Drugs Used for Hyperthyroidism and Hypothyroidism

HYPERTHYROIDISM

1. Thionamides (Antithyroid Drugs)

• Both inhibit thyroid peroxidase (TPO), blocking iodine organification and coupling of iodotyrosines - thereby preventing T3 and T4 synthesis
• PTU additionally inhibits peripheral deiodination of T4 to T3 (methimazole does NOT have this effect)
• Neither drug blocks iodide uptake into the gland
• Onset is slow (3-4 weeks) because stored hormone must be depleted first

• Dose: 10-40 mg/day (starting), maintenance 5-15 mg once daily
• Advantage: once-daily dosing, lower risk of serious liver injury
• Used in Graves' disease, toxic nodules, and iodine-induced hyperthyroidism

• Dose: 100-200 mg PO three times daily (starting)
• Preferred over methimazole in: pregnancy (first trimester), thyroid storm (due to additional peripheral T4→T3 blockade)
• Carries a black box warning for severe hepatitis (sometimes fatal) - avoid in children and as first-line in adults unless no alternatives

• Common: maculopapular rash (4-6%), nausea, GI distress, arthralgias, fever
• Serious: agranulocytosis (0.1-0.5%) - patients must stop the drug immediately if they develop fever, chills, or sore throat
• PTU-specific: severe hepatitis (black box warning)
• Methimazole-specific: altered sense of taste/smell, cholestatic jaundice (more common than PTU)
• Cross-sensitivity between the two drugs is ~50%, so switching is usually avoided for severe reactions

2. Radioactive Iodine (RAI / ¹³¹I)

• A single oral dose permanently controls hyperthyroidism in ~90% of patients
• Preferred first-line definitive therapy for Graves' disease in most patients
• Contraindicated in pregnancy and breastfeeding
• Main consequence: hypothyroidism (most patients within the first year, then ~3% per year ongoing) - requiring lifelong levothyroxine replacement
• Thionamides must be stopped at least 3 days before RAI therapy (they interfere with uptake)
• Iodine solutions must be stopped at least 2 weeks before RAI

3. Iodides

• Inhibit organification and hormone release (Wolff-Chaikoff effect)
• Decrease size and vascularity of the hyperplastic gland

• Pre-operative preparation (SSKI 40-80 mg bid, started 1-2 weeks before thyroidectomy)
• Preparation before RAI therapy in severe cases
• Note: hyperthyroidism can "escape" the iodide block within weeks, and iodides can paradoxically induce hyperthyroidism in susceptible individuals (Jod-Basedow phenomenon)

4. Beta-Adrenergic Blockers (Symptomatic relief)

• Atenolol 25-100 mg daily (or propranolol)
• Control symptoms from increased adrenergic tone: palpitations, tremor, anxiety, tachycardia
• Propranolol at high doses also mildly inhibits peripheral T4→T3 conversion
• Do not treat the underlying hyperthyroidism - used until definitive therapy takes effect or in transient thyroiditis

5. Anion Inhibitors

• Potassium perchlorate: blocks thyroidal iodide uptake via competitive inhibition of the iodide transporter
• Rarely used clinically due to risk of aplastic anemia
• Main use: blocking thyroidal reuptake in amiodarone-induced hyperthyroidism

6. Glucocorticoids

• Used in thyroid storm and amiodarone-induced hyperthyroidism (type II)
• Inhibit peripheral T4→T3 conversion at high doses

Summary Table - Hyperthyroidism Drugs

HYPOTHYROIDISM

1. Levothyroxine (L-T4) - Drug of Choice

• Synthetic T4 - the standard and preferred treatment for hypothyroidism
• Oral bioavailability: 70-80% (improved with Tirosint liquid-gel formulation)
• T4 is converted to the active T3 in peripheral tissues by deiodinases
• Chemically stable with modest product deterioration during storage
• Dose: weight-based in adults; adjusted by TSH monitoring
• Intravenous route preferred for parenteral use (e.g., myxedema coma)

• Absorption reduced by: calcium carbonate, iron salts, antacids, cholestyramine (take levothyroxine on an empty stomach, 30-60 min before these)
• Metabolism increased by: rifampin, phenobarbital, carbamazepine, phenytoin - patients on these drugs may need higher doses
• Estrogens/oral contraceptives increase TBG, raising total T4 requirements

