Pharm Flashcards
1
Q
A T-score < __ = osteoporosis
A
T-score < -2.5 = osteoporosis
2
Q
In terms of calcium supplements, which supplement needs acid to dissolve and for absorption? (must be taken “at” or “after meals”)
A
Calcium carbonate
3
Q
Which calcium supplement may be taken between meals? (no need for stomach acid for absorption)
A
Calcium citrate
4
Q
Glucocorticoids indicated for severe inflammation, asthma, COPD, bronchitis, ulcerative colitis, etc: (2)
A
Prednisone
Methylpredisolone
5
Q
Inhaled glucocorticoid indicated for asthma or COPD:
A
Budesonide
6
Q
Main adverse effect of glucocorticoids in terms of vitamin D absorption:
A
Impairs vitamin D absorption and impairs metabolic activation in liver and kidney.
7
Q
Anticonvulsants indicated for epileptic seizures: (2)
A
Carbamazepine
Phenytoin
8
Q
Main adverse effect of anticonvulsants in terms of cyp450 and vitamin D:
A
Induction of cyp450 hepatic inactivation of vitamin D
9
Q
Loop diuretic indicated for HTN and HF:
A
Furosemide
10
Q
Adverse effect assoc with furosemide administration in terms of Ca2+:
A
Ca2+ wasting
11
Q
List 2 SERMs in anti-resorptive therapy.
A
Raloxifene
Tamoxifen
12
Q
What is the suffix for bisphosphonates (anti-resorptive therapy)?
A
“-dronate”
E.g., alendronate, pamidronate, etc.
13
Q
What is the only anabolic therapy (activates osteoblasts) available for osteoporosis?
A
Teriparatide
14
Q
Osteopenia is characterized by what T-score range?
A
-2.5 to -1
15
Q
T/F: Women are more likely to reach fracture threshold earlier in life with inadequate Ca2+ and vitamin D.
A
TRUE
16
Q
Explain what happens in an estrogen deficit in terms of the bone resorption and bone formation balance.
A
With an estrogen deficit you see less osteoclasts undergoing apoptosis and more osteoblasts undergoing apoptosis. The result is less bone formation.
17
Q
What are the risks assoc with estrogen replacement therapy?
A
- Breast cancer
- Uterine cancer
- Heart attack
- Stroke
- Thrombosis
18
Q
Front-line SERM used in the prevention and treatment of osteoporosis in postmenopausal women:
A
Raloxifene
Raloxifene is usually chosen for osteoporosis prevention when there is an independent need for breast cancer prophylaxis.
19
Q
Estrogens and SERMS are agonists at estrogen receptors (ER) in:
A
Osteoclasts
20
Q
SERMS are antagonists at estrogen receptors (ER) in:
A
Breast epithelium
21
Q
What is the main risk assoc with use of tamoxifen?
A
Increased uterine bleeding and uterine cancer.
Tamoxifen is a partial agonist in endometrium, which increases the risk of endometrial cancer; “hot flashes.”
22
Q
HRT estrogens, raloxifene, and tamoxifen all increase the risk of:
A
Venous thromboembolic events (MI, stroke)
23
Q
- Approved for tx or prevention of osteoporosis
- Pyrophosphate analogs that bind to the hydroxyapatite crystals in bone and inhibit osteoclasts
A
Bisphosphonates
24
Q
What is the enzyme inhibited by bisphosphonates (BPs)?
What is the result is this inhibition?
A
Farnesyl pyrophosphate synthase (FPP synthase)
Inability to produce prenylated G proteins (proteins that are not prenylated undergo cell death)
25
What is a contraindication of all bisphosphonates?
Pre-existing hypocalcemia
26
What are the adverse effects assoc w oral bisphosphonates?
Esophagitis and esophageal ulcer
I.e., cannot lie down for at 30 min after taking medication
27
What are the benefits of zoledronate?
i.v. injection once/year
Highest affinity for bone
Highest potency (greatest inhibition of FPP synthase)
28
Rare but serious complication of bisphosphonate administration:
Osteonecrosis of the jaw
Especially in those receiving i.v. bisphosphonates (90%), diagnosed with mult myeloma, breast cancer, and prostate cancer (85%), or having tooth extractions/dental trauma (60&).
29
Monoclonal antibody indicated for osteoporosis by inhibiting osteoclast maturation (mimics osteoprotegerin):
Denosumab
"denOSumab affects OSteoclasts"
30
What does denosumab bind to and how does it work?
Denosumab is an Ab against RANKL (an osteoclast differentiating factor) on osteoblasts, which prevents the communication between osteoclasts and osteoblasts.
31
- Anti-resorptive hormone used to inhibit osteoclast action
| - Decreases pain with acute vertebral compression fracture
Calcitonin
32
What is the risk assoc with teriparatide?
Osteosarcoma
33
Indicated for:
- Tx of postmenopausal women with osteoporosis at *high risk* for fracture
- Increase bone mass in men with primary or hypogonadal osteoporosis at *high risk* for fracture
- Tx of men and women with osteoporosis assoc w sustained, systemic glucocorticoid therapy at *high risk* for fracture
Teriparatide
34
Receptors:
- ß-adrenergic
- FSH, LSH, ACTH, TSH
- PTH, PTHrP
- GHRH, CRH
- Glucagon
What is the main effector molecule?
What is the primary signaling pathway? (what is stimulated?)
Effectors:
Ga(s) >>>>>> Ca2+ channels
Signaling pathway:
Stimulation of cAMP >>>>>>>>> Calmodulin, Ca2+-dependent kinases
35
Receptors:
- a-adrenergic
- Somatostatin
What is the main effector molecule?
What is the primary signaling pathway? (what is inhibited and activated?)
Effector:
-Ga(i)
Signaling pathway:
- Inhibition of cAMP production
- Activation of K+, Ca2+ channels
36
Receptors:
- TRH
- GnRH
What is the main effector molecule?
What is the primary signaling pathway?
