ERS17 Pharmacological Agents In The Treatment Of Thyroid Disorders Flashcards
Follicular cells Active vs Inactive
Inactive: Flattened
Active: Columnar / Cuboidal
Release of Thyroid hormone
Cold, Trauma, Stress
—> Hypothalamus
—> TRH
—> Anterior pituitary
—> TSH (Thyrotropin)
—> Thyroid
—> T3, T4 (T4 —> T3 in peripheral esp. liver)
-ve regulation:
Somatostatin —(inhibit)—> TSH (in addition to inhibit GH secretion)
-ve feedback:
T3, T4 —> Anterior pituitary
Thyroid hormone synthesis
Iodine: ingested as iodide in diet
Iodide trapping
—> via Na/I symporter
—> oxidised to Iodine by Peroxidase with H2O2
—> Iodine react with Tyrosine (in Thyroglobulin) (Organification: Synthesis of Thyroid hormone) (within Follicular cells)
—> T3, T4 (Iodothyronines: stored in colloid on Thyroglobulin)
—> secreted into Follicular cells upon stimulation by TSH
—> colloid droplets fuse with lysosomes
—> T3, T4 cleaved from Thyroglobulin by Protease in Follicular cells
—> T3, T4 released into circulation
T3 vs T4
T3 (active):
- 99.5% bound to plasma proteins
- small pool in circulation (2nM) —> thyroid contribute 20%, rest from peripheral conversion (liver)
- mainly intracellular
- fast onset: 2-3 hrs
- fast turnover rate, quickly metabolised (t1/2: 1 day)
T4 (inactive):
- 99.95% bound to plasma proteins
- large pool in circulation (90nM)
- mainly circulation
- slow onset (must be converted to T3): 2-3 days
- slow turnover rate, slowly metabolised (t1/2: 1 week)
MOA of Thyroid hormones
T3, T4 enter target cells
—> T4 converted to T3 in cytoplasm
—> T3 go into nucleus
—> T3 bind to receptor (corepressor dissociate from receptor, coactivator bind to receptor)
—> T3-receptor-coactivator complex (active)
—> bind to DNA
—> trigger DNA transcription
—> Pre-mRNA production —> mRNA
—> protein production
—> response
***Functions of Thyroid hormone
Metabolism:
1. Regulate Insulin, Glucagon, Glucocorticoid
- Regulate Enzyme activity of carbohydrate metabolism directly
—> Overall: ↑ Metabolism of carbohydrates, fats, proteins - SNS activity —> Regulate activity of Catecholamines
(E / NE cannot function well without Thyroid hormone —> Thyroid hormone ↑ adrenergic receptors esp. β receptors —> permissive effect) - ↑ in O2 consumption + heat production
—> Calorigenic action: important as part of response to cold environment
Growth and development:
1. Stimulate cell growth directly
2. **↑ GH secretion + its effects
3. Maintain normal response to PTH, Calcitonin
—> Overall: **Normal growth of body, Maturation of CNS, Skeletal development
Causes of Hypothyroidism (Myxedema: edema of mucus)
Lack of Thyroid hormone
—> cannot metabolise mucopolysaccharides well
—> accumulation of mucopolysaccharides under skin
- Hypopituitarism (↓ TSH secretion)
- Hashimoto’s thyroiditis (AutoAb —> Cell-mediated immune response directed against Follicles) (most)
- Goitrogens (Interfere Iodine uptake in Thyroid gland —> disrupt thyroid hormone production e.g. cabbage); Drugs (e.g. Lithium)
- Dietary deficiency of iodine
Hypothyroidism symptoms
- ↓ Basal metabolic rate
- ↓ CO (∵ E/NE cannot function properly)
- Tiredness (∵ poor metabolism —> ↓ glucose, a.a. uptake)
- ↓ Appetite (∵ low energy requirement)
- Dry skin (∵ less active sebaceous gland + feel cold —> ↓ sweating)
- Irreversible mental retardation + dwarfism (in early life) —> newborn screening
Treatment of hypothyroidism
Severe / Acute hypothyroidism e.g. Hypothyroid coma
- Liothyronine (T3) (∵ quick action)
Routine replacement therapy:
- Thyroxine (T4) (∵ longer t1/2, OD dose)
SE:
1. Thyrotoxicosis (i.e. Hyperthyroidism: ↑ BP, ↑ HR, feeling hot)
- Risk of ***worsening ischaemic symptoms (caution in CVS disease) (∵ coronary vasoconstriction)
- worsen angina, arrhythmia, heart failure - Risk of **Acute adrenal crisis
- CI in uncorrected adrenal insufficiency
