Thyroid Pharm Flashcards
How commonly are thyroid drugs prescribed
thyroid hormones consistently in top 10 of most frequently prescribed drugs
What activates the hypothalamic-pituitary-thyroid axis
circadian rhythms, prolonged cold exposure, acute psychosis
what can suppress the hypothalamic-pituitary-thyroid axis
severe stress
what stimulates pituitary release of TSH
TRH
what inhibits pituitary release of TSH
somatostatin, dopamine, glucocorticoids
major regulated step of thyroid hormone biosynthesis
uptake of iodide into thyroid gland; stimulated by TSH via G-protein coupled receptor – increased cAMP
what blocks iodide uptake
anions of similar size, like SCN, ClO4, I- itself
- high concentrations of iodide >6mg, autoregulatory action via decreased expression of transporter)
- cAMP generation inhibited by Lithium, which can cause hypothyroid sxs in anti-manic therapy
Role of thyroid peroxidase
oxidize iodide and incorporate into tyrosine residues on TG
- couples precursors MIT and DIT
Thyrotropin releasing hormone
- tripeptide, administered IV with halflife of 4-5 min
- activates phospholipase C– increases IP3– increases intracellular Ca++
- this stimulates TSH production (and prolactin), which stimulates thyroid to produce T4
- TRH blocked by T3 and somatostatin; potentiated by lack of T3
use of thyrotropin releasing hormone
test for pituitary reserve of TSH in suspected hypothyroidism and for hyperthyroidism
- Unlabeled- antisedative effect for phenobarbital, benzos, EtOH overdose; high dose TRH may improve spimal cord injury outcomes
- orphan drug for prevention in infant respiratory distress syndrome
TRH side effects
duration only a few min: urge to urinate, metallic taste, nausea, light-headedness
Thyroid Stimulating Hormone (drug)
- aka thyrotropin
- glycoprotein of alpha/beta subunits; prepared rom bovine source
- IM or SC, t1/2 about 1 hr
- stimulates cAMP via adenylate cyclase – increased iodine uptake and producon of thyroid hormone
- blocked by Lithium
Use of pharm TSH
- metastatic thyroid carcinoma (enhances radioactive uptake of I-131
side effects of TSH administration
nausea/vomiting, thyroid tenderness, allergic sxs, hyperthyroid sxs
MOA of thyroid hormones
enter cell via active transport. T4 converted to T3 via deiodinase. T3 enters nucleus to bind receptor
- most effects mediated by increase in RNA then protein synthesis– increased Na/K ATPase – increased ATP turnover and O2 consumption – calorigenic effect
- also increases in myosin ATPase and sarcoplasmic reticulum Ca ATPase
- get increased fat/carb/protein consumption and metabolism
effects of thyroid hormones
- optimal growth, development, function, maintenance of all body tissue
- development of nervous, skeletal, reproductive tissues. hypo can cause dwarfism and mental retardation
- influence secretion /degradation of other hormones
- increased symp activity via thyroid hyperactivity– especially cardiovascular due to increased beta adrenergic receptors and adenylyl cyclase activity
causes of hypothyroid
Hashimoto’s most common; radiation exposure, surgery, iodine deficient, enzyme defects, pituitary disease (low TSH), rare hypothalamic disease (low TRH, low TSH)
treatment for hypothyroid
replacement therapy with levothyroxine (T4)
- children need more per kilogram of body weight
- require 6-8 wks for steady state; look at TSH 6-8 wks post dose adjustment and every 6-12 months after euthyroid state
- may need increased dose for pregnancy due to increased TBG and increased placental metabolism of T4-T3– check every 1-3 months
- use caution if underlying cardiac disease
how often to monitor pts with hypothyroid
check TSH 6-8 weeks post dose adjustment and every 6-12 months once in euthyroid state obtained
myxedema coma
(end state of untreated hypothyroidism)
- acute medical emergency
- hyponatremia, hypoglycemia, hypothermia, shock, death possible
how to treat myxedema coma
large doses with IV loading dose of T4 then daily dosing- can do T4/T3 combo or just T3 too
- may need hydrocortisone to prevent adrenal crisis as thyroid hormone may increase its metabolism (get low cortisol)
Drugs for hypothyroid
Levothyroxine (T4) adn Tiiodothyronine (T3)
- Levo– take on empty stomach
drugs increasing hormone protein binding
Estrogens, Selective estrogen receptor modulators, tamoxifen
