Pharmacodynamics of Drugs Acting on Endocrine System
Session 8: Pharmacodynamics of Drugs Acting on Endocrine System
Total Session Time: 120 minutes
Prerequisites
None
Learning Tasks
By the end of this session students are expected to be able to:
Describe mechanism of action of Drugs Acting on Endocrine System
Describe drug interactions associated with Drugs Acting on Endocrine System
Describe side effects of Drugs Acting on Endocrine System
Describe contraindications of Drugs Acting on Endocrine System
Resources Needed:
Flip charts, marker pens, and masking tape
Black/white board and chalk/whiteboard markers
Computer and LCD Projector
Handout 8.1: Pharmacodynamics of drugs for thyroid disorders and reproductive function
SESSION OVERVIEW
Step
Time
Activity/
Content
Step
Time
Activity/
Content
Step
Time
Method
Content
Method
Method
1
1
05 minutes
05 minutes
Presentation
Introduction, Learning Tasks
Introduction, Learning Tasks
2
2
45 minutes
45 minutes
Presentation/
Mechanism of Action of Drugs Acting on
Mechanism of Action of Drugs Acting on
2
2
45 minutes
45 minutes
Buzzing
Endocrine System
Endocrine System
Buzzing
Endocrine System
Endocrine System
3
3
20 minutes
20 minutes
Presentation/
Drug Interactions Associated With Drugs
Drug Interactions Associated With Drugs
3
3
20 minutes
20 minutes
brainstorming
Acting on Endocrine System
Acting on Endocrine System
brainstorming
Acting on Endocrine System
Acting on Endocrine System
4
4
20 minutes
20 minutes
Presentation
Side Effects of Drugs Acting on Endocrine
Side Effects of Drugs Acting on Endocrine
4
4
20 minutes
20 minutes
Presentation
System
System
System
System
5
5
20 minutes
20 minutes
Presentation/
Contraindications of Drugs Acting on
Contraindications of Drugs Acting on
5
5
20 minutes
20 minutes
Brainstorming
Endocrine System
Endocrine System
Brainstorming
Endocrine System
Endocrine System
6
6
05 minutes
05 minutes
Presentation
Key Points
Key Points
7
7
05 minutes
05 minutes
Presentation
Evaluation
Evaluation
PST 05104 Pharmacology & Therapeutics 57 NTA Level 5 Semester 1 Facilitator Guide
SESSION CONTENTS
STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)
READ or ASK students to read the learning tasks and clarify
ASK students if they have any questions before continuing.
STEP 2: Mechanism of Action of Drugs Acting on Endocrine System (45 minutes)
Activity: Buzzing (5 minutes)
ASK students to pair up and buzz on the following question for 2 minutes
What asre the mechanisms of action of Drugs Acting on Endocrine system?
ALLOW few pairs to respond and let other pairs add on points not mentioned
WRITE their response on the flip chart/board
CLARIFY and SUMMARIZE by using the content below
Drugs for Diabetes Mellitus
Insulins
Insulin acts by binding to transmembrane glycoprotein receptors. Receptor occupancy results in:
Activation of insulin-dependent glucose transport processes (in adipose tissue and muscle) via a transporter known as ‗Glut-4‘;
Inhibition of adenylyl cyclase-dependent metabolism (lipolysis, proteolysis, glycogenolysis);
Intracellular accumulation of potassium and phosphate, which is linked to glucose transport in some tissues.
Secondary effects include increased cellular amino acid uptake, increased DNA and RNA synthesis and increased oxidative phosphorylation.
Biguanides (Metformin)
Mechanism remains uncertain.
Effects of metformin include:
Reduced glucose absorption from the gut
Facilitation of glucose entry into muscle by a non-insulin responsive mechanism
Inhibition of gluconeogenesis in the liver
Suppression of oxidative glucose metabolism and enhanced anaerobic glycolysis.
PST 05104 Pharmacology & Therapeutics 58 NTA Level 5 Semester 1 Facilitator Guide
Sulphonylureas (tolbutamide, glibenclamide, gliclazide) and Related Drugs
The hypoglycaemic effect of these drugs depends on the presence of functioning B
cells.
