HLI 4 Flashcards
What are autacoids, duration of action, examples and functions
- Chemical mediators which are synthesised and function in a localised area or tissue – ‘local hormone’
- Typically short lived and rapidly degraded
- Complex effects mediated through multiple receptor types
○ e.g. histamine, serotonin, eicosanoids - Key mediators of inflammatory processes
- Important targets for anti-inflammatory therapies
Histamine where stored, what released by and what response is it essential in
- Found in most tissues, stored at high concentrations in lungs, skin, GI tract (clinical signs)
- Cellular level: stored in mast cells, basophils, ECL cells (stomach), histaminergic neurons (brain)
- Histamine release stimulated by antigen binding to IgE
○ Essential role in type I hypersensitivity
What are the 4 receptors for histmine and there locations
H1 receptors: - Smooth muscle, endothelium, brain H2 receptors: - Gastric mucosa, cardiac muscle, brain, mast cells (negative feedback) H3 receptors: - Brain: pre-synaptic H4 receptors: - Leukocyte chemotaxis
Histamine effects on gastric secretion and examples of drugs
- Histamine stimulates the secretion of gastric acid through action on H2 receptors located on parietal cells
- Histamine is stored in enterochromaffin-like (ECL) cells in gastric fundus
- Covered during Digestive System lectures
○ e.g. cimetidine, ranitidine - anti-histamines
Effects on smooth muscle and cardiovascular of histamine
Effects on smooth muscle
- Acting on H1 receptors, contracts smooth muscle in ileum, bronchi, bronchioles and uterus
- Contraction of most smooth muscle except blood vessels (vasodilation)
Effects on cardiovascular system
- Vasodilation via H1 receptors in vascular smooth muscle
- ↑ heart rate and contractility via cardiac H2 receptors
- ↑ vascular permeability via H1 receptors on endothelial cells
Histamine effects on the neurological system
- Neurotransmitter in the brain
- H1 post-synaptic receptors:
○ Stimulates sensory nerves to cause itch - H3 pre-synaptic receptors:
○ Inhibit the release of a number of neurotransmitters
How is histamine used in veterinary medicine
- Histamine itself not used therapeutically due to multiple effects
- H1 and H2 antihistamines are widely used in small & large animal veterinary clinical work for the following indications:
○ Allergic reactions (bites/stings, allergic skin disease) - H1
○ Gastric ulceration (treatment and prevention) - H2
H1 antihistamines function and side effects
Function
- Relaxation of bronchiolar and intestinal smooth muscle
- Inhibition of vasodilation and increased vascular permeability
Inhibition of itch sensation by prevention of sensory nerve stimulation
- antimotion sickness
Side effects
- sedation - as H1 receptors found on the brain
What are the differences between first and second generation H1-antihistamines and which more effective in veterinary medicine
First generation antihistamines
- (e.g. diphenhydramine, chlorpheniramine)
- These drugs cross the BBB and therefore produce CNS side-effects (sedation)
• Second generation antihistamines
- (e.g. loratadine, cetirizine)
- Less lipid soluble, so limited ability to cross the BBB (blood-brain barrier) , reduced central effects (sedation)
- Used widely in humans, limited efficacy in veterinary patients and not widely used
○ Due to importance of sedation in the patients - scratch-itch cycle and they only make it worse, really need to reduce the itch sensation
H2 antihistamines functions and examples
- Reduce gastric acid secretion from parietal cells
○ e.g. cimetidine, ranitidine: remember DVM1! - Also mast cells - negative feedback, histamine release acts back on the mast cells to stop further production of histamine
What chemicals are involved in bee stings and the main chemical and where it is present
- Profound oedematous, very rapid and localised response - dictated by autacoids (act as local hormones)
Serotonin
• Serotonin = 5-hydroxytryptamine (5-HT)
• Present in high concentrations:
1. GI tract (enterochromaffin cells, enteric neurons)
2. Platelets
3. CNS (neurotransmitter)
List 4 main functions of serotonin
- Regulation of gut motility
- Platelet aggregation
- Body temperature
- Sleep, aggression and mood
What are the functions of seratonin in the CNS and smooth muscle
