Endocrine pharmacology Flashcards
Where do peptide hormones bind?
extracellular receptors
Where do steroid hormones bind?
intracellular receptors
where do thyroid hormones bind?
nuclear receptors
What is pharmacokinetics
what an individual does to a drug
What is pharmacodynamics?
what a drug does to an individual
What are the factors of pharmacokinetics?
- absorption
- distribution
- metabolism
- excretion
What are the factors of pharmacodynamics?
- receptor binding
- action on ion channels
- action on enzymes
- cytotoxic agents
What does prolactin do?
stimulate lactation
Where is prolactin secreted?
lactotrophs in anterior pituitary
how is prolactin regulated?
under tonic inhibition by dopamine
how can prolactin levels be changed?
anything that alters/inhibits dopamine levels
What is the result of hyperprolactinaemia?
hypogonadotrophic hypogonadism
What drugs can effect prolactin?
any drug interfering with dopamine action
- antipsychotics
- antiemetics
- antidepressants
- opiates
- H2 receptor antagonists
What is galactorrhoea?
- milky discharge from the nipples
What is a microprolactinoma?
<1cm
What is a macroprolactinoma?
> 1cm
How is prolactinoma treated?
- dopamine D2 agonists (1st line)
Name commone dopamine agonists?
- cabergoline
- quinagolide
- bromocriptine
What is vasopressin?
- Antidiuretic hormone (peptide)
- secreted from posterior pituitary
- regulating serum osmolarity
When is ADH released?
in response to low plasma volume/ increased serum osmolality
Where are V1 receptors and what are their actions?
- in vascular smooth muscle
- vasoconstriction
Where are V2 receptors found and what are their actions?
- distal tubule
- aquaporin channels to reabsorb water
Name a vasopressin therapy
- desmopressin
synthetic analogue, no vasoconstricting effects, longer half life
Briefly describe the physiology of the thyroid hormones
hypothalamus secreted thyrotropin releasing hormone, which acts on the pituitary to release thyroid stimulating hormone, which acts on the thyroid to release thyroxine (T4) and triiodothyronine (T3)
T4 predominant peripherally. Can convert to T3 (active)
How is maintenance therapy for cranial diabetes insipidus given?
Oral - bioavailability low, therefore high doses are required
o Sublingual
o Intranasal
How is acute therapy for diabetes insipidis given?
Subcutaneous
o Intramuscular
o Intravenous (variceal bleeding/shock)
Name a T4 drug
Levothyroxine
How should Levothyroxine be taken?
Daily dose, advised to be taken in the morning on an
empty stomach
Incomplete gastric absorption – can be affected by other medication
o Not advised to combine with PPI
How does levothyroxine work?
- travels bound to protein
- metabolised to T3
long half life
What are the treatment options of thyroid disorders?
- drugs
- radiation
- surgery
Name types of anti-thyroid drugs
Thionamides:
- carbimazole
- propylthiouracil
Describe the features of carbimazole
Drug of choice
o Absorbed well from gut and converted to methimazole via first pass metabolism
o Half-life of methimazole is 12-15 hours
Describe the features of propylthiouracil
PTU
Less active and shorter half-life so higher doses twice daily are required
o Usually second line
o Associated with some liver toxicity
o NB: Better safety data in pregnancy than carbimazole
What is a side effect of thionamides?
agranulocytosis (low white cell count)
Describe the mechanism of action of anti-thyroid drugs
Reduce thyroid hormone synthesis
o Inhibit iodide oxidation
o Inhibit iodination of tyrosine
o Inhibit coupling of iodotyrosines
Why should management of thyroid medication be monitored?
It can take a few weeks to reduce circulating hormones
o Repeat analysis of thyroid function is normally done a few months after commencing treatment
What are the additional features of PTU?
also reduces conversion of T4 to T3 peripherally giving some more acute effects
o More beneficial in e.g. a thyroid storm
o Limits the metabolic effects of the hormones
Name non-thionamide treatments for hyperthyroidism
Beta-blockers – overactive thyroid hormones effectively increase SNS over activity
Potassium iodide
o Reduces thyroid hormone release acutely, used in thyroid storm and pre-operatively
Radioactive iodine
o Takes a few months for the gland to become underactive
o 80-90% of patients will subsequently become hypothyroid
Describe glucose homeostasis
Insulin secreted from pancreatic beta cells in response to serum glucose allows glucose entry into
adipose tissue and muscle
- Gluconeogensis primarily in liver allows glucose into circulation, inhibited by insulin
- Counter-regulatory hormones include glucagon, cortisol, growth hormone stimulate
What are the causes of T2DM?