Sulphonylureas, like glucose, depolarize B cells and release insulin.
They do this by binding to sulphonylurea receptors (SUR) and blocking ATP-dependent potassium channels (KATP); the resulting depolarization activates voltage-sensitive Ca2+ channels, in turn causing entry of Ca2+ ions and insulin secretion.
Thiazolidinediones (rosiglitazone and pioglitazone)
Glitazones bind to the peroxisome-proliferating activator receptor γ (PPARγ), a
nuclear receptor found mainly in adipocytes and also in hepatocytes and myocytes.
It works slowly, increasing the sensitivity to insulin possibly via effects of circulating fatty acids on glucose metabolism.
Acarbose
Acarbose is a reversible competitive inhibitor of intestinal α-glucoside hydrolases and delays the absorption of starch and sucrose, but does not affect the absorption of
ingested glucose.
The postprandial glycaemic rise after a meal containing complex carbohydrates is reduced and its peak is delayed.
Mechanism of action of drugs for treatment of thyroid disorders and reproductive function
REFER Students to Handout 8.1: Pharmacodynamics of drugs for thyroid disorders and reproductive function
STEP 3: Drug Interactions Associated with Drugs Acting on Endocrine System (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are drug interactions associated with drugs acting on endocrine system occur?
ALLOW few students to respond
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
Biguanides (Metformin etc)
o Other oral hypoglycaemic drugs are additive with metformin. o Ethanol predisposes to metformin-related lactic acidosis.
PST 05104 Pharmacology & Therapeutics 59 NTA Level 5 Semester 1 Facilitator Guide
Sulphonylureas (tolbutamide, glibenclamide, gliclazide) and Related Drugs
o Monoamine oxidase inhibitors potentiate the activity of sulphonylureas by an unknown mechanism.
o Several drugs (e.g. glucocorticosteroids, growth hormone) antagonize the hypoglycaemic effects of sulphonylureas by virtue of their actions on insulin release or sensitivity.
Thiazolidinediones (rosiglitazone and pioglitazone)
o Glitazones are additive with other oral hypoglycaemic drugs.
o They potentiate insulin, but this combination is contraindicated in some countries because of concerns that it might increase the risk of heart failure.
STEP 4: Side Effects of Drugs Acting on Endocrine System (20 minutes)
The following are the dise effects of drugs for treatment of Diabetes Mellitus;
Insulin: Hypoglycemia, Headache, Allergic reactions, Flu like symptoms, Weight gain, Hypokalemia, Lipoatrophy, Itching, Rash , Injection site reaction
Chlorpropamide: Has appreciably more side effects, mainly because of its very prolonged duration of action and the consequent hazard of hypoglycaemia and it should no longer be used. It may also cause facial flushing after drinking alcohol; this effect does not normally occur with other drugs
Glibenclamide: Common side effects include stomach upset and low blood sugar (hypoglycaemia), weight gain, constipation
Gliclazide: Hypoglycemia (low blood sugar) hyperglycemia (high blood sugar) oat, cough back, muscle and joint pain headache high blood pressure angina (chest pain) leg swelling diarrhea, constipation, abdominal pain, nausea dizziness skin rash/itching depression
Tolbutamide: Hypoglycemia, weight gain, hypersensitivity: cross allergicity with sulfonamides
Metformin: Anorexia, nausea, vomiting, diarrhea (usually transient), abdominal pain, taste disturbance, lactic acidosis, decreased vitamin B12 absorption, erythema, pruritus and urticaria. Hepatitis also reported
PST 05104 Pharmacology & Therapeutics 60 NTA Level 5 Semester 1 Facilitator Guide
STEP 5: Contraindications of Drugs Acting on Endocrine System (20 minutes)
Activity: Brainstorming (5 minutes)
Ask students to brainstorm on the following question:
What are the contraindications of drugs acting on endocrine system? ALLOW few students to respond?
