Cutaneous Sensation and Psychodermatology (including diseases and medications) Flashcards
Where is the itch sensation limited to?
Skin, mucosa, and cornea
Describe Merkel cells
Light touch
Slow-adapting Aβ sensory fiber
Located along the stratum basale between keratinocytes
Also can be associated with hair
Meissner’s corpuscle
Describe Messiner’s corpuscle
Touch (dynamic skin deformation)
Rapidly-adapting Aβ sensory fiber
Merklel cell
Describe Ruffini corpuscle
Stretch
Slow-adapting Aβ sensory fiber
Pacinian corpuscle
Pacinian corpuscle
Describe Pacinian corpuscles
High pressure, vibration
Rapidly-adapting Aβ sensory fiber
Single non-myelinated nerve fiber enclosed by a multi-layer connective tissue capsule
Describe the sensation of hair follicles
Light touch, low-frequency vibration
All types of sensory fibers
What are the three intercommunicating plexuses of arteries and veins?
1) Deep plexus (interface of dermis and subcutis - some branches supply lower hair follicle and epitrichial sweat glands)
2) Middle plexus (level of the sebaceous gland and supplies arrector pili, middle hair follicle, and sebaceous glands)
3) Superficial plexus (capillary loops just below the epidermis - supplies upper hair follicle and epidermis)
Describe arterioles
endothelial cells surrounded by smooth muscle cells, most likely function as part of the resistance vessels in skin
If you wanted to stain Merkel cells on histopathology, what stain would you use?
CK20 (green)
IHC NSE (brown)
Ruffini corpusle
Potential new somatosensory organ in dogs
Non-encapsulated free nerve endings
What is one sentence that can describe how Merkel’s discs, Meissner’s corpuscles, Ruffini endings, and Pancinian corpuscles experience a finger moving over braille?
Each receptor sensors the same stimuli differently
Which type of nerve fibers typically respond to innocuous touch?
C fibers
Which type of nerve fibers typically respond to nociceptive touch?
Aδ fibers
C fibers
What is a dermatome?
An area of the skin supplied by one spinal nerve
What supplies the nerves of the skin of the head?
Cranial nerves
What supplies the nerves of the skin of the trunk and forelimbs?
Thoracic spinal nerves
What supplies the nerves of the hind limbs?
Pelvic spinal nerves
What are tylotrich hairs?
Large primary follicle surrounded by a ring of neurovascular tissue
Aδ fibers
Rapid
Associated with a tylotrich pad
What are the rapid adapting mechanoreceptors?
Pancinian corpuscle
Meissner corpuscle
Guard and down hairs
Tylotrich hairs
What are tylotrich pads?
Small, hairless, knob-like innervated structure on the haired skin of dogs and cats
Slow adapting mechanoreceptors
What are sinus hairs?
Hair with an endothelia blood sinus and a nearby Pancinian corpuscle
What are the slow adapting mechanoreceptors?
Merkel cell
Ruffini corpuscle
Sinus hair
Tylotrich pad
What do free nerve endings do?
They terminate in the dermis
Associated with “C fibers” and surrounded by Schwann cells
Pencillate (touch, temp, pain, itch)
Papillary (around hair, sense cold)
What do transient receptor potential channel (TRP)s sense?
pH
Chemical agents
Temperature
Osmolality
What does transient receptor potential ankyrin1 (TRPA1) do?
Sense cold and pungent taste (wasabi, horseradish, garlic, cinnamon)
Expressed on Aδ and c fibers
What does transient receptor potential melastatin 8 (TRPM8) do?
Sense cold, menthol, mint, and icilin
What is icilin?
A synthetic cooling agent that produces a strong sensation of cold in humans and animals
What does topical application of menthol and icilin activate?
Transient receptor potential melastatin 8 (TRPM8)
What does transient receptor potential vanilloid 1 (TRPV1) do?
Detects noxious heat and pain-producing substances like capsaicin
What does topical application of capsaicin activate?
Transient receptor potential vanilloid 1 (TRPV1)
What are transient receptor potentials?
