VIVA: Pharmacology - Endocrine Flashcards
(43 cards)
How can corticosteroids be classified?
- Duration of action:
- Short to medium-acting (e.g. dexamethasone)
- Long-acting (e.g. betamethasone) - Anti-inflammatory activity*:
- Hydrocortisone 1, prednisolone 5, dexamethasone 30 - Mineralocorticoid activity* (i.e. salt-retaining):
- Fludrocortisone 250x that of hydrocortisone - Topical vs non-topical
How does carbimazole act in thyroid disease?
Metabolised to methimazole
Major action is to block hormone synthesis of T3 and T4*
Inhibits thyroid peroxidase to limit organification of iodine*
Also blocks coupling of iodotyrosines
Small action in blocking peripheral deiodination of T3 and T4
Slow onset as T4 may take weeks to become depleted
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What are the major side effects of carbimazole?
Maculopapular rash, urticaria, pruritis (common)
Nausea and GI upset (occurs early)
Bone marrow suppression* (neutropaenia, reversible agranulocytosis)
Lupus reaction
Arthralgia
Vasculitis
Jaundice/hepatitis
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How does carbimazole differ from propylthiouracil?
- Carbimazole is a prodrug*, and is converted to methimazole in vivo (methimazole is 10x more potent)
- PTU has greater action in inhibiting peripheral deiodination of T3 and T4
- PTU is strongly protein bound (preferred in pregnancy, not secreted in breast milk)
- PTU has short half-life 1.5 vs 6hrs (PTU given QID, carbimazole daily)
- PTU bioavailability 50-80% vs carbimazole 100%
- PTU excreted in urine as glucuronide metabolite <24hrs, carbimazole in 48+ hrs
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Describe the mechanism of action of corticosteroids at a cellular level
Most of known effects via widely distributed glucocorticoid receptors*
Present in blood in bound form on corticosteroid binding globulin (CBG)
Enters cell as free molecule
Intracellular receptor bound to stabilising proteins (most important is heat shock protein 90, Hsp90)
Complex binds molecule of cortisol then is actively transported into nucleus where it binds to glucocorticoid receptor elements (GRE)* on the gene
Interacts with DNA and nuclear proteins regulating transcription
Resulting mRNA exported to cytoplasm for protein production* for final hormone response
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What are the side effects of corticosteroid use?
Short term (<2 weeks):
- Insomnia
- Behaviour changes
- Acute peptic ulcer
- Acute pancreatitis
- Hyperglycaemia
Long-term:
- Cushing’s syndrome (moon facies, fat redistribution, fine hair growth, acne) secondary to hormonal actions (rate of development is a function of the dose and patient genetics)
- Hyperglycaemia, diabetes mellitus
- Myopathy
- Osteoporosis
- Cataracts, glaucoma
- HTN
- Aseptic necrosis
- Psychiatric (hypomania, acute psychosis, depression)
- Na+ and fluid retention
- K+ loss
- Adrenal suppression* / Addisonian crisis (>2 weeks)
- Poor wound healing, thin skin, easy bruising
Immunosuppressant*
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What is the usual dose of dexamethasone for treatment of croup?
0.15-0.60mg/kg PO as a single dose
How can dexamethasone be administered?
3/4 needed to pass:
- Oral
- IV
- IM
- Topical
What are the pharmacological differences between dexamethasone and hydrocortisone?
Dexamethasone has 30x greater anti-inflammatory potency, and longer duration of action
Dexamethasone has no salt-retaining activity
Describe the anti-inflammatory and immunosuppressive effects of glucocorticoids
2 needed to pass:
- Effects on concentration, distribution and function of peripheral leucocytes
- Suppression of inflammatory mediators (cytokines, chemokines)
- Inhibit function of macrophages and antigen presenting cells
- Inhibit phospholipase A2 and COX2 -> decrease prostaglandins, leukotrienes, platelet activating factor
- Decrease histamine release by mast cells
- Reduce antibody production (in high doses)
In what situations could you use dexamethasone?
3 examples needed to pass:
- Diagnosis (dexa suppression test)
- Anti-inflammatory effect
- Croup
Outline the groups of drugs that are used to treat hyperglycaemia in diabetes mellitus
Insulin*
Sulfonylureas* (e.g. glipizide)
Biguanides* (e.g. metformin)
Meglitinides (e.g. rapaglinide)
D-phenylalanine derivatives
Thiazolidinediones (e.g. rosiglitazone)
Alpha-glucosidase inhibitors (e.g. acarbose)
Glucagon-like peptide 1 (GLP-1) agonist (e.g. liraglutide)
Sodium-glucose transporter 2 (SGLT2) inhibitor (e.g. dapagliflozin)
Dipeptidyl-peptidase 4 (DPP4) inhibitor (e.g. sitagliptin)
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Contrast the mechanism of action of sulfonylureas and biguanides
Sulfonylureas:
- Increase insulin release from pancreas*
- Reduce serum glucagon levels
- Close potassium channels in extra-pancreatic tissues
Biguanides:
- Action does not depend on functioning pancreatic B cells*
- May directly stimulate glycolysis in tissues with increased glucose removal from blood
- May reduce hepatic gluconeogenesis
- May slow absorption of glucose from the GI tract
- May reduce glucagon levels
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Describe the pharmacologic effects of glucagon
2/3 needed to pass:
1. Metabolic:
- Binds with GPCRs on hepatocytes to increase adenylyl cyclase and cAMP
- Results in catabolism of stored glycogen, raising blood glucose level
- No effect on skeletal muscle
- Also causes release of insulin from pancreatic B-cells, catecholamines from chromaffin cells, and calcitonin from medullary carcinoma cells
2. Cardiac effects:
- Potent inotropic and chronotropic effect on heart via cAMP, without requiring functioning B-receptor
3. Large doses produce smooth muscle relaxation (independent of cAMP)
What are the indications for using glucagon clinically?
