Pharm (lecture focused) Flashcards
Abbreviations used in this section
SE = side effect
Rx = treatment
Corticosteroids - What is the drug that most mimics physiological cortisol?
Hydrocortisone (duration of action: 8-12 hours)
Corticosteroids - What is the drug with the strongest potency?
Dexamethasone (about 25-30x stronger)
Also lasts 3-6x longer (duration of action 36-72 hours)
No mineralocorticoid activity
Corticosteroids - what drug(s) has(have) no mineralocorticoid activity?
Dexamethasone (30x stronger than cortisol)
Triamcinolone (5x stronger)
Corticosteroids - which is used as a replacement for aldosterone?
Fludrocortisone - it has corticosteroid activity, but has much higher affinity for the mineralocorticoid receptors
If you wanted to give a patient something that isn’t as strong as dexamethasone but lasted longer than cortisol, which drug would you use?
Prednisone or prednisolone or any of its derivatives.
They have 4-5x more potency than cortisol and last 12-36 hours (compared to the 8-12 from cortisol and the 36-72 from dexamethasone)
What is an adrenal crisis? Symptoms? What is used to treat it?
Adrenal crisis aka acute adrenal insufficiency
- volume depletion and hypotension (due to combination of loss of aldosterone –> loss of volume and loss of vascular tone due to lack of cortisol)
- hyperkalemia (loss of aldosterone activity)
- hyponatremia (mineralocorticoid deficiency and increased ADH caused by cortisol deficiency)
Treatment
- Do NOT delay while waiting for definitive proof of diagnosis
- Treat with high-dose IV glucocorticoids (ie dexamethasone if no previous dx of adrenal insufficiency)
- Add hydrocortisone until patient stable
- gradual taper to a maintenance dose
Why is hyponatremia seen in adrenal crisis?
Due to 2 reason
- mineralocorticoid deficiency –> loss of Na+ in the tubules
- increased ADH (cortisol has negative feedback on the pituitary secretion of ADH, w/o cortisol –> increased ADH) –> increased volume diluting the low concentration of Na+ –> hyponatremia
Treatment for chronic adrenal insufficiency
Goal is “physiologic” replacement of glucocorticoids and mineralocorticoids
- hydrocortisone (15-20mg) on awakening and 5-10 mg in early afternoon
- fludrocortisone (0.05-0.2mg) orally daily
- liberal salt intake (remember there will be an excessive loss of salts)
“stress-dosing” is needed when a patient is ill
“stress-dosing” situations in patients with adrenal insufficiency
Illness (minor vs major)
emergency treatment of severe stress or trauma
surgeries
21-hydroxylase deficiency treatment
Steroids - usually dexamethasone, prednisone or hydrocortisone
In salt wasting, need fludrocortisone as well
Treat whatever degree of glucocorticoid and mineralocorticoid deficiency exists
Pharmacological treatment of Cushing’s syndrome (6)
- Aminoglutethimide - blocks conversion of cholesterol or pregnenolone (via enzyme P450scc = side chain cleavage)
- Ketoconazole - nonselective inhibitor of adrenal and gonadal steroid synthesis
- Mitotane - nonselective cytotoxic action on adrenal cortex. Bad SE profile
- Metyrapone - relatively selective inhibitor of 11-hydroxylation
- Mifepristone - progesterone receptor antagonist that has glucocorticoid receptor antagonist activity at higher concentration
- Pasireotide - somatostatin analog (blocks release of ACTH from the corticotropes)
Aminoglutethimide
blocks conversion of cholesterol or pregnenolone (via enzyme P450scc aka desmolase)
scc = side chain cleavage
Ketoconazole
nonselective inhibitor of adrenal and gonadal steroid synthesis
most commonly used until recently discovered SE of hepatotoxicity
Mitotane
nonselective cytotoxic action on adrenal cortex.