A class of cationic channels that act as signal transducer by altering membrane potential or intracellular calcium (Ca2+) concentration
Sense heat, cold, and certain chemicals
Which cutaneous sensory receptors respond to touch?
Hair
Tactile disk
Meissner corpuscle
Ruffini corpuscle
Pancinian corpuscle
Which of the following mechanoreceptor has the smallest
receptive?
Merkel cell axon complex
Which cutaneous sensory receptors respond to heat, pain, and itch?
Heat receptor, nociceptor (transient receptor potentials)
Free nerve endings
What is the relative axon diameter and conduction velocity of Aβ/II nerve fibers?
Medium (but largest for cutaneous), medium
What is the relative axon diameter and conduction velocity of Aδ/III nerve fibers?
Small, medium
What is the relative axon diameter and conduction velocity of C/IV nerve fibers?
Smallest, slow
Which type of cutaneous sensory nerve fiver has the largest axon diameter?
Aβ/II
Which type of cutaneous sensory nerve fiver has the smallest axon diameter?
C/IV
Which cutaneous nerve fibers are myelinated?
Aβ/II and Aδ/III
What type of nerve fiber senses epicritic itch?
Aδ/III
What is epicritic itch?
Sharp, well-defined itch
What type of nerve fiber senses protopathic itch?
C/IV
What is protopathic itch?
Poorly localized, sometimes burning itch
Not spontaneous but hyper-responsive to minor stimuli
What is spontaneous itch?
Well-localized at the site of stimulation
Only persists briefly after stimulus is removed
Where are Aβ/II nerve fibers found?
Merkel cells
Meissner’s corpuscles
Ruffini endings
Pacinian corpuscles
Hair follicles
What do Aβ/II nerve fibers sense?
Non-noxious mechanical stimuli
Touch, pressure
Where are Aδ/III nerve fibers found?
Hair follicles
Free nerve endings
What do Aδ/III nerve fibers sense?
Noxious stimuli
Fast pain
Epicritic itch
Mechanical stimuli
Temperature
Where are C/IV nerve fibers found?
Hair follicles
Free nerve endings
What do C/IV nerve fibers sense?
Noxious stimuli
Slow pain (considered the classic pain receptor)
Temperature
Chemicals
Itch (main one for AD itch, primarily protopathic itch)
Do myelinated or unmyelinated nerves have faster conduction?
Myelinated (the signal is protected)
What is alloknesis?
Normally non-itchy stimulus causes an itch or scratching sensation
Associated with C fibers
Common in chronic atopic dermatitis
What is physiologic itch?
Short-lived response to a pruritogen
What is pathologic itch?
AKA neuropathic itch
A chronic, usually intense, itching sensation caused by damage to the nerves that transmit itch
What is referred itch?
Development of a focal area of pruritus during scratching of a different, primary pruritic site
What is conversion itch?
Change of a normal sensation like touch to itch
What is the pathway of cutaneous sensation to the brain?
Peripheral sensory neuron –>
goes up primary afferent neurons through dorsal root ganglion –>
synapses with secondary transmission neurons in dorsal horn –>
cross over to contralateral spinothalamic tract in spinal cord–>
goes up spinothalamic tract to thalamus in the brain –>
goes to sensory cortex of the cerebrum
What is the dorsal root ganglion?
A pseudounipolar neurons relay sensory information to the spinal cord through a characteristic bifurcating axon, which sends one projection to the periphery and the other into the spinal cord
What is the gate control theory of cutaneous sensation/pain/itch?
Theory proposes that the spinal cord contains neural structures that act as a gate to control the flow of pain signals from the body to the brain so the sensation of a noxious stimuli can be blocked by a non-noxious stimuli carried by nerve fibers that reach the brain before the painful input
- substantia gelatinosa cells
- central factors like anxiety and boredom may act to reduce or amplify
What causes itch on inflamed skin?
Infections
Ectoparasites
Allergies
Immune-mediated
Neoplasia
What causes itch on non-inflamed skin?
