MIDTERM II - TOPIC 24-25 Flashcards
24: GLUCOCORTICOIDS 25: JAK-INHIBITORS
1
Q
24: GLUCOCORTICOIDS
A
- These are important as if they are not used correctly, they can be very harmful.
- They are one of the most potent anti-inflammatory medications.
- They are equally useful in each stage of the inflammation procedure including the
- acute phase
- subacute phase
- chronic inflammatory processes.
2
Q
24: GLUCOCORTICOIDS
Main features of applications:
A
- Management of hypoadrenocorticism (Addison’s disease)
- Management of hyperadrenocorticism (Cushing’s syndrome)
- Management of non-adrenal disorders:
- inflammatory,
- allergic and
- autoimmune disorders (immunosuppressive activities)
3
Q
24: GLUCOCORTICOIDS
The natural corticosteroids:
Hench:
A
The natural corticosteroids:
The adrenal cortex synthesizes a variety of steroids.
Steroid base - Cholesterol - Pregnenolone - Corticosteroids (>40 kinds)
Hench:
- Observed that during the pregnancy of the female, the severity of the chronic inflammatory processes is declining.
In the urine,
- Large amount of cortisol
in the blood,
- Elevated level of cortisone
(the metabolite of progesterone hormone).
4
Q
24: GLUCOCORTICOIDS
Types:
A
-
Mineralocorticoids = (Zona glomerulosa)
- aldosterone,
- corticosterone
-
Glucocorticoids = (Zona fasciculata)
- cortisol,
- hydrocortisone,
- cortisone
-
Androgens = (Zona reticularis)
- androstenedione
5
Q
24: GLUCOCORTICOIDS
Hormone synthesis in the adrenal cortex:
A
The cytochrome involved depends on the animals
- age,
- activity,
- inflammatory stage
- Modification of cholesterol to pregnenolone by side-chain cleavage enzyme (desmolase).
- Pregnenolone metabolism can be directed towards the formation of aldosterone, cortisol, or aldosterone.
- Pathways depend on the tissue-specific expression of enzymes (mainly CYP-450) in the different cell types.
6
Q
24: GLUCOCORTICOIDS
Transport:
A
- Approximately 90% of circulating cortisol is bound to plasma proteins,
- Most important
-
Corticosteroid-binding globulin
- (CBG, also referred to as transcortin)
- ALBUMIN.
-
Corticosteroid-binding globulin
- CBG has a high affinity for cortisol but low overall capacity
- ALBUMIN has low cortisol affinity but high overall capacity.
-
Only molecules of cortisol that are unbound to protein (the so-called free fraction) are
- Bioavailable = Available to diffuse through plasma membranes into cells thus,
- Affinity and capacity of plasma binding proteins regulate the availability of active hormone
- = Hormone activity.
7
Q
24: GLUCOCORTICOIDS
Metabolism:
A
- The liver and kidneys are the primary sites of peripheral cortisol metabolism.
- Through reduction and subsequent conjugation to glucuronic acid
- Liver is responsible for inactivating cortisol in the plasma.
- The conjugation reaction makes cortisol more water-soluble
- enabling renal excretion.
- Importantly, the liver and kidneys express different isoforms of the enzyme 11β-hydroxysteroid dehydrogenase
- = A regulator of cortisol activity.
- The two isoforms catalyze opposing reactions.
- In distal collecting duct cells of the kidney,
- 11β-hydroxysteroid dehydrogenase type II (11β-HSD II) converts cortisol to the biologically inactive compound cortisone,
- Which (unlike cortisol) does not bind to the mineralocorticoid receptor.
- In distal collecting duct cells of the kidney,
- In contrast, cortisone can be converted back to cortisol (also referred to as hydrocortisone) in the liver by 11βhydroxysteroid dehydrogenase type I.
- The interplay between these opposing reactions determines overall glucocorticoid activity.
- In addition, the activity of these enzymes is important in glucocorticoid pharmacology.