Effectors:
- Ga(q)
- Ga(11)
Signaling pathway:
-Phospholipase C, DAG, IP3, protein kinase C, voltage-gated Ca2+ channels
37
Receptor tyrosine kinase:
-Insulin
List the effectors.
List the signaling pathways.
Effectors:
-Tyrosine kinases, IRS-1 to IRS-4
Signaling pathways:
- MAP kinases
- PI 3-kinase
- RSK
38
Cytokine receptor-linked kinase:
- GH
- Prolactin
List the 2 effectors.
List the signaling pathways.
Effectors:
- JAK
- Tyrosine kinases
Signaling pathways:
- STAT
- MAP kinase
- PI 3-kinase
- IRS-1, IRS-2
39
Serine kinase:
-TGF-ß
List the effector.
List the signaling pathway.
Effector:
-Serine kinase
Signaling pathway:
-Smads
40
Main effector of Ga(s):
Stimulates adenylyl cyclase >> increased cAMP formation
41
Main effector of Ga(i):
Inhibits adenylyl cyclase >> decreases cAMP formation; opens cardiac K+ channels >> decrease HR
42
Main effector of Ga(q):
Activates phospholipase C >> increase production of IP3, diacylglycerol, and cytoplasmic Ca2+
43
Main effectors of Gß(g):
Same as for Ga subunits; also activates K+ channels, inhibit voltage-gated Ca2+ channels, activate GPCR kinases, activate mitogen-activated protein (MAP) kinase cascade
44
- Mixture of recombinant human IGF-1 and recombinant human IGFBP-3 >> increases the HL of recombinant IGF-1
- Used in the treatment of growth failure in children
- MC adverse effect = hypoglycemia
Mecasermin
45
- Somatostatin analogs used in the treatment of anterior pituitary adenomas that secrete GH (acromegaly/gigantism)
- More potent than somatostatin in inhibiting GH and insulin secretion
- Adverse effects: N/V, GI (steatorrhea, gallstones) and cardiac effects (sinus bradycardia, conduction disturbances)
Octreotide
| Ianreotide
46
- GH receptor antagonist used in the treatment of anterior pituitary adenomas that secrete GH (acromegaly/gigantism)
- Inhibits signal transduction
Pegvisomant
47
- Used in the treatment of hyperprolactinemia
- MOA: Dopamine D2 agonists (coupled to Ga(i/o), which inhibits adenylyl cyclase and decreases cAMP)
- Dopamine acts on lactotroph D2 receptors to decrease prolactin secretion
Bromocriptine
| Cabergoline
48
- Hormone that stimulates uterine contraction and elicits milk ejection in lactating women
- Administered intravenously for initiation and augmentation of labor and intramuscularly for control of postpartum bleeding
Oxytocin
49
Peptide hormone released in response to rising plasma tonicity or falling blood pressure; antidiuretic and vasopressor properties...
Where are V1 receptors located and what is their role?
Where are V2 receptors located and what is their role?
What about extrarenal V2-like receptors?
Vasopressin (ADH)
V1 receptors – found on vascular SM cells and mediate vasoconstriction
V2 receptors – found on renal tubule cells and reduce diuresis through increased water permeability and water resorption in the collecting tubules
Extrarenal V2-like receptors regulate the release of coagulation factor VIII and von Willebrand factor
50
- Long-acting synthetic analog of vasopressin with more V2 receptor activity
- Used to treat pituitary (central) diabetes insipidus, hemophilia A, von Willebrand dz
- Use in caution in pts with CAD due to vasoconstriction
Desmopressin
51
- Vasopressin antagonists
- MOA: antagonism of the V2 receptor promotes the excretion of free water (without loss of serum electrolytes) >> net fluid loss, increased urine output, decreased urine osmolality, and subsequent restoration of normal serum sodium levels
- Used in the treatment of euvolemic and hypervolemic hyponatremia (CHF and SIADH)
Conivaptan (V1 and V2 receptors)
| Tolvaptan (V2 receptors)
52
Thyroid receptors are comparable to nuclear receptors.
T4 has a half life of 7 days and T3 has a half life of 1 day.
Which has a higher affinity?
T3
53
T4 is a prohormone and is converted to T3 by deiodinases. Without T3, transcription is repressed.
T3 travels to the nucleus and binds to TR (thyroid R) and then forms a ________ with RXR (retinoid x R).
The DNA binding domain then binds to the TRE (thryroid response element) in the nucleus leading to transcription
What is the RXR ligand?
Heterodimer
9-cis-retinoic acid (active)
54
Which thyroid receptor subtype specifically regulates lipid and cholesterol metabolism?
B1
55
TQ
Which thyroid receptor subtype is expressed in the hypothalamus, anterior pituitary, and the developing ear & regulates T3's negative feedback inhibition of TRH and TSH?
B2
| if bound is a repressor
56
What effect does thyroid hormone have on growth and development?
Critical role in brain development
Absence of thyroid hormones during the first 6 mo of life leads to irreversible mental retardation and dwarfism (cretinism)
notes:
• Disturbed neuronal migration
• Deranged axonal projections
• Decreased synaptogenesis
Screening of newborn infants in U.S.!

57
What effect does thyroid hormone have on cardiovascular function?
- Incr expression of Funny current channel subunits in pacemaker cells → increased heart rate
- Modulate MHC isoforms (β → α) → enhanced velocity of contraction
- Incr expression of SR Ca2+-ATPase → increased velocity of relaxation
- Incr expression of SR Ca2+ release (ryanodine) channel → increased rate of Ca2+ release and cardiac contractility
- Increased peripheral vasodilation and reduced PVR
- Enhance effects of sympathetic NS on the heart via incr adrenergic receptors and signal transduction intermediates
58
Pt presents w/...dx?
- Sinus tachycardia
- Increased cardiac output
- Cardiac hypertrophy
- *Decreased PVR and increased pulse pressure
- Commonly exhibit atrial fibrillation and ventricular arrhythmias
Hyperthyroid
59
Pt presents w/...dx?