Neuropathic
Systemic
Psychogenic
What is a pruritogen?
Any substance/mediators that cause pruritus
Which are the main amines that are pruritogens?
histamine
serotonin
Which are the main neuropeptides that are pruritogens?
substance P
NGF
Which are the main proteases that are pruritogens?
KLKs
cathepsin S
tryptase/chymase
exogenous proteases (HDM, Staphylococcus sp., mucunain)
Which are the main cytokines that are pruritogens?
TSLP
IL-2
IL-4
IL-13
IL-31***
IL-33
What is a plant that can cause non-histaminergic itch?
Cowhage (Velvet beans) due to the protease mucunain
What are the differences between histaminergic vs non-histaminergic itch pathways?
Histaminergic is mediated by mast cells and basophils
Follow similar pathway skin –> DRG –> spinal cord –> brain but activate some different (and some overlapping) areas of the brain
What are the primary differences between acute and chronic itch?
Acute is histamine dependent and mediated through BNP/NPRA
Chronic is histamine independent and mediated through GRP/GRPR
On which receptor do cannabinoids primarily work?
TRPV1
What are the primary functions of histamine?
Neurotransmission
Itchiness
Contraction of airways
Dilation of blood vessels
Gastric acid secretion
Which histamine receptors are most important for itch?
H1*
H4
Newer generations of antihistamines are more H1 specific
What are H1 histamine receptors primarily involved in?
Acute allergic reactions
- itch
- bronchoconstriction
- vasodilation (potential hypotension)
Sleep disorders
What are H2 histamine receptors primarily involved in?
Gastric acid secretion (increased)
What are H3 histamine receptors primarily involved in?
Neurotransmitter modulation (only exist in the CNS)
What are H4 histamine receptors primarily involved in?
Immunomodulation
- eosinophil shape, mast cells, chemotaxis
Itch
Does histamine induce pruritus in dogs?
Maybe mild itch, esp higher doses according to some studies
- histamine, comp 48/80, anti-canine-IgE injected intradermally
Other study did not find effect
- histamine, serotonin, tryptase, substance P, IL-2 injected intradermally
But does definitely cause a wheal and flare
What is compound 48/80?
A chemical that causes the non-IgE dependent release of histamine from mast cells
Does substance P induce pruritus in dogs?
Unsure, a study did not find effect of substance P when injected intradermally
But it is known to cause neurogenic inflammation
Where is substance P found in the cutaneous sensation pathway?
- interaction between Mrgpr on mast cell and SP on afferent neuron
- interaction between SP on afferent neuron and NK1 in dorsal horn
What are the 3 pathways involved in neurogenic inflammation?
1) chemotaxis and activation
2) vasodilation, permeability, and adhesion
3) dendritic and T-cell priming
*substance P and CGRP involved in all 3
What is the role of nerve growth factor (NGF) in itch associated with atopic dermatitis?
- Increases cutaneous innervation in AD models
- patients with AD have more nerve elongation factors like NGF
- might contribute to the development of chronic pruritus
What is nerve growth factor (NGF)?
- neurotrophic factor essential for the survival and maintenance of primary afferent neurons and sympathetic neurons
- inflammatory mediator associated with pain and itch
Which cells in the skin produce nerve growth factor (NGF)?
Mast cells
Macrophages
Keratinocytes
Fibroblasts
T-cells
What does Il-31 do to mouse dorsal root ganglion neurons?
promotes axonal growth of DRG neurons
Which pruritogenic proteases are produced by keratinocytes?
Kallikreins (KLKs)
Cathepsin S
Which pruritogenic proteases are produced by immune cells?
Cathepsin S
Tryptase
Chymase
How do proteases cause pruritus?
by activating protease-activated receptors (PARs) on nerve endings and keratinocytes
Which cytokine has been demonstrated to cause itch in dogs and cats?
IL-31 (acute, severe itch when injected)
Which are the primary IL-31 producing cells in the skin?
