Endocrine Drugs Flashcards
1
Q
Levothyroxine
A
T4, thyroxine, tetraiodothyronine
- most popular drug for treating chronic hypothyroidism
- if you give a patient T4 you end up with a mixture of T3 and T4 since T4 gets converted to T3 in the periphery
- dosage can be given anywhere from once a day to once a week (depends on the degree of hypothyroidism)
2
Q
Liothyronine
A
T3, triiodothyronine
- not used very often for chronic hypothyroidism - reason being that if you give only T3, pt is not receiving any T4
- -> T3 is most commonly used in emergency cases of severe hypothyroidism (T3 is much more potent than T4)
3
Q
Liotrix
A
T4 + T3 (4 to 1 ratio)
- controversial drug: no evidence that the mixture is any better than T4 alone. Therefore, T4 is the more popular and cheaper drug to use.
4
Q
Propylthiouracil (PTU), Methimazole
A
Thioamides - treat hyperthyroidism
- both drugs inhibit thyroid peroxidase –> inhibition of iodide oxidation in the lumen –> no formation of MIT or DIT.
- PTU in addition will inhibit 5’-diodinase (which inhibits conversion of T4 to T3)
- will not see the effects of thioamides for as long as 3-4 weeks after starting administration. This is because the thyroid has a lot of thyroglobulin with T3 and T4 ready to go when the thioamide is administered.
Methimazole is recommended higher than PTU because PTU has an associated risk of very serious liver toxicity. PTU is generally only used if patients are not responding to Methimazole.
The one exception to this rule is pregnancy - in pregnancy, PTU is recommended. Both drugs cross the placenta but Methimazole does so more easily, exposing the fetus to high amounts
Adverse effects of both Methimazole and PTU: dermatitis, hair loss, agranulocytosis
Pharmacology:
These drugs are concentrated in the thyroid - 4-5 half life elimination rule does not apply here.
Half life of PTU in the blood is about 1 hr, can administer every 5-6 hrs.
Half life of Methimazole is about 7 hr, administered once a day.
5
Q
Dexamethasone
A
- long acting glucocorticoid
- treats hyperthyroidism
- a large dose of Dexamethasone will inhibit conversion of T4 to T3. This is important because T3 is more potent in stimulating thyroid hormone receptors than T4.
- In severe hyperthyroidism (thyroid storm), a large dose of Dexamethasone can be given.
- would not use Dexamethasone long term because dosage is high and there are many adverse side effects
6
Q
Iodide
A
Preparations:
- Lugol’s solution (5% iodine and 10% potassium iodide)
- Potassium iodide
Large doses of iodine will do 2 things:
- inhibit the synthesis of thyroid hormone by inhibiting the oxidation of iodide
- inhibit the release of T3/T4 from the thyroid
Problem: only effective for 2-3 weeks. After that, the effect will wear off and the thyroid will overcome whatever the mechanisms are of inhibition by the iodide and start cranking out T3 and T4 again. Therefore, used for only short term or for emergencies.
7
Q
Radioactive iodine
A
- gamma and beta particle emitter
- taken up and concentrated in the thyroid
- kills thyroid follicular cells in a dose dependent manner –> lower T3 and T4
- too much radiation can result in hypothyroidism –> supplement with T4
8
Q
Beta blockers
A
- treat the symptoms of hyperthyroid (will decrease HR and BP)
- non-selective beta blockers work better than selective beta blockers ex) propanolol
- in asthmatic patients you can substitute with a calcium channel blocker
9
Q
Calcitriol (1,25-dihydroxycalciferol)
A
- vitamin D
- activated in the kidney, which acts immediately and rapidly to elevate calcium levels
- if not needed immediately, use ergosterol or cholesterol derivative (plant or animal source); less expensive than calcitriol
- half life is several hours; binds to binding proteins
10
Q
Paricalcitol
A
- vitamin D analog
- treats secondary hyperparathyroidism (renal disease: not enough calcium around –> secretion of more parathyroid hormone) by decreasing serum PTH levels
- given IV
- short half life
- used in dialysis
- better than calcitriol for 2 reasons: 1. less hypercalcemia occurring 2. no major effects on bone resorption –> less bone loss
- side effects: nausea, vomiting
11
Q
Calcipotriol
A
- vitamin D analog Uses: - suppression of tissue growth - treats psoriasis - efficacy equivalent to corticosteroids - not protein bound --> short half life - no hypercalcemia occurring as a result - applied topically but can irritate area of application, so we don't give it on the face
12
Q
Cinacalcet
A
- Calcium sensor sensitizer
- decreases PTH secretion for any given calcium plasma concentration: sensitizes the entire system to calcium so that at lower concentrations of calcium, less PTH will be secreted
- treats hyperparathyroidism of chronic renal failure
- Caution: hypocalcemia
- long half life
- drug interactions with itraconazole and erythromycin –> extensively metabolized
- adverse effects: GI upset, nausea, vomiting; rarely: hypotension, arrythmia
13
Q
Agents used to treat postmenopausal osteoporosis
A
- estrogen hormone replacement therapy (no longer used)
- raloxifene
- bisphosphonates
- calcitonin
- teriparatide
- denosumab
14
Q
Raloxifene
A
- treats postmenopausal osteoporosis
- estrogen agonist at the receptors on osteoblasts to suppress IL-6 production as well as other signals/cytokines like RANK-L in the activation/maturation of osteoclasts.
