffness, vomiting, diarrhea, KCS.
• Hypertriglyceridemia, hypercholesterolemia, Increase ALT, AST, Alk Phos.
o Cats: conjunctivitis, diarrhea, anorexia, vomiting. Side effects may be transient or self limited with discontinuation or decreased dose.
o Potential teratogens
o For diseases that require alteration or normalization of adenexal structures:
• Schnauzer comedo syndrome
• SA
• Ichthyosis
• Feline acne
• Epitheliotropic lymphoma
• Keratocanthoma
• Sebaceous gland hyperplasia
• Adenomas
Ineffective for primary idiopathic seborrhea of the cocker and basset, and epidermal dysplasia of the westie, paraneoplastic and SCC lesions in cats.
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Etretinate
(again no longer available, except possibly Japan?)
o Give low fat diet
o 1 mg/kg q 24h.
o Indicated for
• Primary idiopathic seborrhea of the Cocker, Springer, Golden, Irish setter, & crosses
• Ichthyosis
• Solar dermatosis
• SCC of dog
• Keratocanthoma may improve (isotretinoin more effective)
Not effective in bassett, westie, or collie. Questionable for SA.
105
Acitretin
has not been documented in dogs/cats as been as effective as etretinate as has been shown in human derm
Currently dosed at the same or ½ the dose of etretinate; Give with food
106
Vitamin A deficiency (hypovitaminosis A)
• Associated with inhibition of cell proliferation and growth
• May lead to squamous metaplasia of a variety of epithelia, abnormal cornification, desquamation, stratification, and diminished wound healing
o Viatmin A enhances wound healing by promoting an early inflammatory response, and by increasing epithelialization, collagen synthesis, fibroplasia and angiogenesis
o Retinoids suppress malignant transformation in vitro caused by chemical carcinogens, ionizing radiation, growth factors, and viruses
o In most cases retinoids interfere with the promotion phase of carcinogensis, and they appear to act better as chemopreventive agents than as therapeutic agents
107
Vitamin A deficiency (hypovitaminosis A) in different species
* Bovine – marked scaling, crusting dermatosis; rough shaggy coat often faded – occurs when no access to greens or in association with chlorinated naphthalene toxicosis
* Porcine- follicular hyperkeratosis
* Feline – scaling follicular plugging, alopecia –
* Hypervitaminosis A (from all liver diet) – disheveled, seborrheic coats
* Canine – one report in mongrel dog – had severe seborrheic skin lesions, nyctalopia, and diarrhea since puppyhood. The skin was thickened, hyperpigmented, and alopecic, with marked follicular hyperkeratosis
* Equine – rough coarse dull hair coat, with a mild to severe inflammatory reaction at the coronary band, prolonged deficiency causes marked hyperkeratosis – this is very rare except in young growing horses maintained under prolonged extremely poor nutritional conditions (particularly if grains, which have a poor vitamin A concentration, are fed with very poor quality hay or straw)
108
Therapy with retinoids
* Types: isotretinoin, acitretin, and tretinoin (all-trans-retinoic acid) topical product.
* Generally classified as first generation (tretinoin, isotretinoin), second generation or monoaromatic (etretinate, acetretin), or third generation or polyaromatic (adapalene, tazarotene)
* Only retinol has all of the known functions of vitamin A
* Etretinate is no longer available because tissue residues in humans can persist for years after drug withdrawal and might result in foetal defects. It was replaced with acitretin, a free-acid metabolite of etretinate.
109
Acitretin (Soriatane)
* Second generation or monoaromatic
* Distribution: Acitretin is more than 99.9% bound to plasma proteins, primarily albumin.
* Absorption: Oral absorption of acitretin is optimal when given with food
* Metabolism: Following oral absorption, acitretin undergoes extensive metabolism and interconversion by simple isomerization to its 13-cis form (cis-acitretin). LIVER
* Elimination:
* Acitretin appears to be comparable to etretinate in efficacy and acute toxicity but b/c it has a much shorted terminal elimination half-life (2 days versus etretinate’s 100 days),
* Indications: disorders of epithelial or follicular development or keratinization. (As info for acitretin is limited specific indications are listed for etretinate)
110
Isotretinoin (accutane)
• Chemically, isotretinoin is 13-cis-retinoic acid and is related to both retinoic acid and retinol (vitamin A).