2/4 needed to pass:
- Severe hypoglycaemia (increases glycogenolysis and gluconeogenesis)
- Beta-blocker overdose (5-10mg IV will reverse hypotension/bradycardia; acts via glucagon receptors and cAMP, independent of B-adrenoceptors)
- Relaxation of intestine during radiology of bowel (or for food bolus)
- In diagnosis of endocrine disorder (e.g. type I DM in which there will be no C-peptide response to glucagon; suspected tumours e.g. insulinoma, phaeochromocytoma, medullary carcinoma as glucagon will cause an increase in hormone)
What are the adverse reactions produced by glucagon?
Transient nausea and vomiting
Hyperglycaemia
Relatively free from severe adverse reaction
What are the effects of hydrocortisone?
Mediated by glucocorticoid receptors:
- Physiologic + permissive effects
- Metabolic effects
- Catabolic and anti-anabolic effects
- Anti-inflammatory and immunosuppressive effects*
- Other effects: CNS, pituitary axis, psychiatric, renal, neonatal lung
Immune effects:
- Impact concentration, distribution and function of peripheral leucocytes*
- Suppress inflammatory mediators* (cytokines, chemokines, prostaglandins, leukotrienes)
- Inhibit tissue macrophages and antigen-presenting cells
- Suppress mast cell degeneration
- Reduce antibody production (in large doses)
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Describe, with an example, the types of exogenous insulins which can be administered
- Ultra-short/short-acting*:
- Clear solution
- Neutral pH
- Contains zinc
- Rapid onset and short duration of action
- E.g. insulin lispro (Humalog), insulin aspart (Novorapid), insulin glulisine (Apidra), neutral insulin (Actrapid) - Intermediate-acting*:
- Turbid solution
- Neutral pH
- Protamine in phosphate buffer (NPH) to prolong action
- E.g. isophane insulin (Humuline, Protaphane), insulin aspart protamine - Long-acting*:
- Clear solution
- Soluble
- Slow onset and prolonged action
- Daily administration mimics basal insulin secretion
- E.g. insulin glargine (Lantus, Optisulin, Toujeo), insulin detemir (Levemir) - Mixed:
- E.g. neutral with isophane insulin (Humulin, Mixtard 30/70 or 50/50), insulin aspart with protamine (Novomix-30), insulin lispro and Lispro protamine (Humalog), insulin aspart with degludec (Ryzodeg)
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Describe the different regimens for insulin administration
2 needed to pass:
1. Basal-bolus:
- Using subcutaneous injections of ultra / short-acting insulin before every meal, and long-acting insulin once or twice daily
2. Continuous subcutaneous infusion:
- Ultra / short-acting insulin via pump with bolus doses activated by patient
3. Split mixed regimens using subcutaneous injections ultra / short-acting (30%) insulin combined with long-acting (70%) insulin once or twice daily
4. IV insulin +/- IV dextrose for DKA
What are the adverse effects of exogenous insulin?
Hypoglycaemia*
Hypoglycaemic unawareness
Weight gain
Allergic reactions (usually due to non-insulin contaminants)
Local reactions (erythema, itching, lipodystrophy, lipoatrophy)
Hypokalaemia
Immune insulin resistance
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What is the mechanism of action of insulin?
Promotes the uptake of glucose from blood into tissues* (especially fat, liver and skeletal muscle), and promotes glycogen synthesis (insulin receptors found on cell membranes)
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How are the differing properties of various classes of insulin used to optimise glycaemic control?
Combination of insulin with different durations of actions* aims to replace basal insulin requirement (50%) and meal requirement (50%)
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Give an alternative use for insulin other than regulation of blood glucose
1 needed to pass:
- Hyperkalaemia
- Ca2+ channel blocker (+/- B blocker) overdose
What pharmacological methods are used to optimise blood sugar control when administering insulin?
- Titration of dose to BSL*
- Pharmacological manipulation of human insulin molecule*:
- Rapid-acting: amino acid reversal/substitution, reducing aggregation properties
- Intermediate-acting: insuline/protamine complexes
- Long-acting: as substitutions, molecular attachments - Mixing of insulin preparations
- Continuous subcutaneous insulin infusion devices
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