8
Q
24: GLUCOCORTICOIDS
Molecular mechanism of glucocorticoid action:
Type of effect
Genomic (classical)
Slow
SPECIFITY?
RECEPTOR
ACTIONS
A
Specificity
Receptor
Actions
Specific
Cytosolic
Glucocorticoid
Receptor (cGCR)
Anti-Inflammatory
Immunomodulatory
Replacement therapy
9
Q
24: GLUCOCORTICOIDS
Molecular mechanism of glucocorticoid action:
Type of effect
Nongenomic (secondary)
SPECIFICITY
RECEPTOR
ACTIONS
A
Specific
Cytosolic
Glucocorticoid
Receptor (cGCR)
RAPID EFFECT IN SHOCK:
- Reduced ion transport across plasma membranes (Na, Ca).
- Reduced antigen-induced phosphorylation of proteins e.g. phospholipase A2.
10
Q
24: GLUCOCORTICOIDS
Molecular mechanism of glucocorticoid action:
Rapid
SPECIFICITY
RECEPTOR
ACTION
A
Specific
Membrane bound
Glucocorticoid
Receptor (mGCR)
NEURO- AND CARDIOPROTECTIVE EFFECT:
- Increased activity of endothelial nitric oxide synthase (eNOS),
11
Q
24: GLUCOCORTICOIDS
Molecular mechanism of glucocorticoid action:
Only high doses
SPECIFICITY
RECEPTOR
ACTION
A
Specific
Non-receptorial
(interaction with cell membrane)
vasodilation of coronaries and cerebral vessels
12
Q
24: GLUCOCORTICOIDS
Molecular mechanism of glucocorticoid action:
Cytosolic glucocorticoid receptor (cGCR):
A
- The highly lipophilic glucocorticoids cross the cytoplasmic membrane.
- In cytoplasm molecules bound to the cGCR (cytosolic glucocorticoid receptor).
- Glucocorticoids are transported into the nucleus in bounded form.
- The glucocorticoids can occupy the mineralocorticoid receptors as well, but with smaller affinity (overlapping).
Many genes contain glucocorticosteroid response elements (GREs).
13
Q
24: GLUCOCORTICOIDS
Cytosolic glucocorticoid receptor (cGCR)
Activation:
A
- The binding of the activated glucocorticoid receptor homodimer to a GRE in the promoter region of steroid-sensitive genes leads to
- Transcription of genes encoding anti-inflammatory mediators such as
- annexin-1 (lipocortin-1),
- secretory leukoprotease inhibitor (SLPI),
- interleukin10 (IL-10)
- inhibitor of nuclear factor B (IB)
14
Q
24: GLUCOCORTICOIDS
Cytosolic glucocorticoid receptor (cGCR)
Inhibition:
A
- Through transrepression, the glucocorticoid receptor–corticosteroid complex interacts with large co-activator molecules with intrinsic histone acetyltransferase (HAT) activity (such as cyclic AMP response element binding protein, CBP),
-
Activated by proinflammatory transcription factors (such as NF-B and AP1),
- Switching off expression of the inflammatory genes that are activated by these transcription factors.
??
15
Q
24: GLUCOCORTICOIDS
Physiological effects of corticosteroids:
Effect what
A
Physiological effects of corticosteroids:
- Carbohydrate metabolism:
- Lipid/fat metabolism:
- Protein metabolism:
- Water-electrolyte balance:
- Bones:
- Cardio-vascular system:
- Blood cell formation:
- Hormonal system:
16
Q
24: GLUCOCORTICOIDS
Physiological effects of corticosteroids:
- Carbohydrate metabolism
A
Carbohydrate metabolism:
- Stimulated gluconeogenesis,
- slightly increased glycogenolysis,
- inhibited glucose-transport into the cells,
- increased insulin-resistance,
- increased blood sugar level,
- long-lasting application causes steroid-diabetes.
17
Q
24: GLUCOCORTICOIDS
Lipid/fat metabolism:
A
Lipid/fat metabolism:
- Increased lipolysis,
- high levels of free fatty acids in plasma (cholesterol and phospholipids too).