WRITE their responses on the flip chart/ board
CLARIFY and SUMMARISE by using the content below
The following are the contraindications for drugs for Diabetes Mellitus
o Insulin: Is contraindicated in persons who have Hypersensitivity to any ingredient of the product and during episodes of hypoglycemia
o Glibenclalmide: Is contraindicated in diabetic emergencies (ketoacidosis, hyperosmolar coma), advanced hepatic or renal insufficiencies, pregnancy and nursing period
o Gliclazide: Is contraindicated in following conditions, pregnancy, lactation, hypersensitivity
o Tolbutamide: Is contraindicated in patients with known hypersensitivity or allergy to the drug
o Metformin Is contraindicated in patients with any condition that could increase the risk of lactic acidosis, including kidney disorders , lung disease and liver disease
o For other contraindications please see NTA level 4
STEP 6: Key Points (5 minutes)
Drugs affecting hormonal actions have different mechanisms
Drugs affecting hormonal actions have many adverse effects
Drugs affecting hormonal actions exhibit many interactions with other drugs
STEP 7: Evaluation (5 minutes)
What is the mechanism of action of insulin?
What are adverse effects of Sulphonylureas?
Why is not advised to combine MAOIs and sulphonyl urea?
PST 05104 Pharmacology & Therapeutics 61 NTA Level 5 Semester 1 Facilitator Guide
References
Katzung, B. G. (2018). Basic and clinical pharmacology. New York: Mcgraw Hill Education.
Santos, R. R., Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang & Dale Farmacologia. Rio de Janeiro: Elsevier.
Tripathi, K. (2018). Essentials of Medical Pharmacology. Place of publication not identified:
Jaypee Brothers Medical P.
Ministry of Health and Social Welfare. (2013). Standard Treatment Guidelines & National Essential Medicines List Tanzania Mainland (4th ed.). Dar es salaam, Tanzania government printers.
Sally S.R, Jeanne C.S. (2000). Introductory Clinical Pharmacology (6th ed) New York, Lippincott Williams and Wilkins.
School of Pharmaceutical sciences. (2011).Tanzania Pharmaceutical Handbook (2nd ed.).
Dar es Salaam, ARDHI University press.
The Royal Pharmaceutical Society of Great Britain. (2007). Martindale, the Extra Pharmacopoeia (5TH ed). London, pharmaceutical press.
The Royal Pharmaceutical Society of Great Britain. 2009. British National Formulary (59th ed). London, BMJ Group and RPS Publishing.
PST 05104 Pharmacology & Therapeutics 62 NTA Level 5 Semester 1 Facilitator Guide
Handout 8.1 Pharmacodynamics of drugs used for treatment of thyroids disorders and reproductive function
Mechanism of actions of Drugs for Thyroid Disorders Hypothyroidism
Thyroxine and Tri-Iodothyronine o Thyroxine is a prohormone.
o After entering cells it is converted to T3, which binds to the thyroid hormone nuclear receptor and the ligand–receptor complex increases transcription of genes involved in the following cellular functions: stimulation of metabolism – raised basal metabolic rate, promotion of normal growth and maturation ( particularly of the central nervous system and skeleton) and sensitization to the effects of catecholamines.
Hyperthyrodism
Antithyroid drugs
Carbimazole
o The action of carbimazole is via its active metabolite methimazole, which is a substrate-inhibitor of peroxidase and is itself iodinated and degraded within the thyroid, diverting oxidized iodine away from thyroglobulin and decreasing thyroid hormone biosynthesis.
Propylthiouracil
o Propylthiouracil has similar actions, uses and toxic effects to carbimazole, but in addition inhibits the peripheral conversion of T4 to active T3.
o It is used (by specialists) in pregnancy (see below) and has some advantages over carbimazole in this setting.
β-Adrenoceptor Antagonists
o Beta-blockers improve symptoms of hyperthyroidism, including anxiety, tachycardia and tremor.
o They inhibit the conversion of T4 to T3 in the tissues.
