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Which nervous system, autonomic or somatic, controls bronchial tone?
Which division of the autonomic nervous system dilates/constricts bronchial smooth muscle?
- Dilates - sympathetic
- Constricts - parasympathetic
Which receptors in bronchial smooth muscle respond to sympathetic stimulation? How do they respond to stimulation?
B2 receptors - increase cAMP in bronchial smooth muscle and relax bronchial smooth muscle.
Sympathetic stimulation inhibits the release of ... from mast cells?
Which receptors in bronchial smooth muscle respond to parasympathetic stimulation? How do they respond to stimulation?
M3 receptors - increase IP3 and intracellular Ca2+ which causes constriction of bronchial smooth muscle
What is the other target in bronchial smooth muscle? What are the effects of its stimulation?
PDE - PDE is responsible for breaking down cAMP and cGMP so if you inhibit PDE it leads to an increase in the presence of these mediators, which results in relaxation of smooth muscle
List the three classes of drugs used to achieve bronchodilation pharmacologically
- B-adrenergic agonists
- Anticholinergic (antimuscarinic) drugs
- Methylxanthines (PDE inhibitors)
For a drug to be maintained within the lungs we want a high/low lipid solubility?
Low lipid solubility (high water solubility) so it will not cross cell membranes to distribute systemically throughout the body
What is the endogenous form of B-adrenoreceptor agonists?
When is adrenaline used in veterinary medicine and why?
- Only for the emergency treatment of life threatening bronchoconstriction as adrenaline will have many other side effects as it affects B1 and alpha receptors as well as B2 receptors
What B-adrenoreceptor agonists are more commonly used in vet med?
B2 adrenoreceptor specific agonists e.g. clenbuterol
What are the side effects of B-adrenorecetor agonists?
- CVS: increased heart rate, palpitations
- Skeletal muscle: tremors
True or false: tolerance is seen with the use of B-adrenoreceptor agonists?
True - they are therefore only suitable for intermittent use
What is the mechanism of action of the anticholinergic drugs?
They block endogenous parasympathetic tone
What are the side effects of anticholinergic drugs?
CNS stimulation and GI inhibition
What is a quaternary derivative?
It is a charged molecule
What is a quaternary derivative of atropine? Why does it have minimal side effects?
Ipratropium bromide - it has limited absorption as it is a charged molecule so it therefore has minimal systemic side effects
What is the mechanism of action of the methylxanthines?
They are PDE inhibitors. This leads to a decrease in cAMP and bronchial smooth muscle relaxation.
Apart from smooth muscle relaxation what other beneficial effects do the methylxanthines have?
Decrease inflammatory mediators and inhibit adenosine
What are the side effects of methylxanthines?
- GI: nausea and vomiting
- Cardiac: cardiac stimulation
- CNS: alertness
What are the three classes of drugs used for treatment of allergic and inflammatory disorders?
Corticosteroids, NSAIDS and leukotriene inhibitors
What are the two types of corticosteroids naturally produced by the body?
Glucocorticoids and mineralocorticoids
What organ produces corticosteroids?
The adrenal gland
What part of the adrenal gland produces glucocorticoids and mineralocorticoids?
True or false: corticosteroids and produced and stored until they are needed?
False - they are synthesised and released as required
Corticosteroids are produced from ...?
What zone of the adrenal cortex produces cortisol and corticosterone? What stimulates this?
- Zona fasiculata
- ACTH from the pituitary gland
Describe the natural pathway for glucocorticoid production
- CRF is transferred by the portal blood system directly to the anterior pituitary to the pars intermedia cells to produce ACTH. ACTH stimulates production of glucocorticoids in the adrenal gland.
- Glucocorticoids feed back at the level of the hypothalamus and anterior pituitary to inhibit ACTH release.
What are the two most commonly used glucocorticoids?
Dexamethasone and betamethasone
Glucocorticoids act through cell membrane/nuclear hormone receptors?
