thyroid pharmacology, androgens and antiandrogens, diabetes mellitus, corticosteroids Flashcards
what is hypothyroidism? hyperthyroidism?
- Hypothyroidism - Low T4 & High TSH
* Hyperthyroidism - High T4 & Low TSH.
hypothyroidism treatment?
o The treatment for all forms of hypothyroidism is replacement therapy with either T3 or T4.
o Synthetic Levothyroxine sodium salt (T4) is the form of choice for most cases.
o Note the administered T4 is converted to T3 in vivo.
o Liothyronine sodium (L-T3): It is faster-acting, has higher oral bioavailability, but has a shorter half-life and is more expensive.
o T3 is the active form but it is degraded rapidly.
hyperthyroidism treatment?
o 1. Antithyroid agents: Inhibit the Synthesis of T3 & T4.
o 2. Iodide Salt: inhibits iodination of tyrosine & thyroid hormone release. Effective for a maximum of 2 weeks.
o 3. Iodinated Radiocontrast media: Suppresses the peripheral conversion of T4 to T3.
o 4. Radioactive iodine (RAI) therapy: 131I (radioiodine) ablation of thyroid tissue (The most popular method).
o 5. Surgery: Thyroidectomy - Surgical removal of the thyroid is occasionally used as a treatment.
o 6. Beta-blocker: As an adjunct to inhibit the hyper- sympathetic function of hyperthyroidism.
antithyroid agents - thiourea drugs?
thyroid pharmacology -
• Propylthiouracil (PTU) & Methimazole
o Note: PTU (but not methimazole) also inhibits the conversion of T4 to T3 in peripheral tissues. XX
• Propylthiouracil (PTU) & Methimazole
• Indications:
• In GRAVE’s Disease (Hyperthyroidism], Thiourea drugs are used to induce remission or control symptoms prior to surgery or administration of radioactive iodine treatment.
• Since synthesis of thyroid hormone rather than its release is inhibited, the onset of activity of these drugs is usually slow, often requiring 2 weeks for the full effect to manifest. So, if you give KI, it will block the release of T3 and T4.
• Potassium Iodide (KI) duration of effect is short lived [2 weeks]. By that time PTU or Methimazole treatment would have reduced T3/T4 production.
• Adverse effect:
o Skin rash (common) urticarial papular rash
o Severe immunological reactions such as leukopenia, agranulocytosis, or vasculitis.
o these effects are usually reversible upon withdrawal of the drugs.
o PTU & Methimazole must be used cautiously during pregnancy and in nursing women.
o since both agents can cross the placenta and enter breast milk. (methimazole > PTU).
o Q: What might happen if we treated a pregnant woman aggressively with a thiourea - PTU?
o (risk of developing cretinism in the developing fetus).
iodide salt treatment for hyperthyroidism
• Iodide Salt:
o It inhibits iodination of tyrosine & thyroid hormone release (acts for a short term 10 days to 2 weeks days) decreases vascularity, helpful in reducing the size.
o Usual forms - Lugol’s solution
o (iodine and potassium iodide).
o Mechanisms:
o - inhibit iodination of tyrosine & thyroid hormone release.
o - decrease the size and vascularity of the hyperplastic thyroid gland.
o -onset of action occurs rapidly within 2-7 days. Shorter duration
o Potassium iodide solution: Short term – Lugol’s Iodine
o the effects are transient - because the thyroid gland “escapes” from the iodide block after several weeks of treatment.
o Indication:
o - used on a short-term basis to treat patients with “thyroid storm”.
o - prepare patients for thyroid surgery.
o - Inhibit the release of thyroid hormones following
o radioactive Iodine (RAI) therapy.
o Adverse effect:
o - skin rashes & other hypersensitivity reactions
Iodinated Radio-contrast media
o Certain iodinated radiocontrast media (e.g. Ipodate effectively suppress the conversion of T4 to T3 via 5’-deiodinase in the liver, kidney, and other peripheral tissues.
o Inhibition of hormone release from the thyroid may also play a part.
o Ipodate has proved to be very useful in rapidly reducing T3 concentrations in thyrotoxicosis.
radioactive iodine RAI (131I)
o 131I is used for thyroid ablation, its half life is 8 days.
o 123I is used for thyroid function test short half life-13 hr.
o Radioactive Iodine is taken up and concentrated in the thyroid gland – emits g and b radiation destroying thyroid tissue without endangering other tissues.
o Unlike thiourea drugs and iodide salts, an effective dose of [131I] can produce a permanent cure of thyrotoxicosis without surgery.
o After RAI treatment, iodide salts are used to inhibit thyroid hormone release.
o [131I] should NOT be used in pregnant or nursing women as it may affect the fetus/newborn.
beta blockers thyroid stuff
o β -adrenergic receptor antagonists such as Propranolol are particularly useful in controlling tachycardia and other cardiac abnormalities of severe acute Thyrotoxicosis (thyroid storm).
o Thyroid hormone and the sympathetic nervous system act synergistically on cardiovascular function, so increased levels of thyroid hormone causes tachycardia & arrhythmia. Therefore, non-selective b- blockers such as propranolol are always given in thyroid storm and severe hyperthyroidism to control enhanced sympathetic drive and tachycardia.
synthetic androgens, preparations of testosterone
androgens and antiands -
17α methyl testosterone (oral or sublingual preparations are availabled)
• Testosterone propionate (androgenic ester) parenteral - s.c or i.m. route.