- *Bradycardia
- Decreased cardiac output
- Pericardial effusion
- *Increased PVR
- Elevated mean arterial pressure and decreased pulse pressure
- *Development of myxedematous cardiomyopathy & HF
Hypothyroid
60
What effect does thyroid hormone have on metabolic rate and thermogenesis?
- Necessary for both obligatory and adaptive thermogenesis
- Increase basal metabolic rate, O2 consumption, and the rate of ATP hydrolysis-->heat
- Incr Ca2+-ATPase in SR of skeletal muscle and Ca2+ release-Ca2+ uptake cycling
- Metabolic “futile cycling” (glycolysis/gluconeogenesis, lipolysis/lipogenesis)
- Expression of uncoupling proteins to dissipate mitochondrial proton gradient (adaptive-->heat)
- Make metabolic processes less thermodynamically efficient for the sake of producing heat
61
What effect does thyroid hormone have on carbohydrate metabolism?
- Enhance carbohydrate absorption in GI tract
- Stimulate glycogen breakdown
- Stimulate gluconeogenesis
- Compensatory increase in insulin release=hyperinsulinemia
- May lead to insulin-resistance
- Incr insulin-dependent transport of glucose into cells
- Patients on insulin will need an incr dose of insulin if treated with thyroid hormone preparations
62
What effect does thyroid hormone have on lipid metabolism?
- Incr appetite
- Incr lipolysis
- Incr plasma free fatty acids
- Incr mitochondria size and number
- Incr β-oxidation of fatty acids
- Incr conversion of cholesterol to bile acids and bile acid secretion
- Incr LDL receptors by hepatocytes
- Decr blood LDL cholesterol and total cholesterol
63
Hyperthyroid patients have increased appetite but no weight gain
Plasma LDL and cholesterol levels are inversely proportional to T3/T4 levels
So can we use thyroid hormone preparations as anti-obesity drugs?
No, other than hypothyroid pts
- Euthyroid=ineffective for weight reduction
- Higher doses may produce serious or even life- threatening manifestations of cardiovascular toxicity and behavioral abnormalities
64
Cardiovascular effects of thyroid hormones are predominantly due to the stimulation of which thyroid receptor?
If we wanted to make an anti-obesity drug, which receptor would we want to selectively stimulate?
- Cardiovascular effects due to TRα1
- Effects of T3/T4 on the liver are mediated predominantly by TRβ1
Selective agonists at TRβ1 would potentially treat obesity and hypercholestrolemia!
-No cardiac side effects
- Decreased plasma LDL and cholesterol
- Reduced weight gain
65
```
Drug class?
Synthetic
-Levothyroxine (Synthroid)
-Liothyronine (Cytomel)
-Liotrix(Thyrolar)
Animal origin
-Desiccated thyroid
```
Synthetic thyroid hormone for hypothyroid pts
66
- Synthetic T4 for oral and parenteral use
- L-Thyroxine stereoisomer
- Needs conversion to T3 by tissue deiodinases
- Delayed onset compared with a T3 preparation
- Lower cost
- Long half-life (7 days) permitting once a day dosing
- Less side effects as compared to a T3 preparation
SE:
- Cardiovascular: tachycardia, arrhythmias
- CNS: anxiety, insomnia
- Metabolic: weight loss, hyperthermia, diarrhea
What are the indications for the drug described above?
Levothyroxine
- Replacement therapy in hypothyroid patients
- Suppression therapy in euthyroid patients with thyroid nodules or goiter (may achieve the regression of the disease)...if give more thyroid then block TSH-->less thyroid produced
67
Drugs that impaired absorption of levothyroxine, leading to incr dosage?
-Aluminum-containing antacids
-Bile acid sequestrants (cholestyramine,
colestipol, colesevelam)
-Phosphate binders (lanthanum carbonate, sevelamer)
-Proton pump inhibitors
-Raloxifene
-Sucralfate
68
Which two B-blockers impair thyroxine T4 → T3 conversion, leading to an incr in dose?
- Amiodarone
| - *Propranolol
69
Drugs that incr metabolism of levothyroxine via CYP3A4, leading to incr dosage?
- Carbamapzepine
- Phenytoin
- Rifampin
- Sertraline
70
Drugs in which the mechanism is uncertain or multifactorial, leading to incr dosage of levothyroxine?
- Estrogen, tamoxifen
- Ethionamide
- Tyrosine kinase inhibitors (imatinib, sorafenib, sunitinib)
- Statins (Lovastatin, simvastatin)
71
Drugs that decr thyroid binding globulin (TBG) or displacement of T3/T4 from TBG leading to decr dosage of levothyroxine?
- Androgen therapy in women
- Corticosteroids
- *Salicylates
- Mefenamic acid
- Furosemide
72
- Synthetic T3 preparation
- More expensive than Levothyroxine
- Shorter half-life (24 h) requires multiple daily dosing
- Rapid onset of effects
- 3 to 4 times as potent compared with Levothyroxine
Adverse effects
- Increased risk for cardiovascular toxicity
- Contraindicated in patients with cardiac disease
Clinical use of the drugs described?
Liothyronine
- Only used for acute insufficiency
- Myxedematous coma (i.v. infusion)
73
If a hyperthyroid pt is taking warfarin (anticoag), how will its dose be adjusted and why? What if pt is hypothyroid?
Warfarin's effects are increased if the pt is hyperthyroid, so must DECR the dosage
If hypothyroid, the effects of warfarin are dec so must increase its dose
74
If a hyperthyroid pt is taking insulin, digoxin, sedatives (benzo), or analgesics (opiates), how will those drugs dose be adjusted and why? What if pt is hypothyroid?
These drugs' effects are DECREASED if the pt is hyperthyroid, so the dosage must be INCREASED.