What is the mechanism of action of the glucocorticoids?
They act through nuclear hormone receptors to alter protein synthesis (either inhibit or stimulate production of certain proteins)
What effect does dose have on the action of glucocorticoids?
The higher the dose the greater the effect: (low dose) physiological function --> anti-inflammatory activity --> immunosuppressive --> cytotoxicity (high dose)
Give an example of a corticosteroid that has a short (<24hrs) and long (>24hrs) duration of action
- Short - prednisolone, prednisone, methylprednisolone
- Long - dexamethasone, betamethasone, triamcinolone
What would a water soluble salt vs a formulation cortiosteroid be used for?
Water soluble salt can be administered IV and so are used largely of acute conditions e.g. allergies or shock. Whereas a formulation is more useful for sustained therapy.
What route of administration of glucocorticoids might be used to treat the skin for problems like allergy or inflammation?
What does COPD and RAO stand for?
Chronic obstructive pulmonary disease and recurrent airway obstruction
Match the drugs to the condition: antibiotics, bronchodilators, glucocorticoids, to open airways, for infection, to reduce inflammation
- Antibiotics - for infection
- Bronchodilators - to open airways
- Glucocorticoids - to reduce inflammation
Why must treatment of exogenous corticosteroids be withdrawn gradually?
Exogenous corticosteroids cause negative feedback on the hypothalamus. This causes suppression of ACTH followed by atrophy of the adrenal gland. Therefore sudden termination of exogenous corticosteroid can lead to a life-threatening crisis as the animal can no longer produce endogenous corticosteroids.
List some side effects of corticosteroids
Gastric and corneal ulceration, suppression of responses, muscle and cutaneous atrophy, hyperglycaemia, osteoporotic effect, sodium and water retention and loss of potassium, polyuria and polydypsia, increased susceptibility to infection, iatrogenic Cushing's, suppression of HPA leading to Addison's disease on drug withdrawal, laminitis
What is Addison's disease?
Deficiency of adrenocortical steroid production (mineralocorticoid and glucocorticoid deficiency)
What are the three causes of Addison's disease
- Usually immune mediated destruction of adrenal cortices
- Spontaneous central hypoadrenocorticism less common (produce too little ACTH)
- Central hypoadrenocorticism is most commonly iatrogenic
List some symptoms of Addison's disease
Anorexia, vomiting, diarrhoea, weakness, exercise intolerance, polydipisia and polyuria
How do you diagnose Addison's disease?
Measure hormones in the blood. Circulating ATCH concentrations are increased in primary (adrenal Addison's) but not so in central hypoadrenocorticism
What is the acute/chronic treatment for Addison's?
- Acute - this is a medical emergency, hydrocortisone sodium succinate is given IV
- Chronic - animal requires permanent mineralocorticoid therapy
What is Cushing's disease?
Overproduction of glucocorticoids
What are the possible causes of Cushing's disease?
- Pituitary adenoma (ACTH increased)
- Adrenal tumour (ACTH very low)
- Iatrogenic Cushing's can result from prolonged treatment with glucocorticoids
List some symptoms of Cushing's disease
Polydypsia, polyuria, polyphagia, elevated liver enzymes, pot belly, thin skin, coat changes, muscle wastage
Give examples of breeds commonly affected by Cushing's disease
Poodles, Dachshunds, Terriers, German Shepherds, Golden Retrievers
What are the three main tests for Cushing's syndrome?
- ACTH test: elevated corticosteroids before ACTH and a rise after administration
- Low dose dexamethasone suppression test: in Cushing's the animal will not suppress cortisol
- High dose dexamethasone suppression test: used to differentiate between pituitary and adrenal problem. If pituitary high dose will suppress cortisol production, if adrenal it will not.
What are the two ways to treat Cushing's disease?
Enzyme blockers or drugs that remove layers of the adrenal cortex