• Stanozolol (synthetic anabolic steroid derived from Dihydrotestosterone with less androgenic activity and more anabolic activity).
Actions:
1) Androgenic action:
• Maturation of testis, prostate, seminal vesicle, scrotum and penis.
• Skin: Increases the sebaceous gland secretion, thickening of skin, acne. Increases the body hair distribution- [axillary, pubic and beard - male type hair development]
2) Anabolic action: consider giving in cachectic patients, prolonged illness.
• Increase in muscle mass.
• Increases in protein anabolism.
Hypogonadism
Testosterone replacement stimulates the anterior pituitary to increase gonadotropins and promotes secondary sex characteristics.
• In osteoporosis.
• In trauma: To decrease protein loss. To promote + ve nitrogen balance.
• In Post operative Convalescence.
• In the management of intractable anaemia.
Adverse effects:
• Acne, Prostatic hyperplasia and hypertrophy.
• Behavioural changes, Aggressiveness, Psychotic symptoms.
• Hepatic Dysfunction- Cholestatic Jaundice is encountered (esp. with 17α methyl substituted synthetic steroids - anabolic, androgens & progestins).
control of androgen secretion and sites of action of antiandrogens
Leuprolide, a synthetic Gn-RH analogue, agonist, Decreases FSH/LH production. After an initial flare, it decreases male gonadal function.**
Abarelix – antagonist does not have the initial flare. Both are useful in the management of prostate cancer by Decreasing LH-dependent testosterone production. Testosterone is essential for the prostate hypertrophy and hyperplasia.**
Therapeutic uses: To treat Prostate Cancer (Leuprolide/Abarelix)
finasteride
antiandrogen - • It is a Steroid.
• It inhibits the conversion of testosterone to Dihydrotestosterone(DHT),
• DHT: an active metabolite that mediates the androgenic action of Testosterone by inhibiting 5α reductase enzyme. DHT is the active androgen.
• Finasteride is the 5α Reductase Inhibitor.**
Use: Prostate Cancer and Hirsutism (Finasteride)
spironolactone
androgens and antiandr.
Note: Spironolactone, a steroid antagonist that decreases the biosynthesis of Testosterone in the Leydig cells of testis besides serving as a major Aldosterone Competitive Antagonist.
It also blocks the dihydrotestosterone mediated androgenic responses.
So, it is useful in treating HIRSUTISM besides being a K+ conserving diuretic.
• It is a Synthetic Steroid - a Competitive Antagonist of Aldosterone.
MOA - antiandrogen…
MOA:
1) It inhibits 17α hydroxylase; thus it decreases testosterone biosynthesis.
2) It also blocks DHT receptors in the hair follicle - thus inhibiting the action of Testosterone at the hair follicles.
Therapeutic Uses:
• Treatment and management of Hirsutism.**
• Management of primary hyperaldosteronism.
• Antihypertensive – for volume overload hypertension.
• It is also a K+ Sparing Diuretic.
flutamide and cyproterone
androgen and antian…
Both are Antiandrogens – DHT RECEPTOR BLOCKERS/Antagonists
Both are Antiandrogens – DHT RECEPTOR BLOCKERS/Antagonists
➢ Flutamide: A non-steroid – It is an Anilide.
Competes with DHT for intracellular androgen receptors and blocks the action of testosterone – it is a competitive DHT antagonist.**
The main adverse effect is – it is hepatotoxic.
Note: When flutamide and leuprolide are combined, there is a synergistic effect and there is no initial flare.
Use: Management of Prostate Cancer.
➢ Cyproterone acetate:
Antiandrogenic Steroid and it is also a most potent Progestin.
Blocks testosterone (DHT) Receptor.
Use of Cyproterone: To treat Hirsutism, To decrease Libido & aggressiveness in male sexual offenders. Note: Cyproterone acetate is a steroid - a potent Progesterone agonist (progestin) & an antiandrogen while flutamide is a non-steroid antiandrogen.
glucocorticoids
Downregulate PLA2 (phospholipase A2) activity via proteins called Annexins – formerly called Lipocortins)
Decrease Cytokines and
the Release of Inflammatory Mediators: –
decrease ILs, PGs,
decrease LTs, NFκB.
↑ vasoconstriction &
↓ capillary permeability
Different corticosteroid preparations
Primarily Glucocorticoid (duration), (anti-inflm potency), (salt-retaining potency) Cortisol 8-12 1 1 Prednisone 12-24 4 0.3 Triamcinolone 15-24 5 0 Dexamethasone24-36 30 0
Primarily Mineralocorticoid
Aldosterone 1-2 0.3 3000
Fludrocortisone 8-12 10 125-250
fludrocortisol
Fludrocortisol is a much more potent mineralocorticoid but has corticoteroid antiinflammatory activity – only used as a topical anti-inflammatory agent. It can be given orally to treat Addison’s Disease and for Orthostatic Hypotension. XXX
corticosteroid administration
Corticosteroids: Administration,
Therapeutics
• Routes of Administration of various Corticosteroids.
