endocrine and GIT pharmacology

Question 1

Thyroid Pharmacology
How does carbimazole act in thyroid disease?

Answer 1

Metabolised to methimazole
Major action is to block hormone synthesis (T3 and T4 )
Inhibits thyroid peroxidase enzyme which limits the organification of iodine.
Small action in blocking peripheral deiodination of T3 and T4
Slow onset as T4 may take weeks to be depleted

Question 2

What are the major side effects of carbimazole?

Answer 2

● Rash - maculopapular
● Pruritus
Bone marrow suppression: neutropaenia, agranulocytosis (reversible)
● Jaundice/hepatitis
● Nausea and GI effects
● Arthralgia
● Vasculitis

Question 3

How does carbimazole differ from propylthiouracil?

Answer 3

● Carbimazole is a prodrug - converted to methimazole in vivo. Methimazole is 10
times more potent than carbimazole.
● PTU has greater action in inhibiting peripheral deiodination of T4 and T3
● PTU has a shorter half life 1.5 vs 6 hours. So means PTU given QID and
Carbimazole once daily
● PTU bioavailability 50-80% vs carbimazole 100%
● PTU excreted in the urine as a glucuronide metabolite in <24 hours, carbimazole
takes over 48 hours

Question 4

Corticosteroids
Describe the mechanism of action of corticosteroids as a cellular level

Answer 4

● Most of known effects are via widely distributed glucocorticoid receptors
● The drug is present in the blood in bound form on corticosteroid binding globulin
● Enters the cell as a free molecule
● The intracellular receptor is bound to stabilising support proteins
● The complex binds a molecule of cortisol and then is actively transported into the
nucleus where it binds to glucocorticoid receptor elements on the gene
● Interacts with DNA and nuclear proteins that regulate transcription, resulting in
mRNA exported to cytoplasm for protein production for the final hormone
response

Question 5

What are the effects of corticosteroids?

Answer 5

This is a question about pharmacodynamics
● Cardiac - Permissive effect on catecholamines
● Metabolic - catabolic, anti-anabolic effects
● Anti-inflammatory effects - influences the effect, concentration and distribution of
peripheral leukocytes, suppresses inflammatory mediators, inhibits tissue
macrophages.
● CNS effects - insomnia

Question 6

What are the effects of chronic steroid use?

Answer 6

● Cushing’s syndrome
● Peptic ulcers
● Cataracts + glaucoma
● Psychosis and/or depression
● Hypertension
● Adrenal suppression with use for > 2 weeks

Question 7

Diabetes Drugs
Outline the groups of drugs used to treat diabetes

Answer 7

● Insulin
● Sulfonylureas
● Biguanides
● Meglitinides
● Alpha glucosidase inhibitors

Question 8

What are the pharmacokinetics of sulfonylureas?

Answer 8

A: Oral administration with 80% bioavailability
D: Protein bound with a volume of distribution of approx 20L
M: Hepatic metabolism to products which are inactive or have very low activity. Variable
but moderate half life of 8 - 24 hours
E: Renally excreted

Question 9

Contrast the mechanism of action of sulfonylureas and biguanides

Answer 9

Sulfonylureas i.e. glipizide
● Increase insulin release from the pancreas (specifically from pancreatic beta
cells)
● They bind to a cell surface receptor and cause depolarisation by inhibition of K+
efflux. This leads to release of preformed insulin
● Reduce serum glucagon levels
● Also facilitates closure of potassium channels in extrapancreatic tissues

Biguanides i.e. metformin
● Action does not depend on functioning pancreatic beta cells
● Mechanism is still unclear but evidence that it:
● May directly stimulate glycolysis in tissues with increase glucose removal from
blood
● May reduce hepatic gluconeogenesis
● May slow absorption of glucose from the GI tract
● May reduce glucagon levels

Question 10

Describe the pharmacokinetics of metformin

Answer 10

A: well absorbed
D: Not protein bound
M: Not metabolised
E: Elimination via kidney excretion as an unchanged compound with an elimination half
life of 1.5 to 3 hours

Question 11

What are some of the side effects of metformin?