PST 05104 Pharmacology & Therapeutics 63 NTA Level 5 Semester 1 Facilitator Guide
Radioactive Iodine
o Radioactive iodine (I131) is safe in non-pregnant adults and has largely replaced surgery in the treatment of hyperthyroidism, except when there are local mechanical complications, such as tracheal obstruction.
Mechanism of action for Drugs Affecting Reproductive Function
Estrogens
Natural: estrone sulfate,17β-estradiol , estriol , sysnthetic : ethinyl estradiol, mestranol
Estrogens are transcription factors; they modify messenger RNA (mRNA) synthesis
directly.
Estrogens enter the cell passively (no receptor required) and bind to estrogen receptors in the nucleus, which then dimerize and bind DNA directly to regions called estrogen-responsive elements (EREs) and influence gene transcription.
Contraceptives
Combined Oral Contraceptives (COC)
The main contraceptive action of the combined oral contraceptive (COC) is to suppress ovulation by interfering with gonadotrophin release by the pituitary via negative feedback on the hypothalamus. This prevents the mid-cycle rise in LH which triggers ovulation.
Progestins
o Progesterone, megestrol acetate, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norgestrel, levonorgestrel, desogestrel, norgestimate, gestodene, dienogest
o Progestins are transcription factors; they modify mRNA synthesis directly.
o Progestins enter the cell passively (no receptor required) and bind to progesterone receptors in the nucleus, which then dimerize and bind DNA directly and influence gene transcription.
Anti-progestogens
Mifepristone
o Mifepristone is a competitive antagonist of progesterone.
o It is used as a medical alternative to surgical termination of early pregnancy (currently up to 63 days‘ gestation, although it is also effective during the second trimester).
o A single oral dose of mifepristone is followed by gemeprost (a prostaglandin that ripens and softens the cervix), as a vaginal pessary unless abortion is already complete.
Reproductive hormones antagonists
Oestrogen receptor antagonists
o Oestrogen receptor antagonists include tamoxifen which is licensed for breast cancer and an ovulatory infertility, fulvestrant which is licensed for the treatment of oestrogen receptor-positive metastatic or locally advanced breast cancer in post-
PST 05104 Pharmacology & Therapeutics 64 NTA Level 5 Semester 1 Facilitator Guide
menopausal women, and toremifene which is licensed for hormone-dependent metastatic breast cancer in post-menopausal women.
Estrogens also mediate cell proliferation, in both normal and malignant cells.
There are two estrogen receptors (ERα and ERβ), both of which either increase or decrease transcription of target genes.
Binding of agonist to the estrogen receptor recruits co-activators which help to stimulate transcription. The net effect of this is to initiate transcription.
Aromatase inhibitors
Aromatization is the process of converting a nonaromatic ring into an aromatic ring
and is catalyzed by aromatase, a P450 enzyme.
Aromatization converts androgens into estrogens.
The aromatase inhibitors block the conversion of androgens oestrogens in the peripheral tissues.
They do not inhibit ovarian oestrogen synthesis and are not suitable for use in premenopausal women who will continue to secrete ovarian oestrogens.
Currently licensed agents include anastrozole, letrozole and exemestane.
The gonadorelin analogues
Goserelin is licensed for the management of advanced breast cancer in premenopausal women.
It acts by initially stimulating and then depressing luteinizing hormone released by the pituitary, which in turn reduces oestrogen production.
The inducers of gonadotrophin release
Induce gonadotrophin release by occupying oestrogen receptors in the hypothalamus, thereby interfering with feedback mechanisms.
Drug interactions
Contraceptives
Combined Oral Contraceptives (COC)
Oestrogens increase clotting factors and reduce the efficacy of oral anticoagulants. o Thus a need for frequent monitoring of the international normalized ratio (INR).
Antihypertensive therapy may be adversely affected by oral contraceptives, at least partly because of increased circulating renin substrate.
Enzyme inducers (e.g. rifampicin, carbamazepine, phenytoin, nelfinavir, nevirapine, ritonavir, St John‘s wort) decrease the plasma levels of contraceptive oestrogen, thus decreasing the effectiveness of the combined contraceptive pill.
