Top 100 Drugs: Oestrogens & progestogens, Hormone antagonists/agonists in breast/prostate cancers, 5-alpha-reductase inhibitors, Phosphodiesterase inhibitors, Levothyroxine

MOA of oestrogens and progestogens?

-LH and FSH control ovulation and ovarian production of oestrogen and progesterone

-in turn, oestrogen and progesterone exert predominantly negative feedback on LH and FSH

-in hormonal contraception, oestrogens and progestogens are given to suppress LH/FSH release, and hence ovulation

what are some effects that oestrogens and progestogens have outside the ovary?

-reduced menstrual pain and bleeding

-reduced acne

-helps w hot flushes in menopause to replace oestrogen

important adverse effects with oestrogens and progestogens?

-hormonal contraception may cause irregular bleeding and mood changes

-oestrogens in combined hormonal contraception double the risk of VTE

-increased risk of CVD and stroke

-increased risk of breast and cervical cancer

warnings with oestrogens and progestogens?

-contraindicated in breast cancer

-Combined hormonal contraception should be avoided in those with a personal/family history of VTE, thrombogenic mutation or risk factors of CVD

-women who have a uterus shouldn’t receive oestrogen only HRT due to the risk of endometrial benign prostatic enlargement

important interactions with oestrogens and progestogens?

-CYP P450 inducers may reduce contraceptive efficacy, particularly progestogen-only forms

-absorption of lamotrigine may be reduced, impairing seizure control

MOA of hormone agonists/antagonists for cancer?

-2/3 of breast cancers express oestrogen receptors which stimulate cell proliferation

-antagonising oestrogen therefore suppresses tumour growth in ER positive cancers

how does tamoxifen work?

-it is a selective oestrogen receptor modulator which acts to prevent oestrogen binding to its receptor

how do anastrozole and letrozole work?

-they are aromatase inhibitors

-they interfere with synthesis of oestrogens outside the ovary by inhibiting the conversion of androgens to oestrogens by aromatase

-they are ineffective in women with functioning ovaries because they have relatively little effect on ovarian oestrogen synthesis

explain how prostrate cancers respond to hormone therapies?

-they respond to hormone therapies that suppress androgens

-GnRH analogues initially over stimulate production of luteinising hormone in the anterior pituitary, but GnRH receptors are then rapidly downregulated causing LH and consequently androgens to decrease medication castration levels

-androgen receptor inhibitors like bicalutamdide directly block androgen receptors to prevent testosterone driven cancer cell growth

important adverse effects with hormone agonists/antagonists for cancer?

-oestrogen depletion eg vaginal dryness, hot flushes, loss of bone density

-tamoxifen increases the risk of venous thromboembolism and endometrial cancer

-rarely, tamoxifen and aromatase inhibitors can cause agranulocytosis and liver failure

-antiandrogen therapy may lead to hair loss, gynaecomastia and mood disturbance

-bicalumatide may cause photosensitivity

warnings with hormone agonists/antagonists for cancer?

-tamoxifen contraindicated in pregnancy and breastfeeding

-aromatase inhibitors shouldn’t be used in pre-menopausal women unless ovarial function is suppressed or ablated

-initial overstimulation of LH production by goserelin and leuprorelin may stimulate tumour growth

important interactions with hormone agonists/antagonists for cancer?

-tamoxifen inhibits a CYP450 enzyme responsible for metabolising warfarin, increasing the risk of bleeding

-the SSRIs fluoxetine and paroxetine inhibit hepatic activation of tamoxifen

MOA of 5-alpha reductase inhibitors ?

-they reduce the size of the prostate gland

-they do this by inhibiting the intracellular enzyme 5-a reductase

-this converts testosterone into dihydrotestosterone which stimulates prostatic growth

-inhibition will reduce prostatic growth and thus improve urinary flow

how long does 5-alpha reductase inhibitors take to work?

several months - which is why an alpha blocker is offered for moderate to severe symptoms as it has a more rapid effect

important adverse effects with 5-alpha reductase inhibitors?

-impotence

-reduced libido

-breast tenderness and enlargement

-hair growth

-breast cancer and suicidal thoughts in men (taking finasteride)

warnings with 5-alpha reductase inhibitors?

-exposure of a male foetus to 5-alpha reductase inhibitors may cause abnormal development of the external genitalia - therefore women of childbearing potential do not take these drugs are aren’t exposed to it

important interactions with 5-alpha reductase inhibitors?

-finasteride has no clinically important drug interactions

-dutasteride is metabolised by CYP450 enzymes but the interactions predicted from this are not severe

MOA of phosphodiesterase inhibitors?

-a key indicator in the initiation and maintenance of an erection is nitric oxide

-NO is synthesised in the penis in response to parasympathetic stimulation induced by physical stimulation and psychological arousal

-NO activates soluble guanylyl cyclase which produces the second messenger cGMP

-this activates protein kinase G which causes vasodilation in penile arteries

-the resulting penile egorgement produces an erection

-phosphodiesterase type 5 degrades cGMP to GMP terminating its effect.

-PDE-5 inhibitors therefore increase cGMP concentration in the penis, improving the likelihood of achieving an erection and prolonging its duration

-PDE-5 is also expressed in pulmonary vasculature where is causes pulmonary arterial vasodilation by a similar mechanism

-important adverse effects with phosphodiesterase inhibitors?

most adverse effects of PDE-5 are predictable from their vasodilator action.

-headach, flushing, dizziness, nasal congestion

-hypotension, and arrythmias

-visual symptoms including colour distortion

warnings with phosphodiesterase inhibitors?

-shouldn’t be taken by ppl in whom vasodilation could be dangerous including those with recent stroke or recent ACS, or significant CVD

-AVOID or used at a lower dose in people with severe hepatic or renal impairment

important interactions with phosphodiesterase inhibitors?

-do not prescribe for ppl taking any drug that increases NO concentration especially nitrates

-caution required in people taking other vasodilators including a-blockers and calcium channel blockers

-plasma concentrations and adverse effects of PDE-5 inhibitors are increased by CYP450 inhibitors eg amiodarone, diltiazem and fluconazole

MOA of levothyroxine?

-thyroid gland produces T4 which is converted to the more active T3 in target tissues

-thyroid hormones regulate metabolism and growth

-deficiency of these hormones causes hypothyroidism - symptoms including lethargy, weight gain, constipation and slowing of mental processes

-treated with replacement of these deficient hormones eg Levothyroxine (t4)

describe the pharmokinetics of Liothyronine?

-synthetic T3

-shorter half life

-quicker onset (few hours) and offset (24-48hr) than levothyroxine

-therefore reserved for emergency treatment of severe or acute hypothyroidism

important adverse effects with levothyroxine ?

-adverse effects usually due to excessive doses - so are similar to symptoms of hyperthyroidism

-GI Upset, cardiac and neurological manifestations

-weight loss

warnings with levothyroxine?

-thyroid hormones increase HR and metabolism: therefore can precipitate cardiac ischaemia in people with coronary artery disease - cautiously start treatment at a low dose with monitoring

-in hypopituitarism, corticosteroid therapy must be initiated before thyroid hormone replacement to avoid precipitating acute adrenal insufficiency

important interactions with levothyroxine?

-as GI absorption is reduced by antacids, calcium and iron salts, administration of these drugs need to be separated from levothyroxine by 4 hours

-an increase in levothyroxine dose may be required in ppl taking CYP450 inducers eg phenytoin, carbamazepine

-levothyroxine-induced changes in metabolism can increase requirements for glucose lowering treatments in diabetes and may enhance the effects of warfarin