- drug works everywhere in the body –> increased risk for thromboembolic disorders
- decreases spinal fractures but not effective with hip fractures which is a big issue in osteoporosis
15
Q
Bisphosphonates
A
- treats postmenopausal osteoporosis
- carbon analog of pyrophosphates. phosphates are an important part of bone, because calcium and other ions can bind to it
Unusual pharmacokinetics compared to other drugs:
- orally active but only 10% of the dose is actually absorbed, rest is secreted unchanged
The 10% that gets absorbed gets taken up by bone and has no effect until an osteoclast comes along to resorb that area of bone. Then, the osteoclasts take up the bisphosphonate leading to their ultimate destruction. Osteoclasts secrete acid to resorb the mineral portion of bone. Bisphosphonates inhibit the osteoclastic proton pump, decrease osteoclast formation/activation, increase osteoclast apoptosis
- very short half life
side effects:
- irritating to the GI, esp to the esophagus - do not want any reflux so patients taking bisphosphonates will want to sit up or stand for at least 30 min after taking the drug
- cannot take bisphosphonates with food because it worsens its absorption and you might get risk of GERD –> take with glass of water before eating in the morning
- poor renal function if you have accumulation of too much drug
- very small risk of severe osteoporosis of the jaw and the long bones of the legs
Nitrogen containing bisphosphonates:
- inhibit a step in mevalonic acid pathway involved in protein prenylation (Protein prenylation involves the transfer of either a farnesyl or a geranyl-geranyl moiety to C-terminal cysteine(s) of the target protein)
- mevalonic acid = branched fatty acid that gets connected to certain genes necessary for activation
this is called farnesylation.
Attached RAS protein allows these farnesylated proteins to be inserted in membranes.
N containing bisphosphonates seem to interfere with this insertion –> signal not there –> turn on system –> apoptosis
16
Q
Calcitonin
A
- produced by parafollicular cells aka c-cells in the thyroid
- we use salmon derived calcitonin which is cheaper and can be given cutaneously or intranasally
- not used as much as bisphosphonates in the treatment of osteoporosis
- inhibits osteoclast bone resorption by acting directly on them
- treats Paget’s disease = uncontrolled formation and resorption of bone. Causes lots of pain and disfigurement
2 problems
- tolerance develops to its effect over a few days –> give intermittently, not continuously
- direct analgesic effects - good for treatment of Paget’s disease but don’t know mechanism
17
Q
Teriparatide
A
- fragment of PTH
- promotes formation of bone particularly in the spine and hips
- can be used sequentially with bisphosphonates
- should not be given longer than 2 years due to risk of osteosarcoma
- Give once a day as a single subcutaneous injection. This is pulsatile exposure. Continuous exposure to PTH results in bone resorption but pulsatile exposure promotes bone formation to a greater extent than bone resorption
- usually reserved for postmenopausal women at greater risk for fractures (history, small skeleton, etc)
- can also be used in the treatment of osteoporosis associated with chronic glucocorticoid use
18
Q
Denosumab
A
- human anti-RANKL antibody
- binds to and prevents the RANK ligand from binding to preosteoclasts leading to inhibition of their proliferation, differentiation, and maturation
- inhibits bone resorption and increases bone mineral density
- must be given subcutaneously, once every 6 months or once every month
- contraindicated in hypocalcemia: rash, dermatitis, and rarely, serious infections, pancreatitis, and osteonecrosis of the jaw
- approved treatment for metastatic hypercalcemia due to cancers
19
Q
Lispro
A
- injected insulin
- for post prandial control
- ultra-short acting; rapid onset: peak levels in an hour
- monomer of insulin
- any insulin = good for gestational diabetes
- adverse effects: hypoglycemia and hypoglycemia associated autonomic failure (HAAF) –> tight glycemic control using insulin is contraindicated in infants
20
Q
Regular crystaline insulin
A
- injected insulin
- for post prandial control
- short-acting
- lasts 5-7 hrs
- any insulin = good for gestational diabetes
- adverse effects: hypoglycemia and hypoglycemia associated autonomic failure (HAAF) –> tight glycemic control using insulin is contraindicated in infants
21
Q
NPH insulin
A
- injected insulin
- for baseline glucose monitoring
- intermediate acting
- combines insulin and protamine complexed as isophane
- slow degradation of protamine allows slow onset and long duration
- any insulin = good for gestational diabetes
- adverse effects: hypoglycemia and hypoglycemia associated autonomic failure (HAAF) –> tight glycemic control using insulin is contraindicated in infants
22
Q
Insulin glargine
A
- injected insulin
- for baseline glucose monitoring
- long acting
- slow release form, no peak, duration about 20-24 hrs –> mimics basal 24 hr insulin levels
- less chance of hypoglycemia than NPH insulin