- In the presence of insulin increased lipogenesis,
- it leads to redistribution of fatty tissue and obesity.
18
Q
24: GLUCOCORTICOIDS
Protein metabolism:
A
Protein metabolism:
- Anti-anabolic,
- catabolic action (increased proteolysis),
- causes trophic disturbances (estrias, muscle atrophy, osteoporosis, ulceration).
- Decreased epithelium-regeneration and protective mucus secretion,
- Increased HCl secretion.
- Gastric/duodenal ulcers.
- Delayed wound healing – decreased collagen synthesis.
19
Q
24: GLUCOCORTICOIDS
Water-electrolyte balance:
A
- Smaller doses of glucocorticoids increase the diuresis.
-
Large doses cause
- Na+ and water retention,
- increased K + and Ca2+ elimination.
20
Q
24: GLUCOCORTICOIDS
Bones:
A
- Anti vitamin D action,
- slower production of bone matrix,
- increased excretion of Ca2+.
- In younger animals,
- dwarfism, and
- rickets (rachitis),
- In adults
- osteoporosis occurs.
21
Q
24: GLUCOCORTICOIDS
Cardio-vascular system:
A
- Increased blood pressure,
- higher responsibility to catecholamines,
- large doses increase the volume of blood.
22
Q
24: GLUCOCORTICOIDS
Blood cell formation:
A
-
Slightly increased red blood cell formation,
- even until polycythemia,
-
Slightly increased white blood cell formation (mild leukocytosis and neutrophilia),
- They cause lymphopenia and eosinopenia.
23
Q
24: GLUCOCORTICOIDS
Hormonal system:
A
-
Inhibition of the ACTH and CRH secretion
- because of negative feedback,
- they inhibit the production and effects of GH (STH) as well.
- Furthermore
- inhibitedtheaction of gonadotropic hormones and
- Decreased TSH secretion.
24
Q
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Inhibit the action of? and formation of?
By which mechanisms?
A
Anti-inflammatory action:
Prednisone and other glucocorticoids inhibit the action of COX-2 and the formation of prostaglandins by several mechanisms:
- Repressing COX-2 gene and enzyme expression
- Repressing the expression of cytokines that activate COX-2
- Limiting the available pool of COX-2 substrate (arachidonic acid) by indirectly blocking phospholipase A2.
25
24: GLUCOCORTICOIDS
Anti-inflammatory action:
1. The anti-inflamatory action
2. Because of the suppression of?
3. Treatment of which conditions
4. How does glucocorticoids act?
1. **Glucocorticoids** also **stimulate endogenous anti-inflammatory pathways.**
1. **In combination**, all of these mechanisms create a **powerful anti-inflammatory effect.**
2. Because of this **profound and global suppression of immune and inflammatory responses**,
3. **Glucocorticoids are indicated** for the **treatment of a number of** **autoimmune conditions.**
4. **Glucocorticoids act** by **inducing the synthesis of lipocortins**,
1. a **family of phospholipase A2-regulatory proteins**.
2. One of the **lipocortins, annexin 1**, mediates some of the **anti-inflammatory actions of glucocorticoids.**
26
24: GLUCOCORTICOIDS
***_Anti-inflammatory action:_***
**Cell-type/organs**
**Blood vessels**
ACTION?
MECHANISM?