- methadone, clofibrate, 5 fluorouracil, heroin
drugs decreasing protein binding
salicylates antiseizure meds (phenytoin, carbamazepine) glucocorticoids androgens furosemide
does pituitary respond to total or free hormone levels
free hormone levels
drugs inhibiting 5’-deiodinase
Glucocorticoids
- beta-adrenergic receptor antagonists
- propylthiouracil (higher doses)
- amiodarone
conditions inhibiting 5’ deiodinase
- acute/chronic illness
- caloric deprivation
- malnutrition
- fetal/neonatal period
major factor accounting for pharmacokinetic differences in T3, T4
degree of protein binding
Levothyroxine
synthetic T4; preparation of choice for replacement
- stable, lack of allergenic foreign protein, low cost and longer half life for daily dosing
- oral or IV
- technically can switch between products but advisable to use same product for individual pt– as much as 10% difference between “equivalent” products
Liothyronine
synthetic T3
- well absorbed, rapid action but shorter duration– quicker dosage adjustments
- NOT recommended for routine replacement; high cost
- can add if sxs persist with levo
- avoid n pts with cardiac disease
- used in T3 suppression test!!
what drug used in T3 suppression test
Liothyronine
Liotrix
4: 1 mix of T4 adn T3
- more expensive, no advantage since conversion in periphery; not recommended
- combo therapy may cause increased low TSH and increased markers of bone turnover
Thyroid USP
porcine thyroid extract of thyroxine and liothyronine
- variable T4/T3 ratio– unexpected toxicities
- protein antigenicity
- product instability
- less desirable than levothyroxine
- NOT RECOMMENDED IN HYPOTHYROIDISM
Adverse rxns with thyroid hormone replacement
- Toxicity with excess related to plasma levels and thus equal to signs/sxs
- Children: restlessness, insomnia, accelerated bone maturation/growth
- adults: anxious, heat intolerant, palpitation/tachycardia, tremors, weight loss, increased bowel movements; can precipitate cardiac arrhythmias, angina pectoris, or MI in those with Cardiac disease
DDI with thyroid hormones
increased adrenergic effects with sympathomimetics (epi, decongestants–phenylephrine, pseudoephedrine)
Graves’ Treatment
- modify tissue response (beta blockers/corticosteroids)
- interfere with production of hormone (thionamides, iodides)
- glandular destruction (surgery, radioactive iodine)
Thionamides
Methimazole, Propylthiouracil (PTU–declining use)
- M: 100% absorbed
- PTU more protein bound, so less crosses placenta/secreted into breast milk
- short half lives (5-13 hrs) but drugs accumulated in thyroid and have longer duration of action (P: 12-24; M: 40)
MOA of thionamides
- only work in thyrotoxicosis, not thyroiditis
- prevent T3/T4 synthesis by blocking iodine organification/coupling
- high dose PTU also inhibits conversion of T4 to T3
- synthesis inhibited not release, so need 3-4 weeks to deplete T4 stores
toxicity of thionamide
- adverse rxns: pruritic rash, gastric intolerance, arthralgias
- agranulocytosis most dangerous so routine CBC controversial but do if sore through/fever
- rare hepatotoxicity with PTU but severe enough that routine PTU use is concerning
Iodide as treatment
SSKI (potasium iodide), Lugol’s solution
- rarely used today as sole therapy
- high doses inhibit hormone syntheses (via elevated intracellular I) and hormone release (via elevated plasma I) through inhibiting TG proteolysis
clinical use of iodide
NOT alone
- start AFTER onset of thionamide effects or it can delay thionamide therapy
- used to decrease size/vascularity of hyperplastic gland before surgery (given for 10 days prior to surgery)
Iodine toxicity
uncommon, reversible
- acneiform rash, rhinorrhea, metallic taste, swollen salivary glands
- selective accumulation in salivary glands
Radioactive iodine
- I-131
- oral, rapid absorbtion, concentrated in thyroid to cause slow inflammatory process that destroys parenchyma of gland over weeks to months
advantages of radioactive iodine
easy admin, effective, low expense, not painful
- permanent resolution of hyperthyroidism
disadvantages of radioactive iodine
slow onset/time to peak, some need 2nd dose, can get radiation thyroiditis with CV complications in elderly or susceptible pts, may cause worsening opthalmopathy
- hypothyroidism: 80% require replacement therapy
- DON’t GIVE TO PREGO OR NURSING WOMEN!!