If hypothyroid, the effects of the drugs are incr so must decrease the dose
75
- Tx of hyperthyroid disorders
- MOA: Inhibition of thyroid peroxidase (TPO) so that I- remains inactivated and unable to bind to tyrosine residues-->
- ↓ Thyroglobulin iodination
- Inhibit iodotyrosine coupling reactions
- Depletes T3/T4 after weeks of continued use
AE of the drugs described?
Thioamides:
- Propylthiouracil
- Methimazole
Propylthiouracil also inhibits the peripheral T4 → T3 deiodination (Methimazole does not, only affects thyroid)
AE:
- Early in therapy: nausea, GI distress
- Macropapular rash
- Pregnancy Category D (cause fetal hypothyroidism)
- Hepatotoxicity
- Agranulocytosis
76
Due to its higher potency, higher bioavail, 0% protein binding, longer HL, and less severe liver damage, ________ (a thioamide) is the DOC in adults and children with hyperthyroid.
Methimazole
77
Hyperthyroid pts with any of the following are treated with which drug?
- During the first trimester of pregnancy
- In thyroid storm
- In those experiencing adverse effects with Methimazole
Propylthiouracil
78
Which non-ISA β-blockers are used to tx hyperthyroid pts ?
- Propranolol
- Metoprolol
- Atenolol
- Esmolol
79
MOA of B-blockers in hyperthyroid pts in severe thyrotoxicosis or thyroid storm (aka thyrotoxic crisis)?
- Block the effects of increased sympathetic activation (ONLY tremor, tachy, arrhythmia, sweating NOT wt loss, exopthalmos, or goiter)
- Do not change the production or release of T3/T4
- Do not inhibit the T4 →T3 conversion (except for Propranolol, which inhibits deiodinases when present at high concentrations)
80
MOA and clinical use of potassium iodide (KI) in tx of hyperthyroid disorders?
- inhibit hormone release through inhibition of thyroglobulin proteolysis-->rapid improvement in thyrotoxic symptoms in thyroid storm
- decr size, vascularity, and fragility of hyperplastic gland (good for preop)
81
Interactions of potassium iodide (KI)?
- May delay tx of radioactive iodine if used with thiazimide. Start after thiazamide tx
- Dont use alone because gland will escape form iodide block in 2-8 wks and withdrawal may exacerbate thyrotoxicosis in iodine-enriched gland
- Avoid in preg (fetal goiter...crosses placenta)
- Protects gland in radioactive iodine tx (prophylaxis)
82
Describe the mechanism of action and clinical use of Radioactive iodine (131 I sodium salt (Iodotope))
- Tx of thyrotoxicosis!
- Given orally as Na 131 I and absorbed by thryroid
- Incorporated into storage follicles
- Destructs thyroid parenchyma
- Easy admin, effective, cheap, no pain
- NOT in preg women or nursing mothers because could destroy fetal thyroid gland
83
A 65-year-old man is referred to you from his primary care physician (PCP) for evaluation and management of possible osteoporosis. He saw his PCP for evaluation of low back pain. X-rays of the spine showed some degenerative changes in the lumbar spine plus several wedge deformities in the thoracic spine. The patient is a long-time smoker (up to two packs per day) and has two to four glasses of wine with dinner, more on the weekends. He has chronic bronchitis, presumably from smoking, and has been treated many times with oral prednisone for exacerbations of bronchitis. He is currently on 10 mg/d prednisone. Examination shows kyphosis of the thoracic spine, with some tenderness to fist percussion over the thoracic spine. The DEXA (dual-energy X-ray absorptiometry) measurement of the lumbar spine is "within the normal limits," but the radiologist noted that the reading may be misleading because of degenerative changes. The hip measurement shows a T score (number of standard deviations by which the patient's measured bone density differs from that of a normal young adult) in the femoral neck of –2.2. What further workup should be considered, and what therapy should be initiated?
Reasons for this patient's osteoporosis include: -Heavy smoking history, possible alcoholism, and chronic inflammatory disease treated with glucocorticoids.
- High levels of cytokines from the chronic inflammation activate osteoclasts.
- Glucocorticoids increase urinary losses of calcium, suppress bone formation, and inhibit intestinal calcium absorption as well as decreasing gonadotropin production, leading to hypogonadism.
- Management should include measurement of serum testosterone, serum calcium, and the 24-hour urine calcium level, with treatment as appropriate for these secondary causes, plus initiation of bisphosphonate or denosumab therapy as primary treatment.
84
What is the principal application of thiazides in the treatment of bone mineral disorders?
Reducing renal calcium excretion
85
Thiazides may increase the effectiveness of which hormone? What is the mechanism?
PTH
- Stimulates reabsorption of calcium by the renal tubules
- Acts on calcium reabsorption secondarily by increasing sodium reabsorption in the proximal tubule
- In the distal tubule, block sodium reabsorption at the luminal surface-->incr calcium-sodium exchange at the basolateral membrane-->incr calcium reabsorption into the blood at this site
86
Thiazides have proved to be useful in reducing the hypercalciuria and incidence of urinary stone formation in subjects with idiopathic hypercalciuria.
Part of their efficacy in reducing stone formation may lie in their ability to do what?
- Decrease urine oxalate excretion
- Increase urine magnesium and zinc levels
(both inhibit calcium oxalate stone formation)
87
In hypercalcemia of sufficient severity to produce symptoms, rapid reduction of serum calcium is required. First step is rehydration with saline and diuresis with furosemide.
In saline diuresis of a hypercalcemic pt, the addition of a loop diuretic such as furosemide following rehydration does what?
Enhances urine flow and also inhibits calcium reabsorption in the ascending limb of the loop of Henle
88
- alter bone mineral homeostasis by antagonizing vitamin D-stimulated intestinal calcium transport, stimulating renal calcium excretion, and blocking bone formation
- useful in reversing the hypercalcemia associated with lymphomas and granulomatous diseases such as sarcoidosis (in which unregulated ectopic production of 1,25[OH]2D occurs) or in cases of vitamin D intoxication
- Prolonged administration is a common cause of osteoporosis in adults and can cause stunted skeletal development in children
Glucocorticoids
89
- prevent accelerated bone loss during the immediate postmenopausal period and at least transiently increase bone in postmenopausal women.