• Distribution: The drug is 99.9% bound in human plasma almost exclusively to albumin. Metabolism: The major identified metabolite in blood is 4-oxo-isotretinoin.
• Elimination: The mean elimination half-life of this metabolite is 25 hours (range 17-50 hours).
• MOA – sebaceous gland size, differentiation, and glandular production decreases in humans; rats and mice seb gl not affected except at lethal doses; hamsters show involution of glands only at toxic doses
• Alters lipid composition of sebum by decreasing wax esters(sebum) ; increasing cholesterol esters (skin)
• Also can see increase in stratum granulosum linoleate
• Absorption: When taken with food or milk, the oral absorption of isotretinoin is increased.
• Indications: Appears to be indicated in diseases that require alteration or normalization of adnexal structures, although some epidermal diseases, and beneficial effect may be by limiting sebum production •
***Ineffective – primary idiopathic seborrhea of Cockers and Basset hounds,
111
Tretinoin
• All-trans-retinoic acid
• Retin-A gel, cream and liquid, containing tretinoin are used for the topical treatment of acne, wrinkles and ichthyosis in humans. Retin-A Gel contains tretinoin
• Epidermal effects include:
• Reduction of stratum corneum cohesion, epidermal hyperplasia, amorphous intercellular and intracellular material, tonofilaments, desmosomes, melanosomes, and melanin production, as well as increased Langerhans cells.
• Dermal effects include:
• Increased production of collagen, tropoelastin, fibronectin, and angiogenesis and decreased glycosaminoglycans, collagnease, and gelatinase
Together these effects on keratinocyte behavior differs depending in stage of differentiation and result in:
• Increasing the epidermal turnover time
• Reducing the cohesiveness of keratinocytes
• Normalizing maturation of follicular epithelium AND keratinization of the pilosebaceous unit and prevents obstruction of the follicular unit thus
• Is comedolytic
• and in animal models it can prevent corticosteroid-induced skin atrophy
112
Tazarotene
* Brand name - Tazorac
* A synthetic acetylenic retinoid
* It normalizes abnormal differentiation and proliferation of keratinocytes, that may contribute to decreased corneocyte accumulation and cohesion
* It acts on RAR receptors and results in downregulation of keratinocyte proliferation, differentiation, and inflammation. It does this by a combination of effects, including the induction and activation of new genes, downregulation of AP1, and antagonizing the effects of IFN - .
* Psoriasis.
* Acne:
* Is readily eliminated without adipose tissue storage
113
Adapalene
* Brand name – Differin cream, 0.1
* Mechanistically, adapalene binds to specific retinoic acid nuclear receptors but does not bind to the cytosolic receptor protein. Although the exact mode of action of adapalene is unknown, it is suggested that topical adapalene may normalize the differentiation of follicular epithelial cells resulting in decreased microcomedone formation
* It also inhibits neutrophil activation and lipoxygenase enzymes
114
Feeding of diets enriched in these 6 nutrients may reduce the risk for development of atopic dermatitis in dogs if provided early in life?
In dogs, nutrients such as essential fatty acids, pantothenate, choline, nicotinamide, histidine, and inositol have proven beneficial effects on skin barrier function
115
_______ is a ceramide precursor, and it is hypothesized (but not yet proven) that topical application increases ceramide concentration in the skin.
Phytosphingosine
116
What are the three aromatic amino acids that contribute to changes in hair coat color?
phenylalanine, tryptophan and tyrosine
117
Phenylalanine is metabolized into ___ which is the precursor for melanin synthesis.
tyrosine
118
What are the two essential PUFAs for dogs?
Linoleic acid
| alpha - Linolenic acid
119
PUFAs have more than one double bond (unsaturated). Dogs and cats are unable to synthesize PUFAs when the double bonds are located where? What are these fatty acids called?
When double bonds are located at the 3 and 6 position from the carboxyl end; these fatty acids are referred to as omega-3 and omega-6 fatty acids.
120
What fatty acid is an important component of epidermal ceramides and is involved in maintaining the epidermal water permeability barrier?
Linoleic acid
Dogs can transform linoleum acid into arachidonic acid, but cats have low levels of 6-desaturase activity and cannot synthesize enough arachidonic acid to meet their physiologic requirement.