- toxic to adrenal cells
- most commonly used in adrenal carcinomas where you want to kill a section
Bad SE profile
Metyrapone
relatively selective inhibitor of 11-hydroxylation
Used in to treat and for diagnostic purposes
- If used, should decrease cortisol and corticosterone which should cause a compensatory rise in ACTH
- should also cause an increase in 11-deoxycortisol
Mifepristone
progesterone receptor antagonist that has glucocorticoid receptor antagonist activity at higher concentrations
- More than 3x the binding affinity for the GC receptor than dexamethasone
- no mineralocorticoid activity
Rx:
- to control hyperglycemia secondary to hypercortisolism who have failed or are not cadidates for surgery
- also useful for rapid treatment of cortisol-induced psychosis
SE:
- fatigue
- nausea
- headache
- hypokalemia
- arthralgias
- endometrial thickening in women
- creates generalized glucocorticoid resistance
Pasireotide
Somatostatin analog (agonist) aka GH-inhibiting hormone has a variety of functions:
- Suppresses the release of GI hormone (gastrin, CCK, secretin, motilin, VIP, GIP, enteroglucagon)
- Decreases rate of gastric emptying
- Suppresses the release of pancreatic hormones (inhibits insulin and glucagon release)
- suppresses the exocrine secretory action of pancreas
- blocks release of ACTH from corticotropes via high affinity somatostatin receptor subtype 5
SE:
- hyperglycemia (loss of insulin as stated above)
- GI symptoms (due to suppression of all the GI hormones and delayed gastric emptying)
Function of somatostatin
Suppresses the release of GI hormone (gastrin, CCK, secretin, motilin, VIP, GIP, enteroglucagon)
Decreases rate of gastric emptying
Suppresses the release of pancreatic hormones (inhibits insulin and glucagon release)
suppresses the exocrine secretory action of pancreas
What somatostatin analog is used in treatment of GH adenomas?
Octreotide
SE profile pretty much the same (GI symptoms and hyperglycemia)
Treatment for primary aldosteronism
Surgery
ADH antagonists – spironolactone (has anti-androgenic activity) and eplerenone
Toxicity of corticosteroids
- Insomnia (cortisol usually spike when you wake up and lowest when you sleep. Because its so high, it’s hard to sleep. The lack of sleep ultimately turns into mania resulting in behaviorial symptoms)
- Behaviorial changes (hypomania, acute psychosis)
- acute peptic ulcers (corticosteroids are known to inhibit the biosynthesis of gastric cytoprotective prostaglandins, while suppressing the production of gastric damaging leukotrienes.)
- acute pancreatitis (increased glucose as well as triglycerides mobilization by cortisol can cause excess secretion from the pancreas which increases the likelihood of inflammation)
- all the symptoms associated with Cushings
Why are corticosteroids associated with insomnia? behaviorial changes?
Cortisol usually spikes when you wake up and lowest when you sleep.
Because its so high, it’s hard to sleep. The lack of sleep ultimately turns into mania resulting in behaviorial symptoms
Why are corticosteroids associated with acute peptic ulcers?
corticosteroids are known to inhibit the biosynthesis of gastric cytoprotective prostaglandins
Why are corticosteroids associated with acute pancreatitis?
increased glucose as well as triglycerides mobilization by cortisol can cause excess secretion from the pancreas which increases the likelihood of inflammation
Steps in the synthesis of thyroid hormones
What enzyme(s) catalyze these reactions? Where do these reactions take place?
- (cytoplasm) Trapping (active uptake of iodine via the Na/I+ symporter)
- (cytoplasm) Oxidation of Iodide to iodine (activation)
- (colloid of follicle) Organification (iodide is converted to iodine and then condensed onto tyrosine residues on the polypeptide backbone of thyroglobulin – results in MIT or DIT)
- (colloid of follicle) Coupling (MIT+DIT or DIT+DIT forming T3 or T4)
- (cytoplasm) T3/T4 endocytosed and combined with a lysosome.
- (cytoplasm) Lysosomal enzymes cleave T4 and T3 from thyroglobulin colloid and hormones diffuse from follicle cell into bloodstream.
All the enzymatic reactions are catalyzed by thyroid peroxidase (oxidation, iodination/organification and coupling)!!
What role does thyroid hormone have in embyrological and child development?
Associated with skeletal and neural development via an important role in regulating the expression of genes
- Lack of thyroid hormone will result in short stature and mental status changes (ie retardation, etc…)
Also associated to a lesser degree with liver and heart development,
Synthetic T4
Levothyroxine
Synthetic T3
Liothyronine
What is the preferred thyroid hormone replacement? Why?
T4 (levothyroxine)
Lasts longer. Also avoids the majority of the hyperthyroid effect that may be present if giving T3
Chronic fatigue syndrome
What is it? Treatment?