Permeability decreased
Synthesis of eicosanoids decreased
27
24: GLUCOCORTICOIDS
Anti-inflammatory action:
**Cell-type/organs**
**PMN**
ACTION
MECHANISM
Migration decreased
PMN and macrophage action decreased
PMN = Polymorphonuclear leukocytes (neutro-, eosino, basophil granulocytes)
28
24: GLUCOCORTICOIDS
Anti-inflammatory action:
**Cell-type/organs**
**Lymphocytes**
**Monocytes**
ACTION
MECHANISM
T-cell activity decreased
Phagocytosis decreased
Synthesis of eicosanoids decreased
Alterations of cell membrane
Synthesis of mediators decreased
29
24: GLUCOCORTICOIDS
Anti-inflammatory action:
*_Glucocorticoid activity is determined by:_*
* C3 and C20 = **ketone functional groups**
* C20-21 **side chain at position C17**
* C4 and C5 **double bound,** C11 OH-group\*
**\*(cf. cortisone → hydrocortisone)**
30
24: GLUCOCORTICOIDS
Anti-inflammatory action:
*_Glucocorticoid activity is enhanced by:_*
* Another double bound C1-C2 - prednisolone
* C6 methyl group - methylprednisolone
* C16 hydroxyl-, methyl group - triamcinolone, dexa-, betamethasone
* C6 and/or C9 fluor - fluoroprednisolone, flumetasone
31
24: GLUCOCORTICOIDS
Anti-inflammatory action:
*_Synthetic Glucocorticoids: Structure-action relationship_*
* The **efficacy** of the **glucocorticoids** applied **locally** or **inhalational** way can be **improved by the application** of
* **two flours** or
* **chlorine** in molecules, and
* **acetonide substitution,** etc.
These **changes in structure** **increase the lipophilicity** and **local metabolism** (good availability, less systemic side-effects)
1. **Beclomethasone**
2. **Budesonide**
3. **Fluticasone**
4. **Clobetasol**
5. **Flumetasone**
6. **Triamcinolone acetonide**
7. **Fluocinolone acetonide**
32
24: GLUCOCORTICOIDS
Anti-inflammatory action:
ACTIVE INGREDIENTS
1. **Hydrocortisone**
2. **Cortisone**
3. **Prednisolone**
4. **Methylprednisolone**
5. **Triamcinolone**
6. **Betamethasone**
7. **Dexamethasone**
8. **Cortivazol**
33
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Active indrediens with Strongest and Lowest antiinflammatory effect?
Strongest = **CORTIVAZOL** = 60
Weakest = **CORTISONE** = 0,8
34
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Active substances with mineral corticoid activity
Highest?
Other?
No activity?
* Highest activity = **HYDROCORTISONE = 1**
**Cortisone & Prednisolone = 0,8**
**Methylprednisolone = 0,5**
* No activity =
1. **Triamcinolone**
2. **Betamethasone**
3. **Dexamethasone**
4. **Cortivazol**
35
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Range the substances from shortest to longest biologic half-life (hours)
1. Prednisolone
2. Dexamethasone
3. Betamethasone
4. Cortivazol
5. Hydrocortisone
6. Cortisone
7. Methylprednisolone
8. Triamcinolone
**Hydrocortisone & Cortisone: 8-12 hours**
**Prednisolone , Methylprednisolone, Triamcinolone: 12-36 hours**
**Betamethasone & Dexamethasone: 36-54 hours**
**Cortivazol: \>60 hours**
36
24: GLUCOCORTICOIDS
Anti-inflammatory action:
***_Classification of glucocorticoids based on their action:_***
Short acting
***_Classification of glucocorticoids based on their action:_***
1. *_Short acting (biological half-life less than 1 day):_*
* Cortisol - Cortisone (inactive, liver has to activate first)
37
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Classification of glucocorticoids based on their action:
Middle long acting
1. *_Middle long acting (biological half-life maximum 1-2 days):_*
* **Prednisolone** - Prednisone (inactive, liver has to activate first)
* **Methylprednisolone**
* **Triamcinolone**
38
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Classification of glucocorticoids based on their action:
Long acting
1. *_Long acting (biological half-life more than 2 days):_*
* **Dexamethasone**
* **Betamethasone**
* **Flumetasone**
39
24: GLUCOCORTICOIDS
Anti-inflammatory action:
***_Different glucocorticoid derivatives:_***
1. *_Water-soluble salts (sterile solutions):_*
2. *_Less soluble esters:_*
3. *_Insoluble esters (e.g. valerate):_*
40
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Different glucocorticoid derivatives:
*_Water soluble salts (sterile solutions)_*
*_Water soluble salts (sterile solutions):_* e.g.