121
Arachidonic acid regulated epidermal proliferation via its metabolism into ____.
PGE2
Arachidonic acid is also metabolized into large miner pf other prostaglandins and leukotriene that have important roles in a variety of physiologic and pathologic processes.
122
What group of fatty acids are essential for normal development of the nervous systemic and retina?
Omega-3
123
Omega3 compete with n-6 fatty acids for incorporation into cell membranes and for metabolism by ______ and _______ enzymes.
cyclooxygenase
| lipooxygenase
124
Cats require a dietary source of preformed retinol because they are unable to synthesize it from it precursor _______.
B-carotene
Hypervitaminosis A in cats is seen with excessive amounts of liver.
125
Vitamin D is produces in the skin and has its major impact on calcium heomstasis. In addition, 1,25 dihydroxy vitamin D impacts _____ and ______.
keratinocyte proliferation and differentiation.
126
Vitamin E is a natural antioxidant that is important for maintaining stability of the cell membrane. Vitamin E along with selenium function to do what process during lipid metabolism?
Diets that are high in PUFAs increase oxidative stress through increased production of free radicals during their metabolism. The dietary requirement for vitamin E, therefore, is linked to the dietary intake of PUFA, and high fat diets can induce a relative deficiency of vitamin E.
127
Cats fed diets high in red tune or other PUFA-rich foods without receiving vitamin E supplements, may develop what disease?
pansteatitis
Lipid per oxidation in these cats results in necrosis and inflammation of subcutaneous and intraadominal fat. Biopsies of the affects areas demonstrate the presence of lobular panniculitis with ceroid (product of lipid per oxidation within the lipocyes, macrophages and giant cells.
128
What are the three main ways that supraphysiologic doses of vitamin E can be used for immunomodulatory effects?
antioxidant
stabilized lysosomes
reduces prostaglandin E
increases IL-2
129
What is an integral component of many metalloenzymes involved in regulating metabolism. It is an important cofactor for RNA and DNA polymerases, and particularly important in rapidly dividing cells such as those of the epidermis. It is also essential for biosynthesis of fatty acids and involved in vitamin A metabolism.
Zinc!
It its also required or normal immune function and involved in inflammatory reactions.
130
Bull Terriers with what disease have a genetic defect that inhibits zinc absorption and utilization. Also, this disease has been reported in a litter of Pharaoh hounds.
Lethal Acrodermatitis
Inherited autosomal recessive trait. It has been reported as A46 in black pied Danish Cattle.These dogs don't respond to supplementation. Suspected ZN and CU metabolism and have a 4x increase expression of haptoglobin, glutamine synthetase, prohibition, and K10.
131
What disease has occur primarily in Alaskan malamutes and Siberian huskies and appears to be associated with defective intestinal absorption of zinc?
Syndrome I zinc-responsive dermatosis
132
In some Siberian Huskies, what disease can occur concurrently with low serum zinc?
hypothyroidism
133
Oral zinc supplementation together with dietary correction bring s rapid resolution of zinc responsive dermatosis. What are the recommended initial doses of elemental zinc?
2-3 mg/kg daily
Zinc Sulfate at 10 mg/kg (zinc comprises about 23%)
Zinc methionine and Zinc gluconate are organic compounds containing zinc that have a higher bioavailability and less likely to cause gastric irritation.
134
What can be added to the treatment of Zn Responsive dermatosis that can aid in the bioavailability of zinc by hydrolyzing phytates in food?
phytase
135
How do GC aid in creasing zinc absorption from the GI tract?
Induction of metallothionein, and possibly some direct effect on the skin.
136
Syndrome II zn-responsive dermatosis occurs in what group of dogs?
Rapidly growing puppies and young adult dogs that are fed zn deficient diets, diets high in phytates or diets high in calcium.
** Ca interferes with the absorption of Zn
137
Probiotics are selected from members of normal, healthy intestine microbiota and include what three species?
Lactobacillis
Enterococcus
Bifidobacterium
138
Lactococcus lactis
engineered to produce IL-10, a cytokine that promotes immunologic tolerance.