Trouble converting T4 –> T3
Treat with T3 supplements
Treatment modalities for hyperthyroidism (5)
- Beta blockers (ie propranolol)
- thioamides (PTU, methimazole)
- I131 (irradiate thyroid gland via beta irradiation)
- anions (competitively inhibit the Na/I pump)
- Surgical resection (thryoidectomy)
Thioamides used in the U.S.
PTU (propylthiouracil)
methimazole
Mechanism of action of thioamides
Inhibition of thyroid peroxidase which inhibits:
- the ionization (of iodide)
- organification (attachment to thyroglobulin)
- coupling (formation of T3 and T4)
Major side effect of thioamides
Agranulocytosis
hepatitis
lupus-like syndrome
Which thioamide is used most commonly? why?
Methimazole
More effective. Less side effects (PTU known to cause hepatic toxicity especially in children)
Contraindicated in pregnancies because it has more teratogenic effects on fetus
Which thioamide is used in pregnancy? Why?
PTU
- does not cross (or crosses less) the placenta than methimazole
- methimazole has teratogenic effects
How are thioamides adminstered?
If the patient has thyrotoxicosis, how can the drugs be given?
Normally given orally.
If thyrotoxicosis (excessive hormone in circulation that can be causing some major symptoms), need to bypass the first-pass metabolism
- IV
- rectally (blood vessels in rectum can directly dump into systemics and bypass the liver)
What organs are involved in the synthesis and activation of vitamin D?
- Skin (synthesis occurs in the stratum basale) –> produces cholecalciferol
- Liver (25-hydroxylase) –> produces storage form (calcidiol)
- Kidney (1α-hydroxylase) –> produces active form (calcitriol)
- Gut – responsible for the absorption of vitamin D from foods
Signs and symptoms of hyperparathyroidism
painful bones, renal stones, abdominal groans, and psychiatric moans
- bones – osteitis fibrosa cystica
- stones – nephrolithiasis
- groans – GI disturbances (hypercalcemia-induced ileus)
- moans – or psychiatric depression occur due to persistently elevated serum calcium levels
Treatment for hyperparathyroidism
- Surgery
- bisphosphonates (pamidronate, zoledate, etc…)
- calcimimetics (ie cinacalcet)
Cinacalcet
- Acts as a calcimimetic (i.e. it mimics the action of calcium on tissues) by allosteric activation of the calcium-sensing receptor
- decreases PTH
- Approved for treatment of hyperparathyroidism
Familial hypocalciuric hypercalcemia (FHH)
Autosomal dominant trait
Defect in the calcium sensing receptors in both the kidney and the parathyroid
- Parathyroid can’t sense calcium so thinks there isn’t enough –> increased PTH –> hypercalcemia
- kidney also can’t sense calcium –> increase reabsorption of calcium –> hypocalciuria
Causes of hypercalcemia (besides hyperparathyroidism)
- PTHrP
- local osteolytic factor (multiple myeloma)
- lymphomas that can produce calcitriol
- granulomatous states (production of 1α-hydroxylase from activated macrophages
- FHH
Treatment strategies for hypercalcemia (3)
- expand volume (dilution)
- increase excretion (calcitonin)
- inhibiting resorption (diuretics)
Bisphosphonates
Main 2 that are used: pamidronate and zoledronate
Others: alendronate, risedronate, ibandronate
Inhibits bone resorption via decreasing remodeling space and prolonging mineral acquistion.
SE: esophageal irritation – very irritable drug and if it refluxes up to the LES, it can cause significant irritation (given IV or have patient sitting up and not eat for 30 minutes after taking the drug)
What is the biggest side effect with bisphosphonates? Why?
GI irritation
very irritable drug and if it refluxes up to the LES, it can cause significant irritation (given IV or have patient sitting up and not eat for 30 minutes after taking the drug)
Pharmacological treatments for hypercalcemia (3)
- Bisphosphonates (decreases bone resorption)
- Calcitonin (increases urinary calcium excretion, inhibits bone resorption)
- Corticosteroids (used in hematologic malignancies, granulomatous diseases and Vitamin D intoxication – decreases production of calcitriol)
- Fluids in combination with diuretics
- Dialysis for those w/ renal failure or response to other measures
What is calcitonin used to treat? Why?