1. **sodium** salt ,
2. **phosphate** salt,
3. **succinate** **ester**
* IV,
* (IM),
* intraarticular (into the joints)
41
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Different glucocorticoid derivatives:
Less soluble esters:
Less soluble esters: e.g.
1. **acetate,**
2. **phenylpropionate,**
3. **isonicotinate**
* SC,
* IM - mild depot effect, for several days (sterile suspension)
42
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Different glucocorticoid derivatives:
Insoluble esters
Insoluble esters
1. **Valerate**
* SC,
* IM - depot effect, for several weeks
**Inhibition of HPA-axis = Cushing (sterile suspension)**
43
24: GLUCOCORTICOIDS
Anti-inflammatory action:
***_Pharmacokinetic characteristics of glucocorticoids:_***
1. ***_Absorbtion_***
2. ***_Distribution_***
3. ***_Metabolism_***
4. ***_Excretion_***
*_**1. Absorption**:_* **Good** - **excellent** (GI, mucosal parts, skin←F)
*_**2. Distribution**:_*
* Distribution is **wide**.
* **Protein** **bounding** is **high**.
* **Transcortin** (partly **albumin**) binds the
* **Natural**
* **Synthetic** **steroid preparations** (eg. **progesterone**,
**prednisolone**)
***_3. Metabolism and elimination:_***
* **Liver metabolizes**
* **glucocorticoids,**
* **steroids** become **more water-soluble**,
* mainly via **hydroxylation** of **ketone-groups,**
* and **reduction of double bond** in ring A.
Conjugation occurs in position C3-C21 with glucuronic acid or sulphate. These changes lead to inactivation of glucocorticoids (activation of inactive cortisone and prednisone in the liver (C11 OH)).
***_Excretion_*: Mainly via urine.**
44
24: GLUCOCORTICOIDS
Anti-inflammatory action:
***_Indications:_***
1. Antiinflammatory use (acute and chronic inflammations).
2. Oedema
3. Shock
4. Allergy, anaphylaxis, anaphylactoid reactions.
5. Asthma
6. Autoimmune disorders:
7. Lymphoid tumours.
8. Induction of parturition.
9. Ketosis.
10. Addison’s-disease (+ fludrocortisone).
45
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Indications:
1. Antiinflammatory use
Antiinflammatory use
* **acute**
* **chronic** inflammations
1. **Significant as local too** e.g.
* **ophthalmologic**,
* **outer ear,**
* **mastitis,**
* **fungal skin disorders** (only in combination with ABs and/or antimycotics).
46
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Indications:
Oedema
Oedema
* **decreased capillary permeability**
* **brain** oedema,
* **spinal** cord oedema,
* **pulmonary** oedema
47
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Indications:
**Shock**:
Shock:
* **Adrenaline** + **crystalloid**-infusion,
* IV
* **Large** doses of **water-soluble derivative**s e.g.
* **prednisolone-succinate** 30 mg/kg b.w.).
48
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Indications:
Autoimmune disorders:
Autoimmune disorders:
1. **lupus erythematosus,**
2. **pemphigus**,
3. **myasthenia gravis,**
4. **myositis eosinophilic** - middle long-lasting agents (2-4 mg/kg b.w.).
49
24: GLUCOCORTICOIDS
Anti-inflammatory action:
***_Corticosteroid therapy:_***
1. **Systemic treatments:**
2. **Topical - local treatments:**
50
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
***_Systemic treatments:_***
* **Shock**
* **Life-threatening oedemas**
* **Allergy**
* **Inflammation** of different organs (+ local administration)
* **Local oedemas**
* **Special tumour**s
* (**Ketosis** – **feline anorexia**)
51
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
**Topical - local treatments:**
*_Topical - local treatments:_*
* **Skin**
* **Conjunctiva**, other mucosal parts
* **Musculoskeletal system**
* **Airways**
52
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
***_Side Effects:_***
## Footnote
1. *Intended Organs:*
2*. Inhibited functions:*
3. *Negative effects on metabolism*
4. *Immunosuppressive effect:*
5. *Interaction with hormone-system:*
6. *Catabolic effects:*
53
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
**Side Effects:**
*_Side Effects:_*
1. *Intended Organs:*
2*. Inhibited functions:*
3. *Negative effects on metabolism of:*
4. *Immunosuppressive effect:*
5. *Interaction with hormone-system:*
6. *Catabolic effects*
1. **GI, liver, skin** and **fur** etc.