CD3+CD4+ T cells (likely Th2 cells)
Keratinocytes express the mRNA, but maybe not the final protein in normal skin but maybe in the skin of humans and dogs with AD
Which cells in the skin have IL-31 receptors?
Free nerve endings
Keratinocytes
(also in canine dorsal root ganglia)
Which cell signaling pathways does IL-31 primarily activate?
- JAK 1/2
- STAT 1/2/5
PI3K/AKT
What is the role of IL-31 in feline atopic skin syndrome?
Unsure
Causes pruritus when injected
One study found no differences in systemic or cutaneous IL-31 expression between cats with allergic dermatitis and controls (Older, 2021)
Another study found circulating IL-31 was higher (Dunham, 2018)
What is the itch-scratch cycle?
skin barrier disruption –>
release of cytokines, proteases, AMPs –>
interaction with immune cells (inflammation) –>
more release of neuropeptides, cytokines, and proteases –>
sensory dysfunction –>
signal to brain = scratch –>
cycle continues
What is the role of transient receptor potential channels (TRPs) in the itch neuronal pathway?
Interaction of amines, neuropeptides, and cytokines with receptors in neurons causes the opening of TRP channels which leads to depolarization of neuronal membranes and causing itch sensation
Which molecule is largely responsible for neurogenic inflammation in the skin?
Substance P
What is neurogenic itch?
Itch induced by pruritogens in the absence of neural damage
Itch on inflamed skin
What type of itch does canine syringomyelia cause?
Neuropathic itch
What causes canine syringomyelia?
Exact etiology and pathogenesis are unknown
Thought to develop secondary to an obstruction of cerebrospinal fluid (CSF) flow at the level of the foramen magnum
Most frequently associated with Chiari-like malformation (CM)
Other documented causes include trauma and neoplasia
What is Chiari-like malformation (CM) in dogs?
Mismatch in skull and brain size (brain too big and skull to small)
Blocks the foramen magnum and disrupts the flow of CSF
What breed is predisposed to syringomyelia?
Cocker spaniels - genetically prone to Chiari-like malformation (CM)
What is canine syringomyelia?
A neurological condition in dogs that causes fluid-filled cavities to develop in the spinal cord
What are the clinical signs of canine syringomyelia?
“Phantom scratching” = Dysesthesia (spontaneous or evoked unpleasant sensation)
Maybe a result of alteration of sensory threshold potentially due to spongy degenerative changes to the spinal cord?
5 yr CKCS
Syringomyelia
What happens to substance P in CKCS with syringomyelia?
Significant difference of SP between symptomatic SM and control dogs
(No difference between symptomatic and asymptomatic)
What type of itch is acral mutilation syndrome?
Neuropathic
What causes acral mutilation syndrome in dogs?
Autosomal-recessive with incomplete penetrance
sensory neuropathy (diminution of pain perception)
SNP in GDNF
What breeds has acral mutilation syndrome most frequently been reported in?
German short-haired pointer
English springer spaniel
English/French spaniel
English cocker spaniel
German short-haired pointer, 4mo, sudden and intense licking and chewing causing trauma.
What gene would you test for a mutation?
GDNF
Several months after having his tail docked, a dog presents with a nodule on the tip of the nail and intense tail biting (itch vs pain). What causes this condition?
Regenerative growth of nerves (neuroma)
Tail dock neuroma
What is a radiculopathy?
a condition that occurs when nerve roots in the spine are damaged or compressed
may cause focal neuropathic itch/pain
What is trigeminal trophic syndrome?
a rare condition resulting from self-trauma of the skin after peripheral or central injury to the trigeminal system (CN V)
What is brachioradial pruritus?
a neurological condition that causes intense itching, pain, stinging, or tingling in the upper extremities, usually on the dorsolateral forearm (C5-C6)
What is notalgia paresthetica?
a chronic sensory neuropathy that causes a localized itch or paresthesia in the mid-back, usually on the left side below the shoulder blade (T2-T6)
How do you diagnose a radiculopathy?