- increases urinary calcium excretion (high doses for hypercalcemia)
- inhibits bone resorption (low doses for osteoporosis)
good for acute setting (downregulation of receptors under repeated exposures)
Why is corticosteroids used for hypercalcemia?
used in hematologic malignancies, granulomatous diseases and Vitamin D intoxication
- decreases production of calcitriol
- immune suppression
Why can’t calcitonin be used for long term treatment?
Tachyphylaxis – rapidly diminishing response to successive doses of a drug, rendering it less effective.
- Repeated exposure lead to downregulation of calcitonin receptors
How is magnesium levels associated with PTH levels?
Mg is necessary for PTH to work on target tissues
Hypomagnesemia –> hypoparathyroidism
If you find a patient with hypocalcemia, what other value(s) should you check before doing anything?
Why?
Albumin levels.
Low albumin may result in low calcium values (despite the ionized concentration to be normal)
- when calcium is measured, the lab value is a measure of TOTAL calcium which includes the ionized and the bound. Only the ionized form is active so if albumin is low, the total calcium may be low while the ionized form is still within normal limits.
Most common cause of hypocalcemia
Chronic renal failure
Renal failure –> decreased phosphate excretion –> increased serum phosphate –> increased binding up of calcium by phosphate == hypocalcemia
Treatments for secondary hyperparathyroidism from CRD
- calcitriol or other vit D analogues (CRD results in decreased activation of vit D)
- phosphate binders (sevelamer)
- calcimimetics (cinacalcet) also used
Sevelamer
Phosphate binder
Used to treat secondary hyperparathyroidism (CRD)
Which bisphosphonate(s) is approved for IV use?
Why IV over oral?
Zoledronate. Pamidronate
IV because of GI irritation
Acute phase reaction can occur first 24 hours. Other side effects are rare
Treatments for osteoporosis (4)
SERMs (raloxifene - antagonist for the uterus, agonist for the bone)
Calcitonin - inhibits osteoclast resorption at low doses
teriparatide - PTH analog (only anabolic agent for osteoporosis)
Denosumab - RANK ligand inhibitor
How are SERMs used in treatment for osteoporosis?
Main drug used: Raloxifene
- antagonist of the uterus (can’t take if pregnant)
- agonist of the bone
Estrogen effects:
- increased osteoblast activity
- decreased osteoclast activity
Risks/SE
- increased menopausal symptoms
- increased risk for clots (via increased synthesis of vit K dependent clotting factor)
What is contraindication to using raloxifene? Why?
- Pregnancy. Raloxifene antagonizes the uterus and will prevent endometrial development
Side effects of raloxifene
Increased menopausal symptoms (if of pregnant age –> antagonist of the uterus)
Increased risk for clots
Why is there increased risk for clots associated with SERMs?
Estrogen increases the synthesis of vit K dependent clotting factors producing a hypercoagulable state
Calcitonin - why and how is it used in osteoporosis?
At low doses it causes calcium deposition into the bone via inhibition of osteoclast activity
at high doses, it will increase renal excretion which will actually exacerbate osteoporosis (need to be careful about the dosing)
Can’t use longer than 2 years b/c increased risk of osteoporosis
Teriparatide
- ONLY aproved anabolic agent for osteoporosis
- PTH analog
- PTH normally activate osteoclasts via the activation of osteoblasts. Short bursts of PTH will activate only the osteoblasts without activation of the osteoclasts.
- SEs
- dizziness, palpitations, transient hypercalcemia
- blackbox warning on osteosarcoma in rats
Only approved anabolic agent for osteoporosis
teriparatide
Denosumab
RANK ligand inhibitor –> inhibition of osteoclast activation
RANK-l controls the differentiation, proliferation and survival of osteoblasts
Rank-ligand inhibitor
denosumab
Paget’s disease of the bone
Localized disorder of bone remodeling (as opposed to osteoporosis which is widespread)
- increased osteoclast activity @ one site.
- usually asymptomatic until patient goes in for something else
Osteogenesis imperfecta
Heritable disorder of type I collagen
can cause osteopenia, recurrent fractures, skeletal deformity
can also cause abnormalities of teeth, blue sclerae, ligaments
Why is blue sclera associated with osteogenesis imperfecta?
There is a collagen layer over the lens. If absent, the veins underneath are more pronounced, hence blue sclera.