- Reduce the bone-resorbing action of PTH
- Leads to an increased 1,25(OH)2D level in blood. May result from decreased serum calcium and phosphate and increased PTH.
- Direct effects on bone remodeling.
- Treatment or prevention of postmenopausal osteoporosis.
- However, long-term use has fallen out of favor due to concern about adverse effects.
- Selective estrogen receptor modulators (SERMs) have been developed to retain the beneficial effects on bone while minimizing deleterious effects on breast, uterus, and the cardiovascular system
Estrogen
90
- The first of the selective estrogen receptor modulators (SERMs) to be approved for the prevention of osteoporosis.
- Shares some of the beneficial effects of estrogen on bone without increasing the risk of breast or endometrial cancer (it may actually reduce the risk of breast cancer).
- Although not as effective as estrogen in increasing bone density, has been shown to reduce vertebral fractures.
Raloxifene
91
- Increase bone density and reduce fractures over at least 5 years
- analog of pyrophosphate
- poorly absorbed and must be given on an empty stomach or infused intravenously
- treatment of hypercalcemia associated with malignancy, Paget's disease, and for osteoporosis
- at the higher oral doses used in the treatment of Paget's disease, causes gastric irritation, but this is not a significant problem at the doses recommended for osteoporosis when patients are instructed to take the drug with a glass of water and remain upright
- osteonecrosis of the jaw is another risk
- ability to retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system
- inhibit farnesyl pyrophosphate synthase, an enzyme in the mevalonate pathway that appears to be critical for osteoclast survival
Bisphosphonates:
- Alendronate
- Risedronate
- Ibandronate
92
- human monoclonal antibody directed against RANKL, and is very effective in inhibiting osteoclastogenesis and activity
- given subcutaneously every 6 mo
- risk of infection and less bone turnover (osteonecrosis of the jaw)
Denosumab
93
- recombinant form of PTH 1-34, directly stimulates bone formation
- must be given daily by subcutaneous injection. -efficacy in preventing fractures appears to be similar to bisphosphonates. In all cases, adequate intake of calcium and vitamin D needs to be maintained.
Teriparatide
94
- activates the calcium-sensing receptor (CaSR)in the parathyroid gland--> inhibits PTH secretion
- Treatment of secondary hyperparathyroidism in chronic kidney disease and for the treatment of parathyroid carcinoma.
- CaSR Antagonists are also being developed, and may be useful in conditions of hypoparathyroidism or as a means to stimulate intermittent PTH secretion in the treatment of osteoporosis
Cinacalcet (calcinmimetic)
95
T/F:
| Glucocorticoids have no clear role in the immediate treatment of hypercalcemia
TRUE
However, the chronic hypercalcemia of sarcoidosis, vitamin D intoxication, and certain cancers may respond within several days to glucocorticoid therapy
Reduces sarcoid tissue: the hypercalcemia of sarcoidosis is secondary to increased production of 1,25(OH)2D
Reduces vitamin D-mediated intestinal calcium transport: treatment of hypervitaminosis D
Lytic action decreases tumor mass/activity and inhibits cytokines of osteoclastic cancers: tx of malignancies (ie, multiple myeloma and related lymphoproliferative diseases)
96
What are the major sequelae of chronic kidney disease that impact bone mineral homeostasis?
- Deficient 1,25(OH)2D production
- Retention of phosphate with an associated reduction in ionized calcium levels
- Secondary hyperparathyroidism that results from the parathyroid gland response to lowered serum ionized calcium and low 1,25(OH)2D
(With impaired 1,25(OH)2D production, less calcium is absorbed from the intestine and less bone is resorbed under the influence of PTH. As a result hypocalcemia usually develops, furthering the development of secondary hyperparathyroidism)
97
The most common cause of hypercalcemia is the development of what? In such cases, the
Serum alkaline phosphatase levels tend to be high.
Severe secondary hyperparathyroidism (high PTH) (ex: chronic kidney dz)
Treatment often requires parathyroidectomy.
98
In the absence of kidney function (CKD), any calcium absorbed from the intestine accumulates in the blood. Such patients are very sensitive to the hypercalcemic action of 1,25(OH)2D.
These individuals generally have a high serum calcium but nearly normal alkaline phosphatase and PTH levels.
The bone in such patients may have a high aluminum content, especially in the mineralization front, which blocks normal bone mineralization.
These patients do not respond favorably to parathyroidectomy. Deferoxamine, an agent used to chelate iron, also binds aluminum and is being used to treat this disorder.
adynamic bone disease
99
How do the B cells of the pancreas regulate of insulin secretion?
```
Glucose into B cell via GLUT2-->
Incr ATP-->
ATP inhibits K+channel-->
Depolarizes cell-->
Activate Gs-GPCR-->
Incr AC-->incr cAMP-->PKA-->
Activates VDCC (Ca channel)-->
Incr Ca allows for exocytosis of insulin
```
100
TQ
Glucose, energy substrates, and GPCR-Gs ligands lead to an increase in insulin release within B cells.
What are some examples of the Gs ligands that lead to incr insulin release?
- β2-AR agonists (isoproterenol)
- Incretins (GLP-1 receptor agonists)
- Glucagon
101
TQ
B-blockers, L-type Ca channel blockers (verapamil), and GPCR-Gi ligands all lead to a decr in insulin release.
What are some examples of the Gi ligands that lead to decr insulin release?
- α2-AR agonists (clonidine)
| - Somatostatin
102
Insulin effects metabolism primarily through what pathway?
What about gene expression?