2*. **W*****ound healing, immune processes**
3.
* **Nutrients** (PU/PD, **increased appetite**)
* **Minerals** (Na↑, K↓, Ca ↓)
4. **Reactivation of pre-existing infections**
5. **Addison’s disease - Cushingoid syndrome**
* ***HPA-axis inhibition:*** Following **long-term use reactivation** with
* **ACTH**,
* stepwise elimination,
* avoiding the use of depot preparation,
* alternate day application local treatments (if applicable).
6.
* **Diabetogenic**
* **Muscle wasting**
* **Osteoporosis**
54
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
*_**Contraindications**:_*
*_Contraindications:_*
* **Pre-existing renal impairment**,
* **congestive heart failure**
* **liver disease,**
* **diabetes**
* **Pregnancy** (early and late)
* **Infection** (except certain acute once + ABs)
* **NSAID treatment** (but some combinations exist)
55
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
***_Aspects of the proper corticosteroid use:_***
1. **Single large doses (relatively harmless):**
2. **Depot preparations:**
3. **Chronic administration:**
56
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
Aspects of the proper corticosteroid use:
**Single large doses**
*_Single large doses (relatively harmless):_*
* **Short lasting active agent** and/or **sterile solution** e.g.
* **PREDNISISOLONE**,
* **METHYLPREDNISOLONE** 10-50mg/kg b.w.
* (in difficult cases repeating once or twice).
57
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
Aspects of the proper corticosteroid use:
***_Depot preparations_*:**
*_Depot preparations_*:
* Side-effects **at the injection site as well.**
* The **effect may last for over one month.**
Less than 1 mg/kg b.w.
58
24: GLUCOCORTICOIDS
Anti-inflammatory action:
**Corticosteroid therapy:**
Aspects of the proper corticosteroid use:
***_Chronic administration:_***
*_Chronic administration:_*
* Respecting the **endogen daily cycle** (circadian rhythm).
* As **low as possible dose.**
* **Alternate day therapy** (ADT).
* **Elimination of daily dose stepwise.**
* If it is necessary **reactivation of hypothalamus-Pituitary-Adrenal gland axis**
* ****(e.g. **ACTH injection)**.
59
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
Aspects of the proper corticosteroid use:
**Chronic administration:**
**Usage of Prednisolone and Methylprednisolone**
* The following drugs are for the treatment of allergic diseases,
* **ATOPIC DERMATITIS** mainl
* **Food allergies**,
* **Flea allergy dermatitis** (FAD) etc.
* These diseases are very frequently found in
* **companion animals,**
* **horses** and
* **humans**.
60
***_25: JAK INHIBITORS:_***
***_A_***
***_B_***
***_C_***
***_D_***
***_E_***
A= CYTOKINE RECEPTOR
B=JAK
C= CYTOKINE
D= Transcription
E= STAT
61
25: JAK INHIBITORS:
What is JAK?
* They are Janus kinase inhibitors (JAK = just another kinase).
* These are essential kinases in the
* **function of the immune system.**
62
25: JAK INHIBITORS:
**EXPLANE the IMAGE**
1. Examples of CYTOKINES?
2. What do they bound to?
3. What happens to the JAK
4. When activated - The signal mechanism binds to two?
5. Enter what
1. to induce what?