Biguanides
- Metformin
- decrease hepatic glucose production
- first line treatment (after lifestyle) for T2DM
- SE
- GI – reduce dosage or start lower
- lactic acidosis (rare)
- B12 deficiency
- Contraindications: all has to do with the lactic acidosis
- impaired liver or renal function
Biggest SE of metformin
Lactic acidosis
For this reason, it is contraindicated in renal or hepatic dysfunction (organs responsible for the clearance of lactate)
Contraindication of metformin
why?
liver and renal dysfunction
liver and renal systems involved in the clearance of lactic acid which is a major SE of metformin
Biggest concern with the use of sulfonylureas and meglitinides
Why?
Hypoglycemia
They cause insulin release in an glucose-independent manner
What 2 drugs classes increase insulin in an glucose-independent manner?
What is their mechanism of action?
- Sulfonylureas
- Meglitinides
They work by closing the K/ATPase on β-cell plasma membranes – closure of which decreases the membrane potential (affects the cells ability to depolarize) making it easier to generate action potentions –> easier to release insulin
Sulfonylureas (1st and 2nd gen)
What is the difference between 1st and 2nd gen?
- 1st generation
- chlorpropamide
- tolbutamide
- 2nd generation
- glyburide
- glipizide
1st generation lasts longer but is less potent. 2nd generation lasts shorter, but more potent.
Meglitinides (drugs)
- rapaglinide
- nateglinide
“non-sulfonylurea secretagogues”
GLP-1 analogues (drugs)
- exenatide (twice daily or weekly)
- liraglutide (daily)
- albiglutide (weekly)
- dulaglutide (weekly)
DPP-4 inhibitors (Drugs)
- Sitagliptin
- Alogliptin
- Saxagliptin
- Linagliptin
SGLT2 inhibitors (drugs)
- Canagliflozin
- Dapagliflozin
- Empagliflozin
Think of it as “g” (glucose) flows.
Na/glucose transporters blocked so glucose flows out.
Thiazolidinediones (drugs)
- rosiglitazone
- pioglitazone
What is the major issue when prescribing thiazolidinediones?
How does this affect prescribing this class?
thiazolidinediones activaties PPAR-γ. Because this is gene transcription, it takes weeks to months for the effect to come about
Due to this, this class is never prescribed by itself, always have to give something other drug as short term to carry the patient over until the drug starts to take effect
Thiazolidinediones (mechanism)
Pioglitazone and rosiglitazone
Activates the nuclear transcription factor PPAR-γ –> increases peripheral insulin sensitivity
Sulfonylureas (mechanism of action)
Closes KATP channels on beta-cells plasma membranes
- increases insulin secretion from beta cells (glucose-independent)
Meglitinides (mechanism)
Closes KATP channels on beta-cells plasma membranes
- increases insulin secretion from beta cells (glucose-independent)
Same as sulfonylureas (non-sulfonylurea secretagogues)
Advantages/disadvantages to using thiazolidinediones
Advantages
- no hypoglycemia
Disadvantages
- edema (contraindicated in patients with heart disease)
- takes forever (weeks to months) to take effect
This class is almost never used anymore
α-glucosidase inhibitors (drugs)
- acarbose
- meglitol
α-glucosidase inhibitors (mechanism)
inhibits intestinal α-glucosidase –> inhibits breakdown of carbohydrates and slows down digestion
Biggest SE of using α-glucosidase inhibitors
Inhibition of carbohydrate breakdown results in the carbohydrates being digested by bacteria in the gut resulting in flatulence and osmotic diarrhea
diabetic drugs classes that release insulin in a glucose-dependent manner
GLP-1 analogues and DPP-4 inhibitors
Only drug class for T2DM that can cause weight reduction
GLP-1 analogues
Noninsulin therapies for hyperglycemia
- SGLT2
- Bile acid sequestrants (Colesevelam)
If someone is severely hypoglycemic, what is the treatment at home? In the hospital?
Home: glucagon (IM) + oral glucose/sugar
Hospital: IV dextrose + glucagon (IV)
Amylin
Secreted by beta cells (yes same cells that secret insulin)
Mech: slows gastric emptying, suppresses glucagon secretion, may reduce appetite
Pramlintide
Amylin analog
inject before each meal along w/ insulin
effectiveness is questionable. Overall function is to decrease glucagon secretion –> decrease glucose
Rapid acting insulin analogs (3)
There is no LAG in rapid acting insulins
- Lispro
- Aspart
- Glulisine
Long acting insulin analogs
Detemir, Glargine