• Cortisol is reserved for Replacement Therapy in
Primary Adrenocortical Failure - Addison’s Disease
or in adrenal biosynthetic Enzyme Defects that lead to Adrenal Hyperplasia as ACTH secretion is high With NO endogenous Cortisol Production and release.
• Rest of the Potent long acting synthetic corticosteroids are reserved for the management of severe forms of Inflammation, Autoimmune Diseases and for Immunosuppression.
• While Corticosteroids are important in the treatment of severe forms of inflammation & as an Immuno- suppressant, its long term treatment is accompanied by Iatrogenic Cushing Syndrome, the features of Excess Glucocorticoid activity elaborated in the next slide.
• It also leads to prolonged Suppression of ACTH. So, do slow tapered withdrawal of corticosteroids and do not over-treat the patient for prolonged periods.
Glucocorticoids: Addison’s Disease
Treatment: Oral: Hydrocortisone, Prednisone or Fludrocortisol.
In severe Addisionian Crisis give cortisol hemisuccinate i.v. for rapid onset of action to recover the patient from shock and hypotensive collapse.
For Non-endocrine diseases, potent Corticosteroids are given:
i) Severe Inflammation,
ii) As Immunosuppressant,
iii) Management of autoimmune diseases,
iv) Severe asthma – status asthmaticus
v) Myeloproliferative diseases.
vi) Control Nausea & Vomiting when other agents fail
vii) Overcoming sickness at High Altitude.
Corticosteroid Antagonists - (I) Receptor Antagonists XX
• Spironolactone:
– an antagonist of aldosterone at its receptor:
– Rx - Hypertension, Hirsutism, a K+ Cons. Diuretic.
• Mifepristone (RU 486): Steroid Competitive Antagonist.
– acts as an antagonist at both Glucocorticoid & Progesterone receptors.
– Considered for treatment of Cushing’s syndrome.
– Effective First Trimester Termination of Pregnancy.
Corticosteroid Synthesis Inhibitors (II) XXX
Synthesis Inhibitors:
Used in the treatment of adrenal cancer when surgical therapy is impractical or unsuccessful because of metastases.
• 1. Ketoconazole (an antifungal agent):
– inhibits cytochrome P450 enzymes, therefore inhibiting the
synthesis of all steroids both gluoco and mineralocorticoid.
– used to treat adrenal carcinoma, hirsutism, breast cancer.
• 2. Aminoglutethimide:
blocks the conversion of cholesterol to pregnenolone, the rate limiting step, it inhibits the synthesis of all steroids.
• 3. Metyrapone:– an inhibitor of 11-b hydroxylase decrease Cortisol
Note: Mitotane –– an insecticide analogue of DDD
Destroys Adrenocortical cells. Helpful in the management
of inoperable Adrenal adenocarcinoma.
Insulin sensitizers
Insulin Sensitizers
1. Biguanide – metformin
2. Thiazolidine Diones (TZD) – pioglitazone, rosiglitazone
Insulin Secretagogues
3. KATP Blockers – Sulfonylureas – glyburide; metiglinides – repaglinide
4. GLP-1 Analogs – Incretins Exanitide, Liraglutide
5. DPP4 inhibitor – Sitagliptin, saxagliptin
Insulin and ITS Analogs
6. Fast Acting: I-Lispro, I Aspart, I glusine; Short Acting: Regular Insulin; Intermediate: NPH Insulin; Long Acting: I-Glargine, I-Detemir
OTHER (NOT INSULIN)
7. Alpha-Glucosidase inhibitor – acarbose
8. SGLT2 – inhibitor – renal sodium-glucose co-transporter-2 inhibitor - dapagliflozin
WHO ESSENTIAL MEDICINE STATUS METFORMIN, GLYBURIDE, NPH-Insulin
insulin preparations: onset and duration of activity
rapid acting
ONSET (HRS) PEAK (HRS) DURATION (HRS) COMMENTS
lispro insulin - 0.25; 1; 2-3; no rapid acting insulin should be used intravenously - rapid action is a result of rapid release from subcutaneous tissues
Insulin Aspart - 0.25; 1; 2-3
Glulisine - 0.25; 1; 2-3 - approved, to be marketed shortly
Short-acting
ONSET (HRS) PEAK (HRS) DURATION (HRS) COMMENTS
regular human insulin- 0.5-1; 2-4; 4-6; longer action if larger dose (mass action effect)
Intermediate-acting
ONSET (HRS) PEAK (HRS) DURATION (HRS) COMMENTS
NPH human - 0.5-1; 4-6; 8-16; peak and duration quite variable (neutral protamine hagedorn)
long acting
ONSET (HRS) PEAK (HRS) DURATION (HRS) COMMENTS
Insulin Glargine - 0.5-1; none; 23-26; basal insulin-minimal or no peak - cannot be mixed iwth other insulins - clear insulin forms crystals at in vivo pt.