6. What happens if we inhibit the signaling mechanism?
1. Consequense of inhibition
7. How does these drugs act?
1. What do they inhibit
1. Cytokines e.g.
1. interleukins,
2. interferons, etc.
2. Bound to these **special receptors** = **Tyrosine kinase receptors.**
3. **This JAK** will **phosphorylate itself - T**yrosine amino acid in the protein.
4. This activates a signaling mechanism.
1. Involves the binding of **two STAT molecules** which then bind together and are released from the receptor to enter the
5. **Nucleus t**o
1. **induce inflammatory and allergic reactions**.
6. **Transcription processes will be inhibited** and, as the consequence of this transcription is
1. **inflammation or allergy**, these processes will be prevented i.e. **these drugs are excellent anti-inflammatories** and anti-**allergens**.
7. These drugs do **NOT act as antagonists** (binding to the receptor to inhibit the binding of the cytokines) but instead,
1. **Inhibit the signalling mechanism** that occurs **after the binding of the cytokines.**
63
25: JAK INHIBITORS:
The drugs used to inhibit the signaling mechanism that occurs after binding of the cytokines are used frequently in which species for which reasons?
* Frequently in the **human field (Extremely expensive)** for
* **Inflammatory,**
* **Autoimmune disease or**
* **Cancer.**
* **Rheumatoid arthritis,**
* **Crohn’s disease** (debilitating disease affecting the colon),
* **Leukemia and**
* **Alopecia.**
64
**25: JAK INHIBITORS:**
In the veterinary field, we have one extremely important JAK inhibitor named?
**OCLACITINIB**
65
25: JAK INHIBITORS:
**OCLACITINIB**
1. Expensive?
2. First produced for the indication of ?
3. Now extended to the usage for
4. Name a very frequent allergic skin disease in dogs?
1. Olactinib inhibits primarily which enzyme
2. It also inhibits the action of
3. Which is responsible for ?
4. Which IL is most important, and why?
5. Because of the most important inhibition of which particular interlaukin, what type of itching can be treated?
5. OLACTINIB and cats?
OCLACITINIB.
1. It is **not as expensive as human medicines.**
2. It was first **produced for the indication of atopic dermatitis** but is
3. now extended for **all allergic dermatitis** and **all types of pruritus (itching) in dogs**.
4. **Atopic dermatitis** is a very frequent allergic skin disease in dogs, given as an **atopic reaction** to **inhalation allergens** or contact **allergens** e.g. **pollens** or **insects** in the environment. **This is very difficult to manage and for this purpose, we use this drug.**
1. It inhibits **primary JAK-1** which is a s**ub-type of janus kinase enzymes** and
2. primarily **inhibits the actions of**
1. **IL(interleukins)-4,**
2. **IL-6**
3. **IL-13**
3. Responsible for **allergic** **reactions** and **inflammations associated with allergy,** and
4. **IL-31 (most important)** which is **responsible for the development of pruritus in dogs.**
5. Because of this **IL-31 action inhibition,** **all types of itching can be treated with oclacitinib.**
5. There is **no indication that IL-31 plays a role in cats,** that is why it is **only authorized for dogs.**
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25: JAK INHIBITORS:
OCLACITINIB and INHIBITORY CONCENTRATIONS
1. Which IL is most sensitive?
2. Why is it good?
3. IL-4 and IL- 13 require lower of higher dosage?
4. Why is this good or bad for us?
5. Are OLACTINIB immunosuppressant at all dosage levels?
6. What can happen if you administer OLACTINIB at high dosages for longer periods?
7. What is recommended when administering OLACTINIB over longer periods?
8. Safe drug or not?
1. From this graph, we can see that **IL-31 is the most sensitive.**
2. This is good as it means that **we only need a small dose to initiate an effect.**
3. Others, like **IL-4** and I**L-13,** **require higher concentrations.**
4. What is good for us is that these excellent and very important interleukins, that are **present in antigen presentation**, = **only inhibited at very high concentrations i.e.**
5. Antigen presentation does not usually suffer when oclacitinib is administered and therefore, **OLACTINIB is NOT immunosuppressive at normal dosages.**
1. We must, however, remember that the GM-CSF (granulocyte monocyte stimulating factor) is also inhibited at a high concentrations.