Metabolic effects: Akt pathways
Gene expression: MAP kinases
103
Insulin effects on gene expression:
ETS family of TF:
MEK-->ERK-->Incr ____-->
Cell growth, diff, prolif, survival
AP-1 TF:
Incr JNK-->Incr AP1-->
Cell growth, diff, prolif, apoptosis
```
Forkhead family TF (FOXO1):
Akt-->DECR FoxO1-->
Incr _____ expression & lipogenesis
Decr glycogenolysis, gluconeogenesis
Cell diff and incr prolif
```
ELK1
PPAR-γ
104
Insulin effects on metabolism:
Akt-->GLUT4 (skeletal m. , cardiac myocytes, adipocytes)
Activation of glycolysis
- Incr hexokinases, PFK, PK
- Glycogen synthase
- Inhibition of gluconeogenesis
- Inhibition of glycogenolysis
Inhibition of lipolysis and enhanced lipogensis
Incr protein synthesis via...
Akt-->incr ____-->incr ribosomes-->incr mRNA
Mammalian target of rapamycin (mTOR)
105
TQ
| What are the 3 rapid acting insulin meds?
Aspart (Novolog)
Lispro (Humalog)
Glulisine (Apidra)
106
TQ
| What is the short-acting insulin med?
Regular insulin (Humulin R, Novolin R)
107
TQ
| What is the intermediate-acting insulin?
NPH (Humulin N, Novolin N)
NPH: neutral protamine hagerdorn
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What are the 2 long-acting insulins?
Detemir (Levemir)
| Glargine (Lantus)
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How do insulin medications differ from each other?
Pharmacokinetics
mutations/modifications of native insulins
110
TQ
Which drug?
-Mutations from human sequence blocks assembly of dimers and hexamers-->faster absorption
-Clinical use: postprandial hyperglycemia – taken before the meal
-Onset: 5‐10min
-Duration: 1‐3 hr
-Peak: 30 min‐1 hr
Rapid-acting:
| Aspart, Lispro, Glulisine
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```
TQ
Which drug?
-Unmodified zinc insulin crystals
-Slow absorption rate: form hexamers, which are too bulky to be transported via endothelium into the bloodstream
-Clinical use:
– Basal insulin maintenance
– Overnight coverage
– Postprandial hyperglycemia – inject 45min before the meal
-Onset: 30 min‐1 hr
-Duration: 10 hr
-Peak: 3‐5 hr
```
```
Short‐Acting:
Regular Insulin (Humulin R, Novolin R)
```
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TQ
Which drug?
-Complex of protamine with zinc insulin
-Protamine has to be digested by tissue proteolytic enzymes before insulin can be absorbed
-Clinicial use:
– Basal insulin maintenance and/or overnight coverage
– Use is declining – are being replaced by long- acting insulins
-Onset: 1‐2hr
-Duration: 10-12 hr
-Peak: 4‐12 hr
Intermediate-acting:
-NPH (Neutral Protamine Hagerdorn) preparations
(Humulin N, Novolin N)
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Which drug?
Lys 29 in B chain is myristoylated (lipid, lipophilic)
(rapidly absorbed into blood but binds strongly to albumin)
Long-acting:
Detemir
since attaches to albumin, longer duration b/c takes awhile to degrade and distribute
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Which drug?
AA substitution enhance crystal stability-->
Change pKa of insulin – soluble at low pH (4) but precipitates at pH 7
Long-acting:
Glargine
Precipitates in body so works longer
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What do we use long-acting insulins Detemir and Glargine for?
Basal insulin maintenance
1-2 injections per day
- Onset: 3‐4hr
- Duration: 24 hr
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What are the benefits to using a mixture of insulins?
Rapid + intermediate
- Humulin N + Lispro = Humalog
- Novolin N + Aspart = Novalog
Short + intermediate
- Humulin N + Regular = Humulin
- Novolin N + Regular = Novolin
Mixtures give the quicker onset of rapid- or short- acting insulin, plus the longer duration of NPH
CANT MIX LONG!
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Clinical indications for insulin include T1 and T2 DM, gestational DM, and severe hyperkalemia.
Why do we use insulin to tx hyperkalemia? What is the MOA?
- Insulin + glucose (to prevent hypoglycemic shock) + furosemide
- Insulin (i.v.) rapidly activates Na/K-ATPase to shift K+ from extracellular fluid into cells
- Effect is transient (several hours)
- K+ is eliminated from the body using loop diuretics in the meantime
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Name some common insulin delivery systems?
What are the insulin delivery systems "of the future"?
- SC injections
- Portable pen injectors
- Insulin pumps: continuous SC infusion
Future:
- Bionic pancreas (continous, microchip control, insulin pump that admin insulin AND glucagon, registers HR)
- productionof pancreatic beta cells from human ES or iPS cells → transplantation of engineered tissue
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Adverse effects of insulin?
- Hypoglycemia
- Lipodistrophy (incr lipogenesis): hypertrophy of SC fat at injection site)
- Resistance: IgG ab can neutralize insulin actions
- Allergic rxs: Immediate hypersensitivity rxns via anti-insulin IgE ab-->histamine from mast cells
- Hypokalemia (transport of K from extracellular fluid into cells)
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What are some common causes of hypoglycemia with insulin injections?
- Delay of a meal or missed meal
- Exercise (less glucose, incr insulin absorption due to hyperemic skin)
- Overdose
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TQ
Treated diabetes pt presents with...
-confusion, bizarre behavior, seizures, coma
-tachycardia, palpitations, sweating, tremor
-hunger, nausea
Issue?
Hypoglycemia
- CNS/Behavioral Manifestation
- Sympathetic hyperactivity
- Parasympathetic hyperactivity
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TQ
| What is "hypoglycemia unawareness"?
Pts who are on tight glycemic control with aggressive insulin tx may get used to feeling hypoglycemic-->
Incoherence-->
Not able to give self glucagon-->
Coma
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What are some treatments for hypoglycemia (most common complication of insulin therapy)?
- Glucose (juice, candy, IV)
| - Glucagon (SC)
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Pt has hyperinsulinemia induced hypoglycemia. What do you give?