Clinical manifestation, will be localized pain/itch
May have a history of trauma
Potential imaging (CT, MRI)
Will not be responsive to glucocorticoids (might be to gabapentin)
Which virus can cause facial pruritus in cats?
Feline herpes virus
may be a combination of neurogenic (inflammatory) and neuropathic itch
Why type of itch is acral lick dermatitis typically considered?
Psychogenic
What are the type 6 causes of acral lick dermatitis?
- Allergy
- Orthopedic
- Neurologic
- Neoplasia
- Focal infection
- Behavioral (may be involved in up to 50% of all ALDs)
Which breeds of dogs are predisposed to behavioral acral lick dermatitis?
Large breeds (Doberman pinscher, Great Dane, Labrador retriever, Irish setter, golden retriever, boxer, Weimaraner, German shepherd)
What is the median age of onset for behavioral acral lick dermatitis?
4 yrs
What is the prevalence of feline psychogenic alopecia?
1.2 - 4.7% of itchy cats
In a study where 21 cats were referred to a behavioral service for “psychogenic alopecia”:
- 2 had just psychogenic
- 3 had both psychogenic and medical
- 16 had just medical causes
What is feline psychogenic alopecia?
A form of psychogenic itch
Causes: stress-related overgrooming
What breeds of cats are predisposed to feline psychogenic alopecia?
Siamese
Abyssinian *also predisposed to atopic dermatitis
Asian cats?
What is feline idiopathic ulceration?
Potentially a form of psychogenic itch caused by stress
Results in a traumatic, non-healing ulcer on the dorsal neck/shoulder
One study showed all 15 cats responded to environmental modification alone
What are the recommended treatments for neuropathic itch?
Barriers to reduce scratching
Local anesthetics
What therapies have been found to be ineffective with neuropathic itch?
Anti-histamine
Glucocorticoids
Pain medications
Where do TCA mediations work in the itch pathway?
Brain
Where do SSRI mediations work in the itch pathway?
Brain
Where does mirtazapine work in the itch pathway?
Brain
Where do gabapentin/pregabalin work in the itch pathway?
Brain
Spinal cord
Where do Kappa-opioid agonists work in the itch pathway?
Brain
Spinal cord
Where do NK-1R inhibitors work in the itch pathway?
Brain
Spinal cord
Peripheral nerve fibers
Where do topical medications work in the itch pathway?
Peripheral nerve fibers
Where do antihistamines work in the itch pathway?
Peripheral nerve fibers
Where does lokivetmab work in the itch pathway?
Peripheral nerve fibers
What are the topical anesthetics commonly used in veterinary medicine
Lidocaine
Prilocaine
Pramoxine
How do topical anesthetics work?
Reversibly block/close voltage gated Na+ channels
Prevent the transmission of pain impulses
Duration can vary from 30 min to more than 12 hrs
What is the primary mechanism of action of topical capsaicin?
Interaction with TRPV1
Transient analgesia: desensitization of TRPV1 and functional inhibition of axonal terminals
Long-acting effect: ablation of axonal terminals
How are calcineurin and TRPV1 related?
calcineurin is important for TRPV1 channel opening and synaptic efficacy
What happened to atopic dogs which had twice daily topical application of capsaicin (0.025%) for 6 weeks?
Temporary worsening of pruritus in first week
Significant improvement at end by owners (but not investigators)
What are some topical TRPM8 agonists and how do they work?
Menthol, icilin, cryosin-1
Excitation of Aδ fibers by TRPM8 (cold) inhibits the signaling of C fibers (itch)
What happened to AD who had 2% cyrosin-1 applied twice daily to their skin?
There was no significant difference between two treatment groups
Where do cannabinoids work in the itch pathway?
Peripheral nervous system and central nervous system
There are cannabinoid receptors in many locations in the skin
- keratinocytes
- nerve endings
- Langerhans cells
- fibroblasts
- sweat glands
- sebaceous glands
- hair follicles
- melanocytes
How do cannabinoids work in regards to the neurologic sensation of itch?
