MIDTERM II - TOPIC 24-25 Flashcards
24: GLUCOCORTICOIDS 25: JAK-INHIBITORS
24: GLUCOCORTICOIDS
- 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.
24: GLUCOCORTICOIDS
Main features of applications:
- Management of hypoadrenocorticism (Addison’s disease)
- Management of hyperadrenocorticism (Cushing’s syndrome)
- Management of non-adrenal disorders:
- inflammatory,
- allergic and
- autoimmune disorders (immunosuppressive activities)
24: GLUCOCORTICOIDS
The natural corticosteroids:
Hench:
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).
24: GLUCOCORTICOIDS
Types:
-
Mineralocorticoids = (Zona glomerulosa)
- aldosterone,
- corticosterone
-
Glucocorticoids = (Zona fasciculata)
- cortisol,
- hydrocortisone,
- cortisone
-
Androgens = (Zona reticularis)
- androstenedione
24: GLUCOCORTICOIDS
Hormone synthesis in the adrenal cortex:
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.
24: GLUCOCORTICOIDS
Transport:
- 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.
24: GLUCOCORTICOIDS
Metabolism:
- 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.
24: GLUCOCORTICOIDS
Molecular mechanism of glucocorticoid action:
Type of effect
Genomic (classical)
Slow
SPECIFITY?
RECEPTOR
ACTIONS
Specificity
Receptor
Actions
Specific
Cytosolic
Glucocorticoid
Receptor (cGCR)
Anti-Inflammatory
Immunomodulatory
Replacement therapy
24: GLUCOCORTICOIDS
Molecular mechanism of glucocorticoid action:
Type of effect
Nongenomic (secondary)
SPECIFICITY
RECEPTOR
ACTIONS
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.
24: GLUCOCORTICOIDS
Molecular mechanism of glucocorticoid action:
Rapid
SPECIFICITY
RECEPTOR
ACTION
Specific
Membrane bound
Glucocorticoid
Receptor (mGCR)
NEURO- AND CARDIOPROTECTIVE EFFECT:
- Increased activity of endothelial nitric oxide synthase (eNOS),
24: GLUCOCORTICOIDS
Molecular mechanism of glucocorticoid action:
Only high doses
SPECIFICITY
RECEPTOR
ACTION
Specific
Non-receptorial
(interaction with cell membrane)
vasodilation of coronaries and cerebral vessels
24: GLUCOCORTICOIDS
Molecular mechanism of glucocorticoid action:
Cytosolic glucocorticoid receptor (cGCR):
- 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).
24: GLUCOCORTICOIDS
Cytosolic glucocorticoid receptor (cGCR)
Activation:
- 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)
24: GLUCOCORTICOIDS
Cytosolic glucocorticoid receptor (cGCR)
Inhibition:
- 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.
??
24: GLUCOCORTICOIDS
Physiological effects of corticosteroids:
Effect what
Physiological effects of corticosteroids:
- Carbohydrate metabolism:
- Lipid/fat metabolism:
- Protein metabolism:
- Water-electrolyte balance:
- Bones:
- Cardio-vascular system:
- Blood cell formation:
- Hormonal system:
24: GLUCOCORTICOIDS
Physiological effects of corticosteroids:
- Carbohydrate metabolism
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.
24: GLUCOCORTICOIDS
Lipid/fat metabolism:
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.
24: GLUCOCORTICOIDS
Protein metabolism:
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.
24: GLUCOCORTICOIDS
Water-electrolyte balance:
- Smaller doses of glucocorticoids increase the diuresis.
-
Large doses cause
- Na+ and water retention,
- increased K + and Ca2+ elimination.
24: GLUCOCORTICOIDS
Bones:
- Anti vitamin D action,
- slower production of bone matrix,
- increased excretion of Ca2+.
- In younger animals,
- dwarfism, and
- rickets (rachitis),
- In adults
- osteoporosis occurs.
24: GLUCOCORTICOIDS
Cardio-vascular system:
- Increased blood pressure,
- higher responsibility to catecholamines,
- large doses increase the volume of blood.
24: GLUCOCORTICOIDS
Blood cell formation:
-
Slightly increased red blood cell formation,
- even until polycythemia,
-
Slightly increased white blood cell formation (mild leukocytosis and neutrophilia),
- They cause lymphopenia and eosinopenia.
24: GLUCOCORTICOIDS
Hormonal system:
-
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: GLUCOCORTICOIDS
Anti-inflammatory action:
Inhibit the action of? and formation of?
By which mechanisms?
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.
24: GLUCOCORTICOIDS
Anti-inflammatory action:
- The anti-inflamatory action
- Because of the suppression of?
- Treatment of which conditions
- How does glucocorticoids act?
-
Glucocorticoids also stimulate endogenous anti-inflammatory pathways.
- In combination, all of these mechanisms create a powerful anti-inflammatory effect.
- Because of this profound and global suppression of immune and inflammatory responses,
- Glucocorticoids are indicated for the treatment of a number of autoimmune conditions.
-
Glucocorticoids act by inducing the synthesis of lipocortins,
- a family of phospholipase A2-regulatory proteins.
- One of the lipocortins, annexin 1, mediates some of the anti-inflammatory actions of glucocorticoids.
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Cell-type/organs
Blood vessels
ACTION?
MECHANISM?