139
Lactobacillius paracasei
shown to reduce Th1 and Th2 secretions of inflammatory cytokines while increasing production of TGF-b and IL-10
140
Lactobaciius casei
suppresses allergic responses in a murine model of food allergies.
141
What are the functions, signs of deficiency and signs of toxicity in Vitamin A?
Function: Important for cellular metabolism and regeneration of visual purpose in eyes; required for normal maturation of skin and hair follicles; essential for normal epithelial tissue lining digestive, respiratory and reproductive tracts; required for proper immune system functioning.
Signs of Deficiency: Epidermal hyperkeratosis and scaling, occlusion of sebaceous ducts, papule associated with follicular hyperkeratosis, poor hair coat and alopecia, reproductive failure; increased susceptibility to infections
Signs of Toxicity: Epidermal scaling, unkempt hair coat, anorexia, weight loss, bone decalcification and liver damage.
142
What are the functions, signs of deficiency and signs of toxicity in Vitamin D?
Function: Required for normal calcium absorption and metabolism, essential for normal bone development, Vitamin D also has a role in regulation of keratinocyte proliferation and differentiation.
Signs of Deficiency: Rickets in young, osteomalacia in adults, poor eruption of teeth.
Signs of Toxicity: Increased blood calcium levels, dot tissue calcification, diarrhea, kidney failure and death
143
What are the functions, signs of deficiency and signs of toxicity in Vitamin E?
Function: Antioxidant, protect cells from oxidative damage, may have a role in normal immune function.
Signs of Deficiency: Pansteatitis, seborrhea, impaired immunity (demodicosis)
Signs of Toxicity: anorexia
144
What are the functions, signs of deficiency and signs of toxicity in Vitamin K?
Function: Required for formation of clotting facts and normal blood clotting
Signs of Deficiency: Hemorrhage, increased bleeding times
Signs of Toxicity: none reported
145
What are the functions, signs of deficiency and signs of toxicity in Vitamin C?
Function: Antioxidant, required for formation and maintenance of bone, cartilage, and connective tissue.
Signs of Deficiency:Rickets, impaired wound healing, bleeding, anemia, increased susceptibility to infections.
Signs of Toxicity: none reported
146
What are the functions, signs of deficiency and signs of toxicity in Thiamine (B1)?
Function: Component of two coenzymes essential in carbohydrate metabolism and energy transfer, promotes normal heath and digestion and normal nerve function
Signs of Deficiency: Anorexia, weight loss, committing, dehydration, ventral flexion of neck, paralysis, incoordination.
Signs of Toxicity: Nontoxic
147
What are the functions, signs of deficiency and signs of toxicity in Riboflavin (B2)?
Function: Forms the parts of two coenzymes with roles in energy transfer and protein metabolism component of xanthine oxidase reused for epithelia cell maturation.
Signs of Deficiency: Retarded growth. dry scaly skin , erythema, anemia, pannus.
Signs of Toxicity: Nontoxic
148
What are the functions, signs of deficiency and signs of toxicity in Niacin?
Function: Component of two coenzymes with roles in energy transfer, required for metabolism
Signs of Deficiency:Nlactongue (pellagra), pruritic dermatitis, anemia, emaciation, death.
Signs of Toxicity: Cutaneous flushing and itching
149
What are the functions, signs of deficiency and signs of toxicity in Pyridoxine(B6)?
Function: Part of enzyme involved in protein metabolism, essential for norm metabolism of tryptophan.
Signs of Deficiency: Dermatitis with dull, waxy, alopecia and scaling, high iron levels, seizures.
Signs of Toxicity: Nontoxic
150
What are the functions, signs of deficiency and signs of toxicity in Calcium?
Function: Bone and tooth formation, blood clotting, enzyme activation, muscles contraction and nerve impulse transmission
Signs of Deficiency: Rickets, constipation, anorexia, lameness
Signs of Toxicity: Impaired skeletal development, secondary deficients of other mineral, especially zinc, phosphorus, and copper.
151
What are the functions, signs of deficiency and signs of toxicity in Pantothenic Acid (B5)?
Function: Constituent of CoenzymeA required for normal metabolism of carbs, fats and protein.
Signs of Deficiency: Anorexia, stunted growth, hypoglycemia, uremia, GE, seizures, fatty liver, coma and death.