6. This means that we will initiate a problem if we administer oclacitinib at **high doses for a long period of time** because in this case, **neutrophils, eosinophils and normocytes numbers can be decreased.**
7. **Because of this, when we administer oclacitinib for a long period** of time, it is **recommended to regularly check hematology** parameters.
8. **This is very rare and it is considered a very safe drug.**
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## Footnote
*_Pharmacological effects:_*
1. Anti Inflammatory
2. Antiallergic
3. Antipruritic (anti itching)
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OLACTINIB
*_Pharmacokinetics:_*
1. Administration and Bioavailability?
2. Food?
1. With or without, why?
3. Maximum plasma conc reached when?
1. Quick or slow action?
4. Metabolism
5. Influenced by CYP-450 or not
1. means?
*_Pharmacokinetics:_*
* This drug is **administered orally** as a **tablet**, where it has **excellent absorption** (**bioavailability = 90%**).
* Food **does not impair absorption** i.e.
* given **with** or **without** **food** but it is advised to be given **with food to ensure less frequent vomiting** (**emesis**).
* Maximum plasma concentration is reached **within one hour.**
* This can allow **quick action.**
* Its metabolism is in the **liver** but it does **not influence the CYP-450** enzymes i.e.
* the dose **does NOT have to be increased over time.**
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How to mimimize sideeffects of OLACTINIB for long term administration?
What can we expect?
This is because, to minimize the side effects, at day 14,
* We **switched from BID to SID i**.e.
* We halved the dose administered.
**This is how we can administer oclacitinib long-term safely as the double dose would eventually result in hematology issues or immunosuppression.**
With this, we expect an **increase in itching** however, it will **eventually level off.**
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OLACTINIB
1. What does this graph show?
2. How to decrease vomiting?
3. Longterm side effects of immunosuppression?
4. Due to the long-term usage and side effect, what do you tell the owner?
5. Safe or not?
6. Contraindication
7. What to monitor and how often?
1. This graph shows dogs that were administered **oclacitinib long-term** (2 years). The result is **vomiting and diarrhoea.**
2. Vomiting can be decreased when **administered with food.**
3. Long-term effects of immunosuppression (esp. UTI).
1. **pyoderma**
2. **otitis**
3. **UTI**/cystitis,
4. This is why we ask the owners to **regularly check for symptoms** of a **urinary tract infection.**
5. Otherwise, the drug is **extremely safe.**
6. Because of the **risk of mild immunosuppression**, it is **not recommended in oncological patients** because **cancer development can be enhanced** in the **presence of immunosuppression.**
7. We have to regularly check **hematology**, **biochemistry** does not usually show a change.
1. Neutrophil,
2. eosinophil,
3. monocyte and
4. thrombocyte numbers
1. Can be **decreased** but this is **very rare.**
5. ****Because of this we usually do a **hematology every month** or **every second month.**
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Due to the slight side effect of immunosuppressants, which immunological product(not a drug) was developed?
What kind of immunological product is it?
What does it target?
Highly specific to?
Which species?
What happens if you give it to other species?
Administration route?
The average duration of action?
**LOKIVETMAB**.
* This is an **IL-31 monoclonal antibody** (**MAB**) and
* targets the **IL-31** which is the primary **cause of itching** in these cases.
* This is **highly specific to IL-31.**
* It is an **immunological product with immunological side effects.**
* The ‘KI’ of the name comes from the fact that it is a chimera i.e. it is a canine-ised (it is **only used in dogs** when given to other species can cause an **anaphylactic reaction**) immunoglobulin that was **produced in hamsters.**
* This drug is given **subcutaneously every few week**s, **every month** or **every second month**, **depending on the severity of the inflammation/allergy**.
* The average duration of action is **30 days without any side effect**. Its dose is 0.5-2 mg/kg.
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