Thyroid Drugs Page I

Thyroid Hormones

Chemistry of thyroid hormones:
- Active isomer -- levo (L-form) -- thyroxine, triiodothyronine, reversed iodothyronine (reverse T₄) {dextro (D) form: about 4% of the activity of the L form

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Pharmacokinetics:
- T₄ -- well absorbed from the ileum and duodenum following oral administration-- about 80% absorbed on average
- Modification of absorption:
  - food
  - drugs (e.g., sucralfate, iron, aluminum-containing antacids)
- T₃ -- almost completely absorbed (95%) following oral administration
- T₄ and T₃ absorption may be impaired by myxedema with ileus (may require parenteral administration {IV}, as a result)
- Factors that alter T₄ and T₃ clearance:
  - hyperthyroidism: increases
  - hypothyroidism: decreases
  - Drugs (hepatic microsomal enzymes inducers): Clearance is enhanced;Euthyroid state may be maintained because of thyroid hyperfunction.
    - phenobarbital
    - carbamazepine
    - phenytoin
    - rifampin
- Increases in the number of TBG binding sites (due to pregnancy, estrogen use, oral contraceptive use)
  - more thyroid hormone is bound; elimination rate declines (only free hormone can be eliminated); normal hormone concentration would be eventually restored

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Mechanism of Hormone Action:
1. Unbound T₄ and T₃ diffuse into the cell (passive diffusion, possibly active transport)
2. Inside cell:
  1. T₄ T₃ by 5'-deiodinase
  2. T₃ cell nucleus where T₃ binds to a specific T₃ nuclear receptor
    - Receptor:
      - Two classes of receptors, TR_a TR_b :
        
        multiple isoforms (as a result of alternative splicing)
      - homologous with the c-erb oncogene family
        
        c-erb (cellular (c) homologues of the avian retroviral v-erb A proto-oncogene.)
        
        c-erb -A-a (TR_a)
        
        c-erb -B-_b (TR_b)
        
        TR genes encode for:
        
        T₃ binding domain
        
        DNA-binding domain which attaches to regulatory DNA sequences in genes with T₃ regulated transcription (growth hormone genes, prolactin genes, TSH genes)
        
        Activation and modulation of transcription rates are mediated by thyroid response elements (TREs-- regulatory sequences)
        
        T₃ -TR combined with auxiliary thyroid receptor proteins (TRAPs) interact with TREs to, for example:
        
        inhibit synthesis of TSH
        
        c-erb oncogene family includes:
        
        steroid hormone receptors
        
        vitamin A and D receptors
    - Tissue to tissue variation in response may be due to different concentration of thyroid receptor forms space for (T₃ exists in two molecular forms)

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Thyroid hormones: metabolic actions
- nuclear receptor activation increased RNA and protein synthesis: examples --
  - increased Na/K ATPase increased ATP turnover, increased oxygen consumption --calorigenic effect

Thyroid Hormone Effects*
Physiological system	Hyperthyroidism (thyrotoxicosis)	Hypothyroidism
skin --appendages	warm, moist skin; sweating; fine, thin hair; Plumber's nails; pretibial dermopathy (Graves' disease)	pale, cool, puffy skin; brittle hair and nails
Eyes, face	Upper lid retraction (wide stare); periorbital edema; exophthalmos, diplopia (Graves' disease)	Eyelid drooping; periorbital edema; puffy, nonpitting facies; large tongue
Cardiovascular	decreased peripheral resistance, increased cardiac output, stroke volume, heart rate, pulse pressure; congestive heart failure (high-output); increased contractility,. arrhythmogenic; angina	increased peripheral resistance, decreased cardiac output, stroke volume, heart rate, pulse pressure; congestive heart failure (low output); bradycardia (low voltage ECG with prolonged PR interval, flat T wave); pericardial effusion
Respiratory	dyspnea; reduced vital capacity	hypoventilation (CO₂ retention) pleural effusions
Gastrointestinal	increased appetite; increased bowel movement frequency; hypoproteinemia	decreased appetite, decreased bowel movement frequency; ascites
CNS	Nervousness, hyperkinesia, variable emotional states	lethargy, neuropathy
Musculoskeletal	Weakness; fatigue; hypercalcemia, osteoporosis, increased deep tendon reflex	muscle fatigue, reduced deep tendon reflex, increased alkaline phosphatase, LDH, AST
Renal	Increased renal blood flow; increased GFR; mild polyuria	Decreased renal blood flow; decreased GFR; reduced water excretion
Hematopoietic	anemia (increased RBC turnover); increased erythropoiesis	anemia (decrease production rate, decreased iron absorption, decreased folate acid absorption, autoimmune pernicious anemia),decreased erythropoiesis
Reproductive	decreased fertility; menstrual irregularity; enhanced gonadal steroid metabolism	infertility;hypermenorrhea, decreased libido; impotence, decreased gonadal steroid metabolism
Metabolic	increased basal rate; negative nitrogen balance, hyperglycemia; increased free fatty acids, decreased cholesterol and triglycerides; increased hormone degradation; increased requirement for fat-and water-soluble vitamins; enhanced drug detoxification	decreased basal rate; delayed insulin degradation, with increased sensitivity; enhanced cholesterol and triglyceride levels; decreased hormone degradation; decreased requirements for fat-and water-soluble vitamins; decreased drug detoxification.