CNS: - Control of vomiting - Mood, sleep, appetite Smooth muscle contraction (all throughout the body including blood vessels unlike histamine) - GI tract - Uterus - Vascular Platelet activation
Metoclopramide what is it, main use and effects and side effects
Serotonin antagonist
- used to control vomiting
1) antimetic effect - serotonin antagonism
2) prokinetic effect - increase movement - can be issue with obstructive disease don’t want to perforate the gut but stop vomiting
CNS side effects - hyperactivity to depression
Cisapride what is it, what used for
Serotonin veterinary applications
- used in the treatment of GI stasis, constipation/megacolon in cats
Selective serotonin reuptake inhibitors (SSRIs) mechanism and function and uses
- Reduces pre-synaptic recycling of 5-HT → increased 5-HT activity in synapse
- Promotes function of serotonin as prevent breakdown in synaptic cleft
- Used in the treatment of aggression, separation anxiety, compulsive behaviours
- Combined with behavioural modification
Eicosanoids what made from main precursor and the two main types
Generated from phospholipid precursors on demand (not stored like histamine)
- produced by most cell types - broad regulatory activities
- Arachidonic acid is the main precursor found within the plasma membrane
- Principle eicosanoids are:
1. Leukotrienes
2. Prostanoids (prostaglandins and thromboxanes)
What occurs in the arachidonic acid pathway ad the enzymes involved
- Arachidonic acid which is then activated upon by two enzymes
○ LOX and COX (two types)
○ COX 2 - inducible form - LOX - leads to leukotrienes and lipoxins
- COX - Prostanoids
○ Different types of COX enzymes will result in different prostanoids produced
○ Certain enzymes are upregulated in different tissues and situations resulting in different prostanoids being produced
§ COX-2 is thought to be upregulated during inflammatory responses resulting in pro-inflammatory prostanoids being produced
Prostanoids roles in inflammation
- Some are powerful vasodilators
- Potentiate the effects of other mediators (e.g. histamine) which increase vascular permeability
- Potentiate the effects of other mediators which sensitise nerves to noxious stimuli
- Some are pyrogenic
- Some have anti-inflammatory effects under specific circumstance
List some specific functions of prostaglandin E2 and F2alpha and thromboxane A2
PGE2 (prostaglandin)
- pyrogenic, GI system, increased mucus secretion, decrease acid secretion, contraction of pregnant uterus
PGF2α (prostaglandin)
- produced in the uterus and cause luteolysis, contraction of uterine muscle in parturition
Thromboxane A2
- from platelets, platelet aggregation and vasocosntrction
What is prostaglandin F2alpha clinical uses
• Manipulation of reproductive cycle in cattle
- Synchronisation of oestrus for fixed-timed artificial insemination (in combination with ovulation-inducing drug)
- Induction of abortion during early pregnancy (e.g. neighbour’s bull jumped the fence!)
• Abortifacient – pregnant women should not handle drug
Leukotrienes what made by, key roles and how used
made by white blood cells (leuko) Key roles: - Potent chemoattractants - Activation of leukocytes - Bronchoconstrictors Used in human medicine for treatment of bronchoconstriction (asthma, COPD)
What are the two main types of corticosteroids and the mains ones main function
- Mineralocorticoids - aldosterone - important for salt and water metabolism, promote reabsorption of Na+
- Glucocorticoids
- Different to mineralocorticoids but do have some of the same effects
Eg: Cortisol - Anti-inflammatory
- Immunosuppressants
- Metabolic effects
- Negative feedback
Cortisol mechanism of action
- a steroid molecules diffuses into a cell and bind to a receptor molecule
- as a result the receptor undergoes a change
- That allows it to bind to a short stretch of DNA called a response element (RE) near a gene
○ Lots of different RE’s that it can bind to resulting in so many different products and therefore effects - The binding modifies the expression of that gene - leads to repression or induction
What are the main 4 glucocorticoid effects
- Metabolic
- Negative feedback
- Anti-inflammatory
- Immunosuppressant
What are the metabolic effects of glucocorticoid and mechanism
- decrease uptake and ultisiation of glucose and increase gluconeogenesis
-> leading to hyperglycaemia