Thyroidectomy
- treatment of choice if large gland
- rare today due to radioactive iodine effetiveness– risks of general anesthesia and parthyroid/recurrent laryngeal nerve damage becomes relatively great
- advantage of rapid, permanent cure of hypoerthyroidism
- get antithyroid drugs until euthyroid (6 weeks) + iodine prior to surgery
- 50-60% need thyroid supplementation post surgery (iatrogenic hypothyroidism)
- can be used in 2nd trimester of pregnancy if needed
Thyroid storm
sudden, acute exacerbation of thyrotoxicosis
- may occur in noncompliant, incompletely treated, or undiagnosed pt with hyperthyroidism who has acute stress (infection, surgery, trauma)
Thyroid storm sxs
fever, flushing, sweating, tachycardia/a fib, high output heart failure, delirium, coma
- hypermetabolism and excessive adrenergic activity
Thyroid storm treatment
- try to control sxs, inhibit release of preformed thyroid hormone, block conversion of T4 to T3
- Propanolol (control CV effects and blocks conversion)
- sodium iodide IV, potassiumiodide drops – slow hormone release
- PTU blocks synthesis and conversion
- Hydorcortisone- protects against shock, blocks conversion, may modulate immune response that makes thyrotoxicosis worse
is levothyroxine narrow or wide therapeutic index
narrow!
where is exogenous thyroid hormone absorbed
ileum/colon; impaired absorption in severe myxedema
drugs impairng absorption of levothyroxine
metal ions (antacids, calcium and levothyroxine) - cipro, bile acid sequestrants, raloxifene, sucralfate
how to take levothyroxine
empty stomach with water; space dose 3 hrs before or 4-6 hrs after interacting drug
formula to calculate fluctuation in drug concentration
2^x
- x = number of half lives in dosing interval
(eg. T4 half life is 7 days, so dosing once a day– 2^(1/7) = 1.1, so 10% fluctuation)
how long til you reach steady state after starting dose
4-5 weeks
how long after changing dose will you reach new steady state for T4
4-5 weeks
how long until resolution of hypothyroid sxs with drugs
resolution begins within 2-3 weeks
Does levothyroxine or triiodothyronine have greater oral bioavailability
Triiodothyronine
Does levothyroxine or triiodothyronine have greater affinity for thyroid hormone receptors
Triiodothyronine (T3)
Does levothyroxine or triiodothyronine have greater potential for CV side effects durign therapy initiation
T3-triiodothyronine
Is levothyroxine or triiodothyronine more expenxive
triiodothyronine
Does levothyroxine or triiodothyronine have longer duration of action
T4
increased risk of osteoporosis
Liothyronine
which drug is porcine thyroid extract
Thyroid USP – contains T3 and T4
which hyperthyroid drugs are synthesis inhibitors
thionamides, iodides
which hyperthyroid drugs are modifying tissue response
Beta blockers, corticosteroids
symptomatic improvement!
which Graves’ treatment is mainly glandular destruction
radioactive iodine and surgery
why do we have lag in thyroid drug response
since we have stores of thyroid hormone in colloid
which beta blocker used in Graves
propanolol (beta 1 and 2 action) blocks conversion but Metoprolol-atenolol are beta1 selective, longer T1/2
is graves causing excessive release or production
excessive production
is thyroiditis causing excessive release or production of hormone
release
Major side effect with tionamides
agranulocytosis
Methimazole or PTU have faster achievement of euthyroid state
Methimazole
what do we use to control CV sxs in graves’
Beta blockers
Does PTU or methimazole have risk of hepatotoxicity
PTU