Decreased neurotransmitter release due to
- Inhibition of Ca2+-channels
- Increasing K+ current
Some endocannabinoids like palmitoylethanolamide stabilize mast cells
What happened to 19 experimental atopic dermatitis dogs who had a topical endocannabinoid reuptake inhibitor applied q12 to q24?
Significant reduction of pruritus compared to the baseline (Day 8) but no difference with placebo
What happened to 19 cats who were fed ultramicronized palmitoylethanolamide?
They were better than placebo (~2x longer to relapse without methylprednisolone)
Which opioid groups are associated with an anti-itch effect?
μ-opioid receptor antagonist (ex. naltrexone)
κ-opioid receptor agonist (ex. asimadoline)
Which opioid group is associated with increased itch?
μ-opioid receptor agonists (ex. morphine)
What happened when 5 atopic dogs were given the anti-NFG mAb ranevetmab?
anti-NGF antibody ranevetmab did not delay pruritus flares after the discontinuation of prednisolone
Where do anti-NGF mAbs work in the itch pathway?
Peripherally
What is an example of a NK-1R inhibitor?
Maropitant
What does maropitant do?
has a similar structure to substance P so act as an antagonist and bind to the substance P receptor neurokinin 1 (NK-1R)
What happened to 12 atopic cats given 2 mg/kg of maropitant q24h for 4 week?
Improved so might be effective in cats, unknown for dogs
(but was open-label and not controlled)
How does gabapentin/pregabalin work in regards to itch and pain?
- inhibits calcium channel ion entry (α2δ-1)
- reduces glutamate levels
- reduces hyperexcitability of neurons of the dorsal horn of the spinal cord
What are examples of NMDA receptor antagonists?
Amantadine
Topiramate
Ketamine
How do NMDA receptor antagonists work in regards to pruritus?
bind directly to the glutamate site of the post-synaptic NMDA receptor to inhibit the action of glutamate (which is released from the presynaptic terminal)
reduces the amount of calcium released into nerve cells
decreases the activity of these neurons and the amount of GABA released
dis-inhibit all thalamocortical pathways
What is the difference between TCAs and SSRIs?
TCAs are considered “first-generation” antidepressants, and SSRIs are considered “second-generation” antidepressants
SSRIs just affect serotonin
TCAs norepinephrine and serotonin
How do SSRIs work?
Increase serotonin levels in the brain by inhibiting the reuptake of serotonin into the synaptic cleft (5-HT re-uptake transporters)
- it can’t go back into the presynatic neuron
- more in the cleft so more goes into the postsynaptic neuron and brain
Probably also has other delayed effects because of delayed onset of activity
How do TCAs work?
Prevent the reabsorption of serotonin and norepinephrine in presynaptic terminals (5-HT re-uptake transporters)
Also block receptors in the body, including histamine, alpha-adrenergic, and muscarinic-acetylcholine receptors
Why do doxepin hydrochloride and amitriptyline hydrochloride have antihistamine effects?
They antagonize histamine H1 receptors
What are examples of SSRIs used in veterinary medicine?
Fluoxetine
Paroxetine
Sertraline
What are examples of TCAs used in veterinary medicine?
Amitriptyline
Clomipramine
Doxepin
How do emollients work on the allergic itch cycle?
Create an occlusive barrier that moisturizes the skin
Improve skin barrier function
Decrease pruritic effect of dry skin/poor skin barrier
What type of moisturizer is colloidal oatmeal?
A humectant
What do humectants do?
are hygroscopic substances that form hydrogen bonds with water molecules
attracts and retains moisture in the air via absorption into the skin
can also pull water into the epidermis from the dermis
How do humectants work on the allergic itch cycle?
Improve skin barrier function
Decrease pruritic effect of dry skin/poor skin barrier
*Emollients are preferred in humans
How is lime sulfur thought to primarily work on the allergic itch cycle?
Dissolve pruritogenic skin surface proteins
How do topical ceramides work in the allergic itch cycle?
Help to restore barrier function, thereby decreasing allergen exposure and inflammatory response
What kind of action does histamine have on nerves in the skin?