- insulin resistance
- impaired insulin secretion
Why does insulin resistance occur?
Usually develops due to combination of lifestyle and
genetic factors
o Insulin signalling impaired at cellular level
Why does impaired insulin secretion occur?
Initial hyperinsulinaemia no longer able to cope with resistance, beta cell failure
What are the 1st line treatments for T2DM?
- metformin
- sulphonylurea (if not tolerant to metformin or weight loss/osmotic symptoms)
In addition to lifestyle measures
What is the 2nd line treatment for T2DM?
Add one of:
- sulphonylurea
- thiazolidinediones
- DPP-IV inhibitor
to 1st line, in addition to lifestyle measures
What are the 3rd line treatments for T2DM?
Add or substitute with one of:
- thiazolidinediones
- DPP-IV inhibitor
- injectable insulin
- GLP-1 agonists
Which T2DM medications are insulin sensitisers?
- biguanides (metformin)
- thiazolidinediones
Which T2DM medications increase insulin?
- sulphonylureas
- GLP-1 agonists
- DPP-4 inhibitors
- insulin
What T2DM medications increase glucose in urine
- SGLT2 inhibitors
Describe the pharmacokinetics of metformin
Rapidly absorbed
o Half-life 2-5 hours initially taken OD, but can be increased to 2 or 3x
o Typical dose = 1g/day
o Excreted unchanged by kidneys
Describe the pharmacodynamics of metformin
Inhibits mitochondiral glycerophosphate dehydrogenase in liver, activates AMPK
Reduced hepatic gluconeogenesis and acts as an insulin sensitiser
What are the side effects of metformin?
GI side effects
Name a type of biguanide
metformin
Name sulphonylureas
- gliclazide
- glipizide
- glibenclamide
Describe the pharmacokinetics of suphonylureas
Well absorbed, peak plasma concentration within 2-4 hours
o Metabolised by liver, but important role of the kidneys
(contraindicated in patients with end-stage renal failure)
o Duration of action up to 24 hours
o Usually given 2x daily
Describe the pharmacodynamics of sulphonylureas
Bind to receptor on beta cells, inhibit KATP channels and permit increased insulin secretion
What are the side effects of sulphonylureas?
Increased circulating insulin, but there is a risk of hypoglycaemia (this can limit their use)
Name thiazolidinediones
- pioglitazone
- rosiglitazone
What is the use of thiazolidinediones?
used to treat insulin resistance associated with diabetes
What are the pharmacokinetics of Thiazolidinediones?
Rapidly absorbed
o Extensive hepatic metabolism
o Pioglitazone is excreted in bile
What are the pharmacodynamics of Thiazolidinediones?
PPARγ agonists
o increase transcription of insulin senstising genes
o PPARγ is a nuclear receptor expressed in adipose tissue, muscle, liver
What are the side effects of thiazolidinediones?
- increased adipogenesis => associated with weight gain
- increased long bone fractures
- fluid retention
- potentially bladder cancer
Describe the incretin system
Gut hormones GLP-1 and GIP enhance insulin secretion in response to oral glucose
Broken down by DPP-4
These drugs increase insulin secretion
Name GLP-1 agonists
- exenatide
- liraglutide
Describe features of GLP-1 agonists
Subcutaneous injection (peptide)
o Based on exendin-4 from Gila monster venom (kills prey by hypoglycaemia)
➢ Increased insulin secretion and weight loss (GI side effects are tolerable (nausea), and also
decrease food intake)
(Should not cause hypoglycaemia)
Name DPP-4 inhibitors
- sitagliptin
- linagliptin
Describe the uses of DPP-4 inhibitors
Linagliptin is commonly used in patients with low renal function (CKD 4/5)
o Oral administration, prevent endogenous GLP-1 breakdown
Name SGLT2 inhibitors
- canagliflozin
- dapagliflozin
- empagliflozin
Describe the pharmacokinetcs of SGLT2 inhibitors
- oral, once daily
- half life 10-13 hours
Describe the pharmacodynamics of SGLT2 inhibitors
Inhibit SGLT2 transporter which normally reabsorbs glucose in proximal convoluted tubule
o Increase glucose excretion
What are the side effects of SGLT2 inhibitors
Potential risk of volume depletion and UTI
➢ Lowers glucose without causing hypoglycaemia
What is the function of insulin in the liver?