Answer 11

GI upset most common and often limits compliance with the drug
High anion gap metabolic acidosis - especially in patients with co-existing renal disease,
EtOH excess or chronic cardiopulmonary disease

Question 12

Insulin
What is the action of insulin?

Answer 12

This is a question about pharmacodynamics
Promotes the uptake of glucose from blood into tissues - especially fat, liver cells and
skeletal muscle. Promotes glycogen synthesis

Question 13

What different formulations of insulin are there?

Answer 13

Rapid and short acting - clear solution, rapid onset, short duration e.g. insulin lispro
Intermediate - turbid solution, protamine buffer to prolong action e.g. protaphane insulin
Long acting - clear solution, slow onset, prolonged action. Daily administration mimics
basal insulin secretion. E.g. insulin glargine

Question 14

How are the different properties of these types of insulin used to optimise
glycaemic control?

Answer 14

Combination of insulins with different durations are used to form a basal bolus routine
where half is given as long acting and the other half is given in divided doses associated
with meals

Question 15

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

Answer 15

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

Question 16

Can you provide any other emergency department uses for insulin aside from
glucose control?

Answer 16

● Treatment of hyperkalaemia
● Management of toxic overdoses i.e. calcium channel blockers or beta blockers

Question 17

What are the possible adverse effects of insulin therapy?

Answer 17

● Hypoglycaemia
● Insulin allergy - usually due to non-insulin contaminants
● Immune insulin resistance
● Lipodystrophy at injection sites

Question 18

Glucagon
Describe the pharmacologic effects of glucagon

Answer 18

Metabolic
● Binds with receptors on liver cells (G protein linked)
● Promotes catabolism of stored glycogen, raining the blood glucose level
● Has no effect on skeletal muscle
● Causes release of insulin from beta cells

Cardiac Effects
● Potent inotropic and chronotropic effect on the heart via cAMP without requiring
functioning beta receptor

Other
● Large doses of glucagon produce relaxation of smooth muscle

Question 19

What are the indications for using glucagon clinically

Answer 19

● Severe hypoglycaemia
● Can be used as an adjunct in anaphylaxis in patients on beta blockers who fail to
respond to adrenaline
● Relaxation of intestine during some radiological procedures
● Diagnosis of endocrine disorders i.e. diabetes, some tumours including
pheochromocytoma
● Previously first line for treatment of beta blocker overdose - used to reverse
hypotension/bradycardia due to the ability to increase cAMP production in the
heart independent of beta-receptor function. Now not really done due to lack of
evidence and superiority of high dose euglycemic insulin therapy.
● Previously also used to treat food bolus but not done anymore due to side effects
and poor effectiveness

Question 20

What are the adverse reactions produced by glucagon?

Answer 20

● Relatively free from severe reactions
● Transient dose-dependent nausea and vomiting
● Hyperglycaemia
● Anaphylaxis always possible

Question 21

Octreotide
What is the mechanism of action of octreotide?

Answer 21

● Somatostatin analog
● Reduced splanchnic and portal blood flow by poorly understood mechanisms and
hence variceal pressures
● Inhibits endocrine and paracrine factor secretion including insulin, glucagon,
gastrin, GH and TSH

Question 22

What are the pharmacokinetics of octreotide?

Answer 22

A: IV, IM, subcut
D:
M: Mostly metabolised by the liver
E: plasma elimination half life is 80 mins, 20% excreted unchanged

Question 23

What are the adverse effects of octreotide

Answer 23

● Anaphylaxis
● Local irritation during injection
● GI symptoms - nausea, vomiting, decreased intestinal motility
● Hypo OR hyperglycaemia - unpredictable
● Cardiac - sinus brady, conduction disturbances

Question 24

What are some of the clinical uses of octreotide?

