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ACEM Primary VIVA > VIVA: Pharmacology - Endocrine > Flashcards

VIVA: Pharmacology - Endocrine Flashcards

1
Q

How can corticosteroids be classified?

A
  1. Duration of action:
    - Short to medium-acting (e.g. dexamethasone)
    - Long-acting (e.g. betamethasone)
  2. Anti-inflammatory activity*:
    - Hydrocortisone 1, prednisolone 5, dexamethasone 30
  3. Mineralocorticoid activity* (i.e. salt-retaining):
    - Fludrocortisone 250x that of hydrocortisone
  4. Topical vs non-topical
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2
Q

How does carbimazole act in thyroid disease?

A

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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3
Q

What are the major side effects of carbimazole?

A

Maculopapular rash, pruritis (common)
Bone marrow suppression* (neutropaenia, reversible agranulocytosis)
Urticaria
Arthralgia
Lupus reaction
Vasculitis
Jaundice/hepatitis
Nausea and GI upset (occurs early)

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4
Q

How does carbimazole differ from propylthiouracil?

A
  • 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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5
Q

Describe the mechanism of action of corticosteroids at a cellular level

A

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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6
Q

What are the side effects of corticosteroid use?

A

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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7
Q

What is the usual dose of dexamethasone for treatment of croup?

A

0.15-0.60mg/kg PO as a single dose

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8
Q

How can dexamethasone be administered?

A

3/4 needed to pass:
- Oral
- IV
- IM
- Topical

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9
Q

What are the pharmacological differences between dexamethasone and hydrocortisone?

A

Dexamethasone has 30x greater anti-inflammatory potency, and longer duration of action
Dexamethasone has no salt-retaining activity

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10
Q

Describe the anti-inflammatory and immunosuppressive effects of glucocorticoids

A

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)

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11
Q

In what situations could you use dexamethasone?

A

3 examples needed to pass:
- Diagnosis (dexa suppression test)
- Anti-inflammatory effect
- Croup

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12
Q

Outline the groups of drugs that are used to treat hyperglycaemia in diabetes mellitus

A

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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13
Q

Contrast the mechanism of action of sulfonylureas and biguanides

A

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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14
Q

Describe the pharmacologic effects of glucagon

A

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

  1. Cardiac effects:
    - Potent inotropic and chronotropic effect on heart via cAMP, without requiring functioning B-receptor
  2. Large doses produce smooth muscle relaxation (independent of cAMP)
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15
Q

What are the indications for using glucagon clinically?

A

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 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)

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16
Q

What are the adverse reactions produced by glucagon?

A

Transient nausea and vomiting
Hyperglycaemia
Relatively free from severe adverse reaction

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17
Q

What are the effects of hydrocortisone?

A

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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18
Q

Describe, with an example, the types of exogenous insulins which can be administered

A
  1. 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)
  2. Intermediate-acting*:
    - Turbid solution
    - Neutral pH
    - Protamine in phosphate buffer (NPH) to prolong action
    - E.g. isophane insulin (Humuline, Protaphane), insulin aspart protamine
  3. 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)
  4. 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)
  • needed to pass with one example from each
19
Q

Describe the different regimens for insulin administration

A

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

20
Q

What are the adverse effects of exogenous insulin?

A

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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21
Q

What is the mechanism of action of insulin?

A

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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22
Q

How are the differing properties of various classes of insulin used to optimise glycaemic control?

A

Combination of insulin with different durations of actions* aims to replace basal insulin requirement (50%) and meal requirement (50%)

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23
Q

Give an alternative use for insulin other than regulation of blood glucose

A

1 needed to pass:
- Hyperkalaemia
- Ca2+ channel blocker (+/- B blocker) overdose

24
Q

What pharmacological methods are used to optimise blood sugar control when administering insulin?

A
  1. Titration of dose to BSL*
  2. 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
  3. Mixing of insulin preparations
  4. Continuous subcutaneous insulin infusion devices
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25
Q

What type of insulin is used for IV infusion and why?

A

Short-acting regular soluble insulin as it immediately dissociates on dilution and so is able to be more precisely delivered

26
Q

Describe the principles of operation of a subcutaneous insulin infusion device

A

External open-loop pump for insulin delivery
Delivers individualised basal and bolus insulin replacement doses based on continuous blood glucose monitoring
Programmed by user
Consists of insulin reservoir, program chip, keypad and display screen attached to subcutaneously inserted infusion set

27
Q

Outline the pharmacokinetics of metformin

A

Well-absorbed
Not protein bound
Not metabolised
Elimination half-life 1.5-3hrs
Excreted by kidney as unchanged compound*

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28
Q

Outline some common side effects of metformin

A

GI most common (20%) and limits compliance*
HAGMA (lactic acidosis*; especially in patients with coexistent renal disease, EtOH, or chronic cardiopulmonary disease)
Decreased vitamin B12 absorption

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29
Q

Contrast the mechanism of action of metformin (biguanide) and glipizide (sulfonylurea)

A

Glipizide:
- Increases insulin release from pancreas* (patients more prone to hypoglycaemia with glipizide compared with metformin)
- Decreases serum glucagon levels
- Potentiates insulin effects on cells through K+ channel closure in extrapancreatic tissues

Mechanism of metformin is unclear but:
- Not dependent on functioning pancreatic B-cells (so doesn’t influence insulin release from pancreas)*
- May reduce hepatic gluconeogenesis
- May directly stimulate glycolysis in tissues with increased glucose removal from blood
- Decreases glucose absorption in the gut
- Reduces plasma glucagon

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30
Q

What is the mechanism of action of octreotide?