How does it work?
Diazoxide (Proglycem)
- Strong hyperglycemic agent: K+ATP channel opener (repolarizes K+ channel to inhibit VG calcium channel influx and therefore inhibit insulin release)
- Inhibits the release of insulin by beta cells
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MOA of glucagon?
-Gs-coulpled GPCR>>Adenylyl cyclase>>phosphorylase→
glycogenolysis
-Incr PEPCK and Glu-6-Pase →
gluconeogenesis
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Glucagon effects on hepatocytes, heart, GI, beta-cells, and chromaffin cells?
- Hepatocytes: incr glucose output + glycogen depletion (NOT in skeletal m. b/c NO glucagon R)
- Acts w/ B1 R on heart-->inotropic and chronotropic effects
- GI SM relaxation
- Incr insulin release by beta-cells
- Incr catecholamine release by chromaffin cells (dont use if pheo)
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Pt presents with extreme bradycardia and has overdosed on atenolol (B-blocker).
What do you give? In what other situations would you give this drug?
Glucagon!!
(Beta-blocker overdose: Incr B R via glucagon R)
Also used in severe hypoglycemia (hepatocytes) and radiology of bowl
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What is commonly given with insulin that acts to:
- Inhibits glucagon secretion
- Enhances insulin sensitivity
- Decreases gastric emptying (slows the rate of GI glucose absorption)
- Causes satiety BUT is a major component of diabetes‐associated β‐cell amyloid deposits in T2DM!
Amylin
| pancreatic hormone synthesized by β‐cells
129
What is the rationale behind modifications to human amylin molecule to create an amylin analog drug?
Pramlintide
| Non-amyloidigenic!!! RAT amylin
proline instead
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TQ
Clinical use of pramlintide and some adverse effects?
- Onset: Rapid
- Duration: 3 hr
- Peak: 20 min
- Type 1, 2 DM post prandial hypoglycemia
- Injected before meals as an adjunct to insulin therapy
* *-Severe hypoglycemia! esp w/ insulin
- D-D: enhances anticholingeric drugs in GI tract (constip)
- GI n/v/d
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- Synthesized by intestinal L‐cells
- Promotes β‐cell proliferation, insulin gene expression, glucose‐dependent insulin secretion
- Inhibits glucagon secretion
- Also causes satiety, inhibits gastric emptying
(incr insulin (T2DM))
What drug is this and why is it not effective?
GLP-1
**Very short half‐life (1-2 min) – not an effective drug
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What is an incretin?
GI hormone that stimulates a decrease in blood glucose levels
Ex: GLP-1
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What are the two categories of incretin mimetics (insulin secretagogues)?
Long-acting GLP-1R agonists
Dipeptidyl peptidase-4 (DPP-4) inhibitors
134
What are the 2 GLP-1 receptor agonists and what is their MOA?
Exenatide
Liraglutide
GLP-1>>cAMP>>PKA>>
1) Incr insulin gene transcription
2) Ca influx-->exocytosis of insulin
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Which GLP-1R agonist is a recombinant form of exendin-4 (from gila monster saliva) and is LESS susceptible to hydrolysis by DPP-4 (inactivate GLP-1)?
Which one is lipid-modified and therefore bound to albumin for a longer HL?
Exenatide
Liraglutide
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What is the clinical use of GLP-1 receptor agonists?
-Type 2 DM who are not adequately controlled by other drugs
(make sure to lower doses of other anti-diabetic meds to avoid hypogly)
-The release of GLP-1 is diminished postprandially in type 2 diabetes patients → inadequate glucagon suppression and excessive hepatic glucose output
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Adverse effects of GLP-1 receptor agonists? How does this differ from pramlintide?
- GI: N/V/D/A
- Lower risk of hypoglycemia vs. Pramlintide: glucose‐dependent insulinotropism.... stimulates insulin secretion during hyperglycemia but NOT during hypoglycemia
- Cases of acute pancreatitis and pancreatic cancer
- Possible link to thyroid cancer
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What are the 4 DDP-4 inhibitors and their MOA?
gliptins
- Sitagliptin (Januvia)
- Linagliptin (Tradjenta)
- Saxagliptin (Onglyza)
- Alogliptin(Nesina)
Inhibits DDP-4>>incr GLP-1
Note: Sitagliptin and alogliptin are competitive inhibitors of DPP-4, whereas saxagliptin bind the enzyme covalently
139
TQ
| What is the clinical use of DDP-4 inhibitors (gliptins) and their AE?
- *ORAL medication!
- Used w/ diet and exercise in patients with type 2 diabetes
AE:
- Hypoglycemia (if combined with insulin secretagogues – their doses have to be adjusted)
- URI and nasopharyngitis
- Link to acute pancreatitis
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1st gen sulfonylureas
2nd gen sulfonylureas
Non-sulfonylureas
What channel to they act on?
1st gen sulfonylureas
2nd gen sulfonylureas
Non-sulfonylureas
K-ATP channel blockers-->incr insulin
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List and compare the difference between first and second generation sulfonylureas?
First generation:
Chlorpropamide, Tolbutamide, Tolazamide
-lower potency – used in high
-Used very infrequently
Second generation
Glipizide, Glyburide, Glimepiride
-Higher potency – used in low mg doses, safer
-As they become generic and less expensive, first generation agents will probably be discontinued
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MOA of sulfonylureas?
Binding to SUR (sulfonylurea receptor) on the K+channel
| Closes K+ current of
Kir6.2-->depol-->insulin release via incr Ca influx
mimics actions of ATP>>insulin release
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Use of sulfonylureas and AE?
Stimulate endogenous insulin release in type 2 DM (requires islet to work so NOT in type 1)
AE:
- Hypoglycemia
- Disulfiram-like effect of alcohol-induced flushing
- Secondary failure – pts initially respond & later cease to respond>>hyperglycemia
- Dermatological/gen. hypersensitivity rxns due to cross-reactivity with other sulfonamides
- Weight gain (increased insulin release)
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Drug-drug interactions of sulfonylureas:
Drug interactions that enhance their hypoglycemic effect?