Answer 24

● Acute oesophageal variceal bleed - to divert blood from the splanchnic circulation
and decrease postal pressure
● Used in sulfonylurea overdose
● Reduce symptoms of hormone secreting tumours e.g. carcinoid syndrome

Question 25

What is the mechanism of action of Terlipressin?

Answer 25

Synthetic vasopressin analogue with relative specificity for splanchnic circulation where it
causes vasoconstriction of these vessels with a reduction in portal pressure

Question 26

What are the pharmacokinetics of terlipressin?

Answer 26

A: Given IV, concentration increases proportionally with the dose administered
D: VD of 6.3L
M: Converted to active metabolite lypressin via tissue peptidases. Not affected by
liver/kidney disease states. Half life of the active metabolite is 3 hours.
E: Less than 1% of terlipressin or lypressin is excreted unchanged

Question 27

What is terlipressin used for?

Answer 27

Mostly in acute management of variceal bleed to divert blood from splanchnic circulation
Also used non-emergently in hepatorenal syndrome

Question 28

What are the adverse effects of terlipressin

Answer 28

● Reduced cardiac output state due to vasoconstriction
● Heart failure or MI
● GI disturbance
● Hyponatraemia - longer term use

Question 29

Name some antiemetics used in the emergency department

Answer 29

● Ondansetron
● Metoclopramide
● Prochlorperazine
● Antihistamine
● Droperidol
● Som benzodiazepines

Question 30

Compare the mechanisms of action of ondansetron and metoclopramide

Answer 30

These drugs are both antiemetics but act on different receptors

Ondasetron: Peripheral 5HT3 blockade (reduces vagal and spinal afferents and sensory
visceral output) + central 5HT3 blockade (inhibits the vomiting centre in the
chemoreceptor trigger zone (CTZ)

Describe the potential adverse effects of metoclopramideDescribe the potential adverse effects of metoclopramide
Metoclopramide: D2 Blockade in the CTZ. ALso a prokinetic which increased
oesophageal motility and promotes gastric emptying.

Question 31

What are the doses and route of ondansetron?

Answer 31

4-8mg Sublingual, oral, subcut or IM

Question 32

Describe the potential adverse effects of metoclopramide

Answer 32

● CNS: restlessness, drowsiness, insomnia, anxiety, agitation. These are common,
occuring in 20% of people especially the elderly.
● Extrapyramidal effects: acute dystonia, akathisia, parkinsonian effects (more
likely with higher doses). Tardive dyskinesia can occur with chronic dosing
● Endo: Hyperprolactinaemia, leading to galactorrhoea, gynacomastia, impotence
and menstruation disorders.

Question 33

What are the potential adverse effects of ondansetron?

Answer 33

Headache, dizziness, constipation, diarrhoea
Uncommonly can cause a small prolongation of QT interval

Question 34

In which disease states would you need to modify the dosing of ondanestron?

Answer 34

Hepatic failure

Question 35

Proton pump inhibitors
Describe the MOA of PPIs

Answer 35

Irreversibly inactivates H/K/ATPase, blocking the proton pump, inhibiting >90% of acid
secretion, for up to 24hours which is the time it takes to synthesis new pumps

Question 36

Why is an IV infusion preferred to a single bolus dose for PPI

Answer 36

It only inactivates actively secreting acid pumps (<10% in fasting patients)
Single dose only suppresses acid secretion for a few hours

Question 37

Regarding oral formulations of proton pump inhibitors, please describe strategies
used to increase their bioavailability and activity.

Answer 37

● PPIs are taken as prodrugs
● They have an acid resistant enteric coating to prevent gastric elimination
● Food decreases the bioavailability so its advised that people take them on an
empty stomach
● They are weak bases so pass into the acidified parietal cells where they bind to
H/K ATPase
● Peak activity occurs in one hour, so best to have 1 hour before a meal