- any insulin = good for gestational diabetes
- adverse effects: hypoglycemia and hypoglycemia associated autonomic failure (HAAF) –> tight glycemic control using insulin is contraindicated in infants
23
Q
Non-insulin hypoglycemics
A
- initial treatment for DM type II (or DM Type I with poor glycemic control despite high insulin)
- insulin secretagogues: sulfonylureas, meglitinides
- biguanides: metformin
- insulin sensitizers: thiazolidinediones (TZD’s)
- inhibitors of carbohydrate absorption: alpha-glucosidase inhibitors
- glycosurics (inhibit renal glucose reabsorption)
- amylin: pramlintide
- incretin mimetics: exenatide, sitiglipin
24
Q
Sulfonylurea
A
- insulin secretagogues
- mechanism: KATP channel is made up of subunits containing sulfonylurea sites
does the same thing ATP does
artifically closes K channel –> Ca influx –> insulin secretion (pancreatic beta cell - has a high capacity glucose transporter that enables glucose to be transported relative to blood glucose (doesn’t saturate) –> glucose is metabolized leading to an increase in the ATP:ADP ratio. ATP binds K+ channel. –> K channel closes –> membrane potential becomes more positive –> opening of calcium channels, Ca influx –> exocytosis of insulin containing vesicles) - prototype drug: Glyburide (Micronase, Glynase)
- metabolized by liver to agents with low hypoglycemic potential (CYP2C9); excreted by kidney
- half life 4 hrs; duration 24 hrs
- approved for mono therapy and in combo tablet with metformin
- adverse effects: hypoglycemia, weight gain, CV complications with long term use (KATP channels are found everywhere in the body, esp in the heart)
- contraindicated in pts treated for pulmonary artery HTN with the endothelin receptor antagonist, bosetan, due to elevated liver enzymes
25
Q
Meglitinides
A
- insulin secretagogue
- prototype: Repaglinide (Prandin)
- can bind to sulfonylurea receptor on KATP channels –> insulin secretion
- primarily used for controlling post prandial blood glucose elevation (good for patients with normal fasting glucose but high postprandial glucose) –> take before meals
- pharmacokinetics: well absorbed, fast onset, peak in 1 hr, half life = 1 hr
metabolized by the liver - use with caution in patients with liver dysfunction - adverse effects: risk of hypoglycemia if meal is skipped, weight gain
- can be given mono therapy or with metformin as a combo tablet
26
Q
Biguanide
A
- prototype: Metformin (Glucophage)
- mechanism of action: activates AMPK (AMP activated protein kinase) in the periphery. when AMP levels are high and ATP is low, this enzyme becomes activated, inhibiting processes that use ATP and stimulates processes that produce it
–> decreased gluconeogenesis, enhance glycolysis and ATP production, decreases FA synthesis, increases oxidation of FA (no weight gain, moderate lipid-lowering effect), and translocation of GLUT4 in skeletal muscle - good for obese puts with DM type II because it does not cause weight gain
- lowers fasting glucose levels, NOT post prandial
- can be given as mono therapy or in combo with insulin, sulfonylureas, meglitanides, TZD’s, alpha-glucosidase inhibitors, uncertain mimetic and pramilintide
- no hypoglycemia with mono therapy, although can occur in combo or with alcohol
- pharmacokinetics: rapidly absorbed through the intestine; peak concentrations in 2 hrs
half life is 1.5-3 hrs, excreted unchanged by the kidney
drug interactions: Cimetidine competitively inhibits renal tubular excretion of metformin - adverse effects: GI effects in 20% of patients (dose related and often transient), reduced B12 absorption, contraindicated in patients with renal disease, alcoholism, or tissue anoxia (cardiopulmonary dysfunction) due to risk of lactic acidosis (If you have a situation where there’s tissue anoxia and you’re not moving substrate through the Krebs cycle and ox phos, you divert over to lactate instead of pyruvate during glycolysis. This can lead to lactic acidosis if you’re pushing substrate too quickly through glycolysis which is what metformin can do when it lowers blood gluocse. )
27
Q
Thiazolidinediones (TZDs)
A
- prototype: Pioglitazone (Actos)
- insulin sensitizer: increase glucose uptake and utilization in skeletal muscle and adipocytes; alter differentiation of preadipocytes (shift from visceral metabolically active type to less active subcutaneous type)
- mechanism: unclear; TZDs are ligands for peroxisome proliferator-activated receptor-gamma (PPAR-gamma), which is a nuclear receptor - involved in expression and modulation of insulin responsive genes. Unfortunately, expression is much higher in adipocytes than muscle –> predisposition for weight gain
- TZD’s act right at the site of DM type 2 defect –> may slow the progression of DM type II
- TZD’s = insulin mimetic but not an insulin secretagogue
- no risk of hypoglycemia when given alone
- approved as mono therapy and with metformin
- metabolized by P450
- adverse effects:
hepatotoxicity (periodic liver enzyme monitoring recommended), CV problems, bladder cancer, weight gain, fluid retention, contraindications = liver disease or advanced CHF