- Decrease gluconeogenesis
- Increase glycogen synthesis
What is the function of insulin on skeletal muscle?
- Increased glucose transport via GLUT 4
- Increase glycogen synthesis
What is the function of insulin on adipose tissue?
- Increased glucose transport via GLUT 4
- Increase lipogenesis and decrease lipolysis
What are the different delivery methods of insulin?
Subcutaneous injection, most common with pre-filled pens/cartridges
Continuous subcutaneous insulin infusion (insulin pumps) - more common in children
Intravenous - during acute illness (e.g. DKA)
Intramuscular - rare
Describe regulation of glucocorticoid and mineralcoricoid release
Hypothalamus > cortocotrophin releasing hormone (CRH)
Pituitary >adrenocorticotrophic hormone (ACTH)
Adrenal > cortisol
> Aldosterone is also controlled by RAAS/[K+]
Describe the circulation of glucocorticoids
Steroid hormones are protein bound in circulation (cortisol
binding globulin) and bind intracellular receptors before entering
the nucleus
Describe the systemic effects of glucocorticoids
1) anti-inflammatory by inhibiting transcription of genes for
proinflammatory cytokines
2) Reduced T-lymphocytes
3) Counter-regulatory metabolic effects – gluconeogenesis,
increase adiposity
4) Improve alertness (circadian rhythm)
5) Mineralocorticoid effect
Which drug is physiologically closest in preparation to cortisol?
hydrocortisone
What is dexamethasone used for?
severe swelling
Describe routes of administration of glucocorticoids
o Topical o Nasal o Inhaled o Oral o Subcutaneous o Intramuscular o Intravenous
What is aldosterone?
a mineralcorticoid stimulated by angiotensin II, ACTH and potassium
What is the action of aldosterone
Main action on Na/K pump - stimulates sodium and water reabsorption and loss of potassium
Why can aldosterone not be given orally?
- metabolised in the liver
What is fludrocortisone?
oral mineralocorticoid used in Addison’s disease and postural hypotension
Name mineralcorticoid receptor antagnosts
- spironalactone
- eplerenone
What is the mechanism of action of spironalactone?
Competitive antagonist at MR, androgen and progesterone receptors
What are the side effects of spironalactone?
gynaecomastia, hyperkalaemia
What is Eplerenone?
Selective MR antagonist, no observed anti-androgen effects
What are the clinical uses of mineralcorticoid receptor antagonists?
Primary aldosteronism (Conn Syndrome)
heart failure
hypertension
What is the action of PTH?
maintains calcium levels and can govern bone density
What are bisphosphonates?
Used to treat osteoporosis, Paget’s disease, metastatic bone disease,
etc.
➢ Reduce bone resorption
Name common bisphosphonates
- adendronate
- pamidronate
- zolendronate
- risedronate
What are the pharmacokinetics of bisphosphonates?
Oral or intravenous administration, depending on preparation, free drug excreted by kidney
o Alendronate oral once weekly on an empty stomach with large glass of water, upright, 30
minutes before breakfast
(Specific instructions because the oral forms can be poorly tolerated)
- Zolendronate intravenous once yearly
What are the pharmacodynamics of bisphosphonates?
Carbon substituted pyrophosphate
o Bind to bone and inhibit osteoclast activity
List other osteoporosis treatments
- calcium & vit D
- denosumab
- teriparatide
- strontium ranelate
- HRT
- SERMs
What is denosumab
monoclonal antibody that inhibits RANK ligand which signals to osteoclasts, therefore
reduces resorption, subcutaneous injection every 6 months
What is teriparatide
recombinant parathyroid hormone, binds to osteoblasts to increase bone formation, requires subcutaneous injection as it is a peptide
What is strontium ranelate
stimulates osteoblasts and inhibits osteoclasts
What are SERMs?
bind to oestrogen receptor and decreases bone resorption