Permeability decreased
Synthesis of eicosanoids decreased
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)
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
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
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
Systemic treatments:
- Shock
- Life-threatening oedemas
- Allergy
- Inflammation of different organs (+ local administration)
- Local oedemas
- Special tumours
- (Ketosis – feline anorexia)
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
Topical - local treatments:
Topical - local treatments:
- Skin
- Conjunctiva, other mucosal parts
- Musculoskeletal system
- Airways
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
Side Effects:
- Intended Organs:
2. Inhibited functions:
- Negative effects on metabolism
- Immunosuppressive effect:
- Interaction with hormone-system:
- Catabolic effects:
24: GLUCOCORTICOIDS
Anti-inflammatory action:
Corticosteroid therapy:
Side Effects:
Side Effects:
- Intended Organs:
2. Inhibited functions:
- Negative effects on metabolism of:
- Immunosuppressive effect:
- Interaction with hormone-system:
- Catabolic effects
- GI, liver, skin and fur etc.
2. Wound healing, immune processes
3.
- Nutrients (PU/PD, increased appetite)
- Minerals (Na↑, K↓, Ca ↓)
- Reactivation of pre-existing infections
- 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
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).
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.
25: JAK INHIBITORS:
A
B
C
D
E
A= CYTOKINE RECEPTOR
B=JAK
C= CYTOKINE
D= Transcription
E= STAT
25: JAK INHIBITORS:
EXPLANE the IMAGE
- Examples of CYTOKINES?
- What do they bound to?
- What happens to the JAK
- When activated - The signal mechanism binds to two?
- Enter what
- to induce what?
- What happens if we inhibit the signaling mechanism?
- Consequense of inhibition
- How does these drugs act?
- What do they inhibit
- Cytokines e.g.
- interleukins,
- interferons, etc.
- Bound to these special receptors = Tyrosine kinase receptors.
- This JAK will phosphorylate itself - Tyrosine amino acid in the protein.
- This activates a signaling mechanism.
- Involves the binding of two STAT molecules which then bind together and are released from the receptor to enter the
-
Nucleus to
- induce inflammatory and allergic reactions.
-
Transcription processes will be inhibited and, as the consequence of this transcription is
- inflammation or allergy, these processes will be prevented i.e. these drugs are excellent anti-inflammatories and anti-allergens.
- These drugs do NOT act as antagonists (binding to the receptor to inhibit the binding of the cytokines) but instead,
- Inhibit the signalling mechanism that occurs after the binding of the cytokines.
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.
25: JAK INHIBITORS:
OCLACITINIB
- Expensive?
- First produced for the indication of ?
- Now extended to the usage for
- Name a very frequent allergic skin disease in dogs?
- Olactinib inhibits primarily which enzyme
- It also inhibits the action of
- Which is responsible for ?
- Which IL is most important, and why?
- Because of the most important inhibition of which particular interlaukin, what type of itching can be treated?
- OLACTINIB and cats?
OCLACITINIB.
- It is not as expensive as human medicines.
- It was first produced for the indication of atopic dermatitis but is
- now extended for all allergic dermatitis and all types of pruritus (itching) in dogs.
-
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.
- It inhibits primary JAK-1 which is a sub-type of janus kinase enzymes and
- primarily inhibits the actions of
- IL(interleukins)-4,
- IL-6
- IL-13
- Responsible for allergic reactions and inflammations associated with allergy, and
- IL-31 (most important) which is responsible for the development of pruritus in dogs.
- Because of this IL-31 action inhibition, all types of itching can be treated with oclacitinib.
- There is no indication that IL-31 plays a role in cats, that is why it is only authorized for dogs.
25: JAK INHIBITORS:
OCLACITINIB and INHIBITORY CONCENTRATIONS
- Which IL is most sensitive?
- Why is it good?
- IL-4 and IL- 13 require lower of higher dosage?
- Why is this good or bad for us?
- Are OLACTINIB immunosuppressant at all dosage levels?
- What can happen if you administer OLACTINIB at high dosages for longer periods?
- What is recommended when administering OLACTINIB over longer periods?
- Safe drug or not?
- From this graph, we can see that IL-31 is the most sensitive.
- This is good as it means that we only need a small dose to initiate an effect.
- Others, like IL-4 and IL-13, require higher concentrations.
- 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.
- Antigen presentation does not usually suffer when oclacitinib is administered and therefore, OLACTINIB is NOT immunosuppressive at normal dosages.
- We must, however, remember that the GM-CSF (granulocyte monocyte stimulating factor) is also inhibited at a high concentrations.
- 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.
- Because of this, when we administer oclacitinib for a long period of time, it is recommended to regularly check hematology parameters.
- This is very rare and it is considered a very safe drug.
25: JAK INHIBITORS:
Pharmacological effects:
- Anti Inflammatory
- Antiallergic
- Antipruritic (anti itching)
25: JAK INHIBITORS:
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.
25: JAK INHIBITORS:
OLACTINIB
- What does this graph show?
- How to decrease vomiting?
- Longterm side effects of immunosuppression?
- Due to the long-term usage and side effect, what do you tell the owner?
- Safe or not?
- Contraindication
- What to monitor and how often?
- This graph shows dogs that were administered oclacitinib long-term (2 years). The result is vomiting and diarrhoea.
- Vomiting can be decreased when administered with food.
- Long-term effects of immunosuppression (esp. UTI).
- pyoderma
- otitis
- UTI/cystitis,
- This is why we ask the owners to regularly check for symptoms of a urinary tract infection.
- Otherwise, the drug is extremely safe.
- 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.
- We have to regularly check hematology, biochemistry does not usually show a change.
- Neutrophil,
- eosinophil,
- monocyte and
- thrombocyte numbers
- Can be decreased but this is very rare.
- Because of this we usually do a hematology every month or every second month.
25: JAK INHIBITORS:
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 weeks, 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.