-Bind w/ & block plasma proteins to prevent binding of drugs>>more is avail (sulfonamides, clofibrate, and salicylates)
Ethanol enhances effect on K-ATP channel
Inhibit CYP enzymes so more avail: azole antifungals, gemfibrozil, cimetidine, etc.
145
Drug-drug interactions of sulfonylureas:
Drug interactions that decr sulfonylureas glucose-lowering effect via:
- Inhibit insulin secretion: beta-blockers, CCBs
- Antagonize their effect on K-ATP channel: diazoxide
- Induce hepatic CYP enzymes: phenytoin, griseofulvin, rifampin, etc.
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What are the 2 meglitinide drugs and their MOA?
Repaglinide
Nateglinide
K-ATP channel inhibition (similar to sulfonylureas)
Short acting
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Clinical use of meglitinides and SE?
- Postprandial hyperglycemia in T2DM
- Orally before meal
- Can be used either alone or in combination
Side effects:
- Hypoglycemia
- Secondary failure
- Weight gain
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TQ
| What are the mechanisms of action of metformin, a biguanide?
- Activation of AMP-dependent protein kinase...exact mechanism is unclear (indirect inhib of complex I in mito?)
- Phosphorylates targets>>
1. Inhibition of lipogenesis and gluconeogenesis
2. . Incr glucose uptake, glycolysis, FA oxi
3. Lower glucose levels in hyperglycemic (but not normoglycemic) states
4. Incr insulin sensitivity
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What is the first-line treatment for T2DM? Why?
Metformin
- Oral
- Superior or equivalent glucose-lowering efficacy compared to other oral medications
- Does not cause hypoglycemia, wt gain
- Alone or in combo
150
AE and contraindications of Metformin?
Most serious AE is lactic acidosis, esp in conditions of hypoxia, renal, and hepatic insuff.
Metformin-related lactic acidosis is mainly due to the inhibition of hepatic gluconeogenesis so buildup of lactate
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TQ
Why cant Metformin be used in conditions predisposing to tissue hypoxia (HF, COPD, renal failure, chronic alcoholism, or cirrhosis)?
Hypoxia-->build up of lactate
Risk of lactic acidosis
152
What are the 2 thiazolidinedione drugs and their MOA?
Pioglitazone
Rosiglitazone
MOA
- Incr insulin sensitivity in peripheral tissue by binding to PPAR-γ nuclear transcription regulator (fat, muscle, liver, tissue, endothelium)=
- Heterodimeric PPARγ/RXR (retinoid X receptor) complex binds to specific DNA PPRE (peroxisome proliferator response element) sequences to either increase or decrease gene transcription
153
Effects of PPARγ activation by thiazolidinediones on gene expression?
- ↑GLUT4 in skeletal muscle: ↑ glucose uptake, ↓ hyperglycemia
- ↑GLUT4 in adipocytes: ↑ glucose uptake, ↓ hyperglycemia, adipocyte differentiation, lipogenesis and expansion of fat tissue
- ↑IRS1, IRS2, PI3K: ↑ insulin sensitivity
- ↑Adiponectin and other adipokines: ↑ insulin sensitivity and ↓ inflammation
-↓PEPCK (rate-limiting gluconeogenic enzyme): inhibition of gluconeogenesis>>
↓ hepatic glucose output>>
↓ hyperglycemia
-↓NF-κB and AP-1 transactivation: antiinflammatory action
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Which drug group?
- Taken orally once daily
- Effects are due to the changes in gene expression
- Onset is delayed: full effect develops after 1-3 months
- Effects persist after drugs are eliminated for weeks-months
- Metabolized by the liver so CYP drug interactions
Thiazolidinediones:
Pioglitazone
Rosiglitazone
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Clinical use of thiazolidinediones?
| Pioglitazone, Rosiglitazone
- Type 2 DM alone or in combo
| - Euglycemic drugs (no hypoglycemia when used alone)
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AE of thiazolidinediones?
| Pioglitazone, Rosiglitazone
- Wt gain
- Edema (incr vasc. permeability and ENaC)
- Hepatotoxicity
- HF (incr water retention)
- Osteoporosis/Incr risk of fractures (suppress MSC differentiation to osteoblasts)
- Bladder cancer?
- Do not demonstrate an increased risk of heart attack
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What are the SGLT-2 inhibitors? (newest class)
What is their MOA?
Gliflozins:
Canagliflozin
Dapagliflozin
Empagliflozin
MOA:
-Block reabsorption of glucose in PCT by SGLT2 to reduce hyperglycemia
Other effects:
- Cause osmotic diuresis
- Induce weight loss
- Reduce blood pressure
- Reduce plasma levels of uric acid
- Do not cause hypoglycemia when used alone
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Clinical use of SGLT-2 inhibitors (canagliflozin) ?
- T2DM as an adjunct to diet and exercise
- Taken orally before the first meal once a day
- In patients with hypovolemia, this condition should be corrected before the start of therapy
159
AE of SGLT-2 inhibitors (canagliflozin) ?
- Glucosuria
- UTIs
- Decr GFR w/ incr plasma creatinine
- Hyperkalemia
- Incr LDL-C
In hypovolemic patients may cause
- Orthostatic hypotension
- Dizziness, syncope
160
What are the alpha-glucosidase inhibitor drugs?
MOA?
Acarbose and Miglitol
Competitive inhibitors of the intestinal α-glucosidases (brush border)>>
Delay digestion and absorption of starch and disaccharides>>
Decr postprandial hyperglycemia
161
Clinical use and AE of alpha-glucosidase inhibitor drugs?
T2 DM monotherapy and in combination with sulfonylureas, in which the glycemic effect is additive
AE:
GI disturbances: flatulence, diarrhea, and abdominal pain