PST 05104 Pharmacology & Therapeutics 65 NTA Level 5 Semester 1 Facilitator Guide
Side effects
Estrogens
Natural: estrone sulfate ,17β-estradiol , estriol , sysnthetic : ethinyl estradiol, mestranol
o Endometrial: Some of the partial agonists have estrogen agonist effects on the endometrium, leading to abnormal cell growth.
o This can manifest as increased endometrial thickness, endometrial polyps, leiomyomas, and even endometrial cancer.
o Thromboembolism: Increased risk of thromboembolic events, including pulmonary embolism, have been observed in large studies.
o Stroke: Stroke has been observed in large studies.
o Hot flashes: Hot flashes mimic the physiology of menopause. o Nausea, vomiting
o Menstrual irregularities: Oligomenorrhea (infrequent periods) and amenorrhea (absent periods) may occur.
o Cataracts
Reproductive hormones antagonists
Aromatase inhibitors
Reduced bone density and increased fractures
Bone protection measures should be taken. These include bisphosphonates, vitamin
Hot flushes from estrogen deficiency (which mimics perimenopausal symptoms)
Nonspecific: nausea, fatigue, increased sweating, peripheral edema, and increased appetite
Progestins
Progesterone, megestrol acetate, medroxyprogesterone acetate, norethindrone,
Androgenic activity: Because of the similarity of progestins to androgens and the conversion of progestins to androgens, androgenic side effects are not uncommon. Levonorgestrel is the most androgenic.
Third-generation progestins are less androgenic than second-generation progestins. o Acne and hirsutism are the most common signs.
o Increased LDL and insulin resistance are also seen.
o DVT: Third-generation progestins may be associated with a higher incidence of DVT than second-generation progestins.
o Vaginal bleeding: The mechanism is not completely understood
Contraindications
Estrogens
Natural: estrone sulfate, 17β-estradiol , estriol , sysnthetic : ethinyl estradiol, mestranol
o Hypercoagulable states: Estrogen is a procoagulant, and estrogen administration is a risk factor for pathologic thromboses (deep vein thrombosis [DVT] and pulmonary embolus [PE]).
PST 05104 Pharmacology & Therapeutics 66 NTA Level 5 Semester 1 Facilitator Guide
Cancers that could demonstrate increased growth in response to estrogen: breast, ovarian, uterine, and endometrial.
Strong risk factors for atherosclerosis: hypertension (HTN), diabetes, high cholesterol,
family history.
Pregnancy: Estrogen plays an important role in maintenance of pregnancy.
Progestins
Progesterone, megestrol acetate, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norgestrel, levonorgestrel, desogestrel, norgestimate, gestodene,
Risks for DVT or PE
Severe migraine headache: There are relationships among estrogen, progesterone, and serotonin levels. Serotonin is implicated in migraine pathophysiology; administration of estrogen or progesterone can potentially exacerbate (or alleviate) migraines.
Unexplained vaginal bleeding: Prolonged progesterone administration can cause vaginal bleeding; it is important to diagnose any pathologic causes of bleeding before
starting treatment that could confound other bleeding.
Breast cancer: Female sex hormones can stimulate breast tissue growth.
Active liver disease
Conditions of concern for hypoestrogenic effects and reduced HDL levels, theoretically increasing cardiovascular risk:
Current and history of ischemic heart disease
History of stroke
Diabetes for over 20 years or with nephropathy, retinopathy, neuropathy, or vascular disease
Progestogen-Only Contraceptives
Include pregnancy, undiagnosed vaginal bleeding, severe arterial disease, liver adenoma and porphyria.
Aromatase inhibitors
Pregnancy (which is a physiologic state requiring increased estrogen).
The inducers of gonadotrophin release
Clomiphene is contraindicated in those with liver disease, ovarian cysts, hormone-dependent tumours and abnormal uterine bleeding of undetermined cause.
PST 05104 Pharmacology & Therapeutics 67 NTA Level 5 Semester 1 Facilitator Guide
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