Pathophysiology of hypothyroidism
- Medical condition defined by deficiency of thyroid hormones:
- Thyroxine (T4)
- Triiodothyronine (T3)
- These hormones play an integral role in various functions:
- Growth and development
- Catecholamine function
- Pituitary hormone synthesis regulation (feedback loop)
- Clinically, a deficiency in these hormones can lead to abnormal changes in:
- Energy levels
- Bowel movements
Thyroid replacement medications
The 3 drugs used for treatment of hypothyroidism are:
- Levothyroxine (L-T4)
- Liothyronine (L-T3)
- Desiccated thyroid extract
- Levothyroxine is a synthetic levo-isomer of T4.
- The prohormone T4 is converted to T3 (active) or reverse T3 (inactive) in the liver and other peripheral tissues via deiodination.
- ↑ T4 and T3 levels lead to:
- Normalization of hormone effects on metabolic, growth, and development functions
- ↓ Pituitary overproduction of thyroid-stimulating hormone (TSH)
- 40%‒80% absorbed from GI tract; can be erratic
- Food can ↓ absorption
- Distribution: Approximately 99% of T4 and T3 binds to plasma proteins (thyroxine-binding globulin (TBG)).
- Deiodination in the liver and other peripheral tissues (including kidneys) to the active form, T3.
- Renal and hepatic impairment can ↓ conversion to T3.
- Urine (primarily)
- Hypothyroidism (primary, secondary, and tertiary)
- Levothyroxine is the drug of choice.
- Goal is to mimic normal endogenous T4 production
- Has a longer half-life than L-T3
- Less chance of hypermetabolic side effects
- Myxedema coma (in combination with L-T3)
- TSH suppression in thyrotropin-dependent thyroid cancers (papillary and follicular)
- Hypermetabolic state:
- Can occur with:
- Elderly individuals
- Initiation of therapy
- Signs and symptoms:
- Tachycardia (including atrial fibrillation)
- Widened pulse pressure
- Weight loss
- Agitation and restlessness
- Can occur with:
- Allergy to the dye or filler:
- Untreated adrenal insufficiency: Levothyroxine can precipitate acute adrenal crisis.
- Associated with ↑ metabolic needs.
- Normal physiologic ↑ in TBG and TSH → ↑ thyroid hormones
- Pregnancy: Mothers require ↑ in L-T4 dosage.
- Remember to change back to prepregnancy dose postpartum.
- Elderly individuals or those with cardiovascular disease:
- Thyroid hormone therapy has inotropic and chronotropic effects on the heart, which can result in angina.
- Older individuals (> 60 years) and those with cardiovascular disease should be started on a lower dose.
- This low dose can be slowly titrated upward (“start low, go slow”)
- Individuals with diabetes mellitus may need to have the dosage of their antidiabetes medication adjusted with administration of L-T4.
Drug and food interactions
- Foods that interfere with absorption (medication should be taken on empty stomach):
- High-fiber foods
- Calcium-containing foods
- Drugs that interfere with absorption:
- Calcium carbonate
- Iron supplements
- Bile acid sequestrants
- Aluminum-containing antacids
- Severe drug interactions:
- Ketamine: hypertension and tachycardia
- Tricyclic antidepressants (TCAs): ↑ arrhythmogenic effect
Drugs that may alter levothyroxine efficacy
|Drugs that ↑ hepatic conversion of T4 to T3||↑ Dosage may be necessary|
|Drugs that ↑ serum TBG concentration||↑ Dosage may be necessary|
|Drugs that ↓ serum TBG concentration||↓ Dosage may be necessary|
- Liothyronine is the synthetic form of active T3.
- Effects are stronger and faster than those of L-T4.
- Well absorbed (approximately 95%)
- Distribution: approximately 99% bound to proteins, such as TBG
- Urine (primarily)
- Not typically used alone owing to short half-life
- Used in individuals who continue to have symptoms despite L-T4 therapy
- Myxedema coma (in conjunction with L-T4)
- Nontoxic goiter
Adverse effects, precautions, and drug interactions
Adverse effects, precautions, and drug interactions are similar to those for L-T4.
- Nonsynthetic thyroid hormone extracted from the thyroid of domesticated animals (e.g., pigs, sheep, cows)
- Contains both T3 and T4 in a ratio that does not naturally occur in human beings
- Absorption: 40%–80%
- Distribution: protein-bound (similar to L-T3 and L-T4)
- Metabolism: T4 component is converted to T3
- Urine (primarily)
Desiccated thyroid is a rarely used treatment for hypothyroidism.
- May be considered for individuals who want a natural treatment
- Not FDA-approved
- Side effects are similar to those for the synthetic thyroid medications
- Manufacturing and quality control issues are common because of variable hormone concentrations.
- T.A. (2013). A review of the pharmacokinetics of levothyroxine for the treatment of hypothyroidism. Touch Endocrinol. https://www.touchendocrinology.com/thyroid/journal-articles/a-review-of-the-pharmacokinetics-of-levothyroxine-for-the-treatment-of-hypothyroidism/
- Synthroid, Levoxyl (levothyroxine) dosing, indications, interactions, adverse effects, and more. (2021). MedScape. Retrieved August 3, 2021, from https://reference.medscape.com/drug/synthroid-levoxyl-levothyroxine-342732#11
- DrugBank Online. (2021). Levothyroxine: uses, interactions, mechanism of action. https://go.drugbank.com/drugs/DB00451
- American Thyroid Association. (2020). Thyroid hormone treatment. http://www.thyroid.org/thyroid-hormone-treatment/
- Ross, D.S. (2021). Treatment of primary hypothyroidism in adults. UpToDate. Retrieved July 31, 2021, from https://www.uptodate.com/contents/treatment-of-primary-hypothyroidism-in-adults
- Dong, B.J., Greenspan, F.S. (2012). Thyroid & antithyroid drugs. In: Katzung, B.G., Masters, S.B., Trevor, A.J. (Eds.), Basic & Clinical Pharmacology, 12th ed. McGraw-Hill Lange, pp. 681–696. https://pharmacomedicale.org/images/cnpm/CNPM_2016/katzung-pharmacology.pdf