• Brand vs. generic: brand-name and generic levothyroxine may not be perfectly bioequivalent in severe congenital hypothyroidism - some experts recommend against switching

2. Liothyronine (L-T3)

• Synthetic T3 - faster onset, shorter half-life than T4
• Oral bioavailability nearly complete (~95%)
• Not preferred as monotherapy (harder to maintain stable levels)
• Used in myxedema coma (IV T3 preferred by some clinicians for rapid effect)
• Also used in combination with levothyroxine in some patients with persistent symptoms

3. Desiccated Thyroid Extract (DTE)

• Derived from desiccated porcine or bovine thyroid
• Contains both T4 and T3 in a fixed ratio (~4:1)
• An alternative in patients who prefer it or have persistent symptoms on levothyroxine alone
• Less predictable dosing compared to synthetic preparations

Summary Table - Hypothyroidism Drugs

• Patients on amiodarone can develop either hypo- or hyperthyroidism; hypothyroidism is managed with levothyroxine even after amiodarone is stopped (due to its very long half-life)
• Drug-induced hypothyroidism (from lithium, tyrosine kinase inhibitors, sunitinib, imatinib, interferon) is managed by either stopping the offending agent or adding levothyroxine
• In pregnancy, PTU is preferred in the first trimester for hyperthyroidism; TSH must be monitored closely as thyroid requirements change throughout pregnancy

Carbamazepine - Uses, Mechanism, and Key Details

Primary Indications

1. Epilepsy (Seizure Disorders)

• Focal (partial onset) seizures - including simple and complex partial seizures
• Focal-to-bilateral tonic-clonic seizures (formerly called generalized tonic-clonic or grand mal)
• It is one of the most widely used antiseizure medications for these seizure types
• Not effective for absence seizures, myoclonic seizures, or atonic seizures - it may actually worsen these

2. Trigeminal Neuralgia

• Carbamazepine is the drug of first choice for trigeminal neuralgia (tic douloureux) - a condition causing severe, lancinating facial pain along the trigeminal nerve distribution
• Highly effective at reducing the frequency and severity of attacks

3. Bipolar Disorder (Mood Stabilizer)

• Approved for acute mania and prophylaxis of bipolar disorder
• Used when lithium is less than optimally effective or not tolerated
• Considered third-line in bipolar after antipsychotics and valproate
• Dosage: start 200 mg twice daily, maintenance 800-1200 mg/day
• May be used alone or in combination with lithium in refractory cases
• Note: Despite structural similarity to tricyclic antidepressants (TCA), carbamazepine does NOT inhibit monoamine transporters and is not used as an antidepressant

Other Off-Label Uses

• Neuropathic pain (various types)
• Alcohol withdrawal (limited evidence, may be poorly tolerated)
• Restless legs syndrome (occasional use)
• Certain psychiatric conditions - as an adjunct

Mechanism of Action

• Blocks voltage-gated sodium channels (Na⁺) - preferentially binds to channels in the inactivated state
• Stabilizes the inactivated state, preventing the channel from returning to the resting (activatable) state
• Shows use-dependent (frequency-dependent) block: high-frequency neuronal firing (as in seizures or pain) is more effectively inhibited than low-frequency firing
• Also shows voltage-dependence: more effective at depolarized membrane potentials (i.e., in hyperexcitable neurons)
• Result: suppresses sustained repetitive firing of action potentials in epileptic foci and in the trigeminal nucleus

Chemistry

Pharmacokinetics

• Oral absorption is slow and erratic; bioavailability ~70-80%
• Highly protein-bound
• Autoinduction: Carbamazepine induces its own metabolism via CYP3A4 - plasma levels fall over the first few weeks, often requiring dose increases
• Blood levels should be re-checked 2 weeks after any dose increase
• Active metabolite: carbamazepine-10,11-epoxide (contributes to both efficacy and toxicity)

Important Drug Interactions

Patients needing contraception must use ≥50 mcg oestrogen preparation or a non-hormonal method.

Adverse Effects

Contraindications / Caution

• Bone marrow suppression (history of)
• AV block
• Structural similarity to TCAs - avoid within 14 days of MAOIs (theoretical)
• Pregnancy: associated with neural tube defects, craniofacial abnormalities (teratogenic - Category D)

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