endocrine and GIT pharmacology Flashcards
Thyroid Pharmacology
How does carbimazole act in thyroid disease?
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
What are the major side effects of carbimazole?
● Rash - maculopapular
● Pruritus
Bone marrow suppression: neutropaenia, agranulocytosis (reversible)
● Jaundice/hepatitis
● Nausea and GI effects
● Arthralgia
● Vasculitis
How does carbimazole differ from propylthiouracil?
● 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
Corticosteroids
Describe the mechanism of action of corticosteroids as a cellular level
● 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
What are the effects of corticosteroids?
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
What are the effects of chronic steroid use?
● Cushing’s syndrome
● Peptic ulcers
● Cataracts + glaucoma
● Psychosis and/or depression
● Hypertension
● Adrenal suppression with use for > 2 weeks
Diabetes Drugs
Outline the groups of drugs used to treat diabetes
● Insulin
● Sulfonylureas
● Biguanides
● Meglitinides
● Alpha glucosidase inhibitors
What are the pharmacokinetics of sulfonylureas?
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
Contrast the mechanism of action of sulfonylureas and biguanides
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
Describe the pharmacokinetics of metformin
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
What are some of the side effects of metformin?
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
Insulin
What is the action of insulin?
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
What different formulations of insulin are there?
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
How are the different properties of these types of insulin used to optimise
glycaemic control?
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
What type of insulin is used for intravenous infusion and why?
Short acting regular soluble insulin as it immediately dissociates on dilution and is able to
be more precisely delivered
Can you provide any other emergency department uses for insulin aside from
glucose control?
● Treatment of hyperkalaemia
● Management of toxic overdoses i.e. calcium channel blockers or beta blockers
What are the possible adverse effects of insulin therapy?
● Hypoglycaemia
● Insulin allergy - usually due to non-insulin contaminants
● Immune insulin resistance
● Lipodystrophy at injection sites
Glucagon
Describe the pharmacologic effects of glucagon
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
What are the indications for using glucagon clinically
● 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
What are the adverse reactions produced by glucagon?
● Relatively free from severe reactions
● Transient dose-dependent nausea and vomiting
● Hyperglycaemia
● Anaphylaxis always possible
Octreotide
What is the mechanism of action of octreotide?
● 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
What are the pharmacokinetics of octreotide?
A: IV, IM, subcut
D:
M: Mostly metabolised by the liver
E: plasma elimination half life is 80 mins, 20% excreted unchanged
What are the adverse effects of octreotide
● Anaphylaxis
● Local irritation during injection
● GI symptoms - nausea, vomiting, decreased intestinal motility
● Hypo OR hyperglycaemia - unpredictable
● Cardiac - sinus brady, conduction disturbances
What are some of the clinical uses of octreotide?
● 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