- ∵ Thyroxine ↑ metabolic clearance of adrenocorticol hormones
- e.g. Cortisol —> **↓ Cortisol level —> Hypoglycaemia, Hypotension, Tiredness, Dizziness, Intolerance to stress / infection
Monitoring:
1. Serum T4 (high in overdose)
2. TSH (low in overdose)
Causes of Hyperthyroidism
- Graves’ disease
- Ab causes prolonged activation of TSH receptors —> excessive T3, T4 secretion - Adenoma
- Drugs e.g. ***Amiodarone (structure contain iodine —> ↑ Thyroid hormone production)
***Hyperthyroidism symptoms
- ↑ Basal metabolic rate
—> ***↑ Appetite (∵ ↑ energy requiremnt)
—> Heat intolerance - Sympathetic overactivity
—> Warm, moist skin (∵ heavy sweating)
—> Sweating
—> Tachycardia (∵ ↑ effect of E/NE by ↑ β receptors) - Tremor / Hyperkinesia (∵ ↑ β receptors in muscle)
- Angina / High-output heart failure (∵ ↑ workload of heart)
- ↑ Nervousness (∵ ↑ β receptors in brain)
- Upper eyelids retraction —> wide stare / Exophalmos
- May cause miscarriage
Short term treatment of Hyperthyroidism
Indication:
1. For Thyrotoxic crisis / Thyroid storm (Thyroid hormone suddenly ↑↑)
—> ↑↑ SNS
—> ↑↑ HR, Contractility, Vasoconstriction
—> Heart failure
- Before surgery
- correct thyroid hormone level - Initial treatment of hyperthyroid patients while Thionamides and 131Iodine are taking effect (long term treatment)
Drugs:
1. β blockers
2. β blockers + ***Lugol’s solution
Propranolol:
- ***Non-selective β blocker
- Relieve Thyrotoxic symptoms
—> β-1 in heart —> ↓ Palpitation / Tachycardia
—> β-2 in skeletal muscle —> ↓ Tremor
—> β-1 in brain —> ↓ Nervousness / Anxiety
Lugol’s solution
5% Iodine + 10% Potassium Iodide (i.e. a lot of iodine)
MOA:
**Wolff-Chaikoff effect: High amount of Iodine **inhibit Thyroid hormone production (as opposed to produce Thyroid hormone)
1. **Inhibition of H2O2 generation —> Inhibit Peroxidase —> Inhibit iodination of Tyrosine residues of Thyroglobulin
2. **Inhibition of T3, T4 release
3. ***↓ Vascularity, Size of thyroid gland
Use:
- 0.1-0.3 ml TDS
- dilute well with milk / water (∵ bad taste)
- rapid onset —> improves thyroxic symptoms within 2-7 days
- used pre-operatively **before Thyroidectomy to ↓ vascularity of thyroid —> ↓ bleeding risk
- NOT for long-term treatment (∵ **desensitisation) (only given for ***10-14 days)
SE:
- Allergy (rash, fever, angioedema, conjunctivitis, bronchitis, pain in salivary glands)
- Secreted in breast milk (inhibit thyroid hormone production in infants —> enlargement of thyroid gland in infants —> CI in breast feeding)
Long term treatment of Hyperthyroidism
- Thionamides (Thioamides / Thioureylenes)
- Radioiodine
- Surgery: for recurrent hyperthyroidism, large goitre, single adenoma
- Thionamides (Thioamides / Thioureylenes)
ALL contain ***Thiocarbamide group (antithyroid activity)
1. Methimazole (active)
2. Carbimazole (inactive) —> in vivo conversion to Methimazole
3. Propylthiouracil
MOA:
1. Inhibit Peroxidase (ALL) —> Inhibit iodination of Tyrosine residues of Thyroglobulin
2. **Inhibit T4 conversion to T3 in peripheral tissue (*Propylthiouracil only)
Use:
- slow onset —> 3-4 weeks to work (for T3/T4 stores in gland to be depleted)
- given for 18 months
- ***higher dose in beginning —> when become euthyroid —> reduce dose
- Carbimazole usually preferred (∵ longer t1/2, OD/BD dose)
- Propylthiouracil (short-acting, TDS):
—> for more acute / severe condition (∵ quicker onset + additional mechanism to ↓ thyroid hormone)
—> for patients with sensitivity reactions to Carbimazole / Methimazole (no cross-sensitivity)
SE:
- ***Skin rash + Pruritis (no need stop drug —> use Antihistamine)
- Bone marrow depression (<1%, thrombocytopenia, agranulocytosis, rare but severe)
- Cross placenta (lowest effective dose + close monitoring, do not stop because risk of miscarriage from hyperthyroidism)
- Secreted in breast milk (stop breast feeding)