Signs of Toxicity:Nontoxic
152
What are the functions, signs of deficiency and signs of toxicity in Folic Acid (B9)?
Function: Required for normal red blood cell development and DNA synthesis.
Signs of Deficiency: Anemia, leukopenia, stunted growth, glossitis
Signs of Toxicity:Nontoxic
153
What are the functions, signs of deficiency and signs of toxicity in Biotin?
Function: Required for metabolism of fats and amino acids, essential for skin and hair health, functions in enzyme systems
Signs of Deficiency: Scaly dermatitis, alopecia, anorexia, weakness, diarrhea
Signs of Toxicity:Nontoxic
154
What are the functions, signs of deficiency and signs of toxicity in Cobalamin (B12)?
Function: Required for synthesis of nucleic acids, involved in purine synthesis and carb/fat metabolism.
Signs of Deficiency: Anemia, impaired growth, incoordination.
Signs of Toxicity: Nontoxic
155
What are the functions, signs of deficiency and signs of toxicity in Phosporus?
Function: Bone and tooth development, part of RNA and DNA.
Signs of Deficiency: Rough hair coat, pica, anorexia, slow growth, rickets, osteomalacia.
Signs of Toxicity: Impaired skeletal development, secondary deficiency of calcium, kidney damage
156
What are the functions, signs of deficiency and signs of toxicity in Sodium?
Function: Muscle contractions, maintenance of body fluid volumes, nerve function
Signs of Deficiency: Salt hunger, pica, weight loss, fatigue, impaired milk secretion, PU, circulatory failure
Signs of Toxicity: Thirst, pruritus, constipation, anorexia, seizures, hypertension
157
What are the functions, signs of deficiency and signs of toxicity in Magnesium?
Function: Enzyme activator, constituent of skeletal tissue, required for muscle and nerve function, roles in every metabolism and protein synthesis.
Signs of Deficiency: Calcification of soft tissues, retarded growth. spreading of toes, hyper irritability, seizures, excess salivation.
Signs of Toxicity: Diarrhea, cystitis and urinary tract disease in cattle.
158
What are the functions, signs of deficiency and signs of toxicity in Zinc?
Function: skin maturation, immune function, many enzyme systems.
Signs of Deficiency: scaly skin (parakeratosis), depigmentation, infertility, impaired wound healing, increased susceptibility to infections.
Signs of Toxicity: Excess will interfere with absorption of calcium, hemolytic anemia.
159
What are the functions, signs of deficiency and signs of toxicity in Copper?
Function: Roles in erythropoiesis, coenzymes, hair pigmentation, reproduction, collagen and elastin synthesis, iron utilization
Signs of Deficiency: Pica, stunted growth, diarrhea, depigmentation of hair, anemia, impaired bone growth.
Signs of Toxicity: Inherited disorder of metabolism on some breeds lead to liver damage
160
What are the functions, signs of deficiency and signs of toxicity in Manganse?
Function: Involved in carbohydrate and lipid metabolism, formation of cartilage
Signs of Deficiency: Infertility, enlarged stiff joints and short little bones
Signs of Toxicity: Infertility, partial albinism (rare)
161
What are the functions, signs of deficiency and signs of toxicity in Iodine?
Function: Required for thyroid hormone synthesis.
Signs of Deficiency: Hypothyroidism, goiter, alopecia, infertility, lethargy, myxedema
Signs of Toxicity: Excess can also result in decreased thyroid function and signs similar to deficiency.
162
How is Vitamin D produced in the skin?
Vitamin D is produced un the skin through stimulation by solar radiation. In the epidermis, vitamin D3 (cholecalciferol) is formed from the pro-vitamin D3 (7-dehydrocholesterol) via previtamin D3 due to exposure to sunlight. The vitamin D binding protein in plasma translocate Vitamin D3 from the skin into circulation. Vitamin D3 is then hydroxylated in the liver to 25-hydroxyvitamin D3, and again hyroxylated in the kidney to form 1,25 hydroxyvitamin D3, which is important in regulating epidermal proliferation and differentiation.
163
A quarter horse pastured in Colorado develops lameness with transverse cracks in the hoof wall of multiple hooves and loss of the long hairs of the mane and tail followed by a generalized partial alopecia. The most likely diagnosis?
selenosis