A

Somatostatin analog
Reduces sphlanchnic and portal blood flow* by poorly understood mechanism, and hence variceal pressures
Inhibits endocrine and paracrine factor secretion including insulin, glucagon, gastrin, GH and TSH

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31
Q

What are the routes of administration of octreotide?

A

2 needed to pass:
- IV
- IM
- Subcutaneous

32
Q

What are the adverse effects of octreotide?

A

2 needed to pass:
- Anaphylaxis
- Local irritation during injection (redness, burning)
- GIT symptoms (nausea, vomiting, abdominal cramps, decreased intestinal motility, bowel obstruction, flatulence, steatorrhoea, cholelithiasis)
- Hypo-/hyper-glycaemia
- Cardiac (sinus bradycardia, conduction disturbances)

33
Q

Describe the pharmacokinetics of octreotide

A

Plasma elimination half-life is 80 mins*
Metabolised by liver (30-40%)
20% excreted unchanged by kidney

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34
Q

What are some of the clinical uses of octreotide?

A

Acute control of bleeding from oesophageal varices*
Sulfonylurea overdose
Reduces symptoms caused by hormone-secreting tumours (e.g. acromegaly, carcinoid, gastrinoma)
Radiolabelled octreotide used to locate endocrine tumours

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35
Q

How is octreotide administered in acute variceal bleeding? Why is an infusion required?

A

IV bolus and infusion* (50mcg bolus then 25-50mcg/hr), or subcutaneous
Infusion needed due to short half-life of octreotide*

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36
Q

What are the pharmacokinetic differences between octreotide and somatostatin?

A

Octreotide is a somatostatin analogue that has a longer half-life than somatostatin (1.5 hrs vs 3 mins), so can be given as an IV infusion or subcutaneously

37
Q

What agents other than octreotide may be useful in the prevention and treatment of upper GI bleeding?

A

PPI: useful in prevention and in bleeding (reduces gastric ulceration)
Terlipressin: vasopressin analogue which causes sphlanchnic vasoconstriction to reduce portal venous pressure
Somatostatin: as per octreotide
Blood products for resuscitation (including platelets if thrombocytopaenic or in massive transfusion)
Correction of underlying bleeding diathesis (e.g. vitamin K if warfarinised)

38
Q

With regard to sulfonylureas, what is the mechanism of action of glipizide?

A
  1. Increases insulin release from the pancreas:
    - Binds to receptor associated with ATP-sensitive K+ channel and inhibits K+ efflux
    - Results in depolarisation and Ca2+ channel opening
    - Ca2+ influx induces release of preformed insulin
    - Patients therefore more prone to hypoglycaemia with sulfonylureas than biguanides
  2. Reduces serum glucagon levels
  3. Closes K+ channel in extrapancreatic tissues
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39
Q

How do the major side effects of biguanides and sulfonylureas differ?

A

Biguanides can cause lactic acidosis*:
- Reduce gluconeogenesis and reduce lactic acid uptake in liver
- More likely in patients with renal disease, alcoholism, liver disease and chronic tissue hypoxia (i.e. chronic cardiopulmonary disease)

Sulfonylureas more commonly cause hypoglycaemia*:
- More likely in elderly and with drugs with long half-life (e.g. chlorpropamide)

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40
Q

What are the clinical advantages of the different oral antidiabetic agents?

A
  1. Biguanides: useful in refractory obesity and where there is insulin resistance
  2. Combination with sulfonylureas in type 2 diabetes
  3. Newer sulfonylureas are liver metabolised so can be used in renal failure
41
Q

What type of drug is gliclazide?

A

Sulfonylurea

42
Q

What are the pharmacokinetics of the sulfonylureas?

A

Administered orally with good oral bioavailability (gliclazide 80%)
Protein bound, Vd ~20L
Hepatically metabolised* to products which are inactive or have very low activity
Renally excreted* (gliclazide 80%)
Variable (but moderate) half-lives (e.g. gliclazide 8hrs, glimepiride 12-24hrs, glipizide 12-24hrs)

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43
Q

What are the potential adverse effects of gliclazide?

A

Hypoglycaemia*
GI upset (nausea, vomiting, abdominal pain, diarrhoea)
Rash/pruritis
Alcohol intolerance (disulfiram reaction, flushing)
Dilutional hyponatraemia (genetic predisposition)
Jaundice
Leucopaenia, thrombocytopaenia (chlorpropamide)

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ACEM Primary VIVA (26 decks)

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