Prolonged stimulation of C fibers
How do antihistamines work?
Reversible competitive binding to histamine receptors (antagonist)
Some can reduce mast cell degranulation
Why do antihistamines have a drying effect in the mouth and eyes?
anticholinergic properties –> decreased histamine activated exocrine secretions (salivary and lacrimal)
Why do antihistamines have an antiemetic effect?
anticholinergic properties –> bund to central muscarinic receptors
What are antihistamines contraindicated with?
Narrow angle glaucoma
Bladder obstruction/atony
GI obstruction/atopny
MAOIs
Pregnancy (some like hydroxyzine are teratogenic)
What are some side effects of antihistamines?
Hypertension/cardiac problems
Lower respiratory tract infections (decreased secretions)
CNS sedation (increased with older generation antihistamines)
GI side effects
Dry mouth and eyes
Urinary retention
Some can lower seizure threshold
Some can have hepatotoxicity
Some are teratogenic
Which type of antihistamine is useful for chronic idiopathic urticaria?
H1 and H2 blockers together
Which antihistamine has been found to be the most effective for cats?
Chlorpheniramine 2 mg/kg q12h (as high as 70%)
Is a very potent H1 antagonist
How are hydroxyzine and cetirizine related?
Cetirizine is the metabolite of hydroxyzine so does not require hepatic metabolism
Is bioavailable in cats, dogs, and horses
Which commonly used antihistamines are first-generation H1 blockers?
Diphenhydramine hydroxychloride
Chlorpheniramine maleate
Hydroxyzine hydrochloride/pamoate
Meclizine hydrochloride
Trimeprazine (aka Temaril)
Cyproheptidine
Which commonly used antihistamines are second-generation H1 blockers?
Cetirizine
Fexofenadine
Loratidine
How does ophytrium work on the allergic itch cycle?
Improves skin barrier by increasing filaggrin, ceramides, and natural moisturizing factors
Decreases secretion of pro-inflammatory cytokines
Limits adhesion of Staph species so decreases pruritogenic proteases
Where are H1 receptors expressed?
endothelial cells of blood vessels
vascular smooth muscle cells
neurons
keratinocytes
immune cells - dendritic cells, monocytes, neutrophils, and lymphocytes
How do essential fatty acids work on the itch pathway?
Omega-3s
- reduce production of eicosanoids (prostaglandins and leukotrienes)
- decreases chemotaxis of neutrophils and monocytes
- decreased expression of leukocyte adhesion molecules
- reduce the activation of mast cells that is triggered by IgE
Omega 6s: primarily improve skin barrier
What is the primary mechanism of glucocorticoids on the allergic itch cycle?
Decrease mRNA synthesis of cytokines and their receptors, phospholipase A2 and COX
- Affect nearly every part of the allergic itch cycle
Why do glucocorticoids have such a wide range of activity?
Changes happen in every cell of the body since corticosteroid receptors are in every cell
How do calcineurin inhibitors work in the allergic itch cycle?
blocks an calcineurin phosphatase –> prevents translocation of NFAT to the nucleus –> prevents transcription of IL-2 –> suppressed T-cell responses
also places a role in dendritic cell differentiation
reduce the size and shape of eosinophils (affects IL-5 and IL-13)
How does oclacitinib affect allergic pruritus?
Preferentially inhibits function of JAK1 dependent cytokines
- IL-31 (pruritus)
- IL-2, IL-4, IL-6, IL-13 (allergy/inflammation)
JAK2 affected but 1.8 fold less
- hematopoiesis so potential suppression with higher doses
JAK 3 affected but 9.9 fold less
- involved in wider immunosuppression
When do plasma levels of oclacitinib peak after oral administration in dogs?
1 hr
Half-life of 3 to 5 hrs
Ok for 24 hours dosing period
What is the primary clearance route of oclacitinib?
predominant clearance route is hepatic with small amounts of renal and biliary elimination
How does lokivetmab work?
binds and neutralizes canine IL-31