ALSO - increase appetite but increase lipolysis and protein catabolism = muscle wasting
What are the negative feedback effects of glucocorticoids and treatment
- Administered corticosteroid suppresses endogenous steroid synthesis → adrenocortical atrophy
- Abrupt cessation of long-term therapy can precipitate an ‘Addisonian crisis’ - body doesn’t have enough acutely
- Can make the animal very ill
- Treatment dose is tapered to allow for recovery of adrenocortical function
what are the anti-inflammatory effects of glucocorticoids treatment
- Inhibits PLA2 → reduced eicosanoid production
- Reduce expression of COX-2 (inducible form) - anti-inflammatory
- Suppress mast cell degranulation (↓ histamine release)
- Potent effects on leukocyte trafficking (see immunosuppressive effects)
What are the immunosuppressive effects of glucocorticoids treatment
- Inhibits extravasation and infiltration of leukocytes
- Inhibits inflammatory actions of leukocytes (e.g. phagocytosis in macrophages)
- Reduces cytokine production
- Partial/complete suppression of a complex range of immune functions
○ Dose-dependent effect
○ Need to give certain dose depending on whether we want anti-inflammatory effect or pro-inflammatory
What are the effects on neutrophils, macrophages and lymphocytes in terms of glucocorticoid treatment
NEUTROPHILS ↓ chemotaxis ↓ margination ↓ bactericidal activity MACROPHAGES ↓ chemotaxis ↓ phagocytosis ↓ Ag presenting and cytokine production LYMPHOCYTES ↓ proliferation ↓ T-cell responses ↓ IL-2 production
List 5 clinical uses of synthetic glucocortcoids
1) allergic skin disease - dermitis, flea
2) allergic respiratory disease - asthma
3) arthritis
4) lymphoma
5) Addison’s disease
What is the potency and duration of action of the glucocorticoids
- Structure of steroid base determines potency
- Solubility of ester determines duration of action
Prednisolone sodium succinate and methylprednisolone acetate what type of drug and duration of action
Corticosteroid
Prednisolone sodium succinate - short action, released for minutes
Methylprednisolone acetate - long acting, released for days to weeks
Dexamethasone sodium phosphate and Dexamethasone phenylpropionate what type of drug and duration of action
Corticosteroid
Dexamethasone sodium phosphate - short acting released for minutes
Dexamethasone phenylpropionate - long acting, released for days to weeks
what are the 2 main common clinical signs from cortcisteroid side effects
- Polyphagia, polydipsia, polyuria - within the first few days
- Thinning of the skin, hair loss, poor wound healing within weeks
5 main side effects of corticosteroids
- Impaired wound healing
- Immunosuppressive doses will increase the risk of secondary infections (bacterial, fungal parasitic)
- Why we use them but always risk - Gastric ulceration
- Diabetes mellitus
- Abortion in late pregnancy
What are some contraindications of glycocorticoids
1) concurrent NSAID use
2) diabetes mellitus
3) pregnancy
4) gastric ulceration
List 3 main principles of corticosteroid therapy
1) Lowest effective dose - slowly decrease the concentration overtime and ask the owner to tell at what dose does the clinical signs come back
2) Shortest course
3) Limit frequency (e.g. alternate day oral administration enables adrenocortical recovery period between each dose)
Azathioprine and Cyclosporin what type of drug and mechanisms
Both immunosuppressant drugs - corticosteroid
Azathioprine
- Interferes with synthesis of purine nucleotides → inhibits DNA synthesis
- Inhibits clonal proliferation during induction phase of the immune response
Cyclosporin
Inhibits T-lymphocyte function by inhibiting cytokine production (IL-2, IFN-ɣ) – helper T-cell activation is blocked - used with atopic skin disease
What are the 3 primary aims of pharmacological control of inflammation
1) - Relief of presenting signs
e.g. pain, swelling, lameness, itch
2) - Maintenance of function
•e.g. improving mobility and range of motion
3) - Arrest of tissue damaging processes
•e.g. reduction in inflammatory cell infiltration/accumulation
What are the 3 primary actions of NSAIDs and main mechaism
- Anti-inflammatory
- Analgesic
- Antipyretic
- All actions relate to inhibition of the actions of COX → inhibit production of prostanoids
What is the mechanism of antipyretic effect of NSAids
NSAIDs inhibit this synthesis of PGE2 in the hypothalamus which is a pyretic