EXAM 1 Drugs

Question 1

Non-insulin Hypoglycemics (7)- Types only.

Answer 1

1. Insulin secretagogues
2. Biguanides
3. Insulin sensitizers
4. Inhibitors of Carbohydrate absorption
5. Glycosurics
6. Amylin
7. Incretin mimetics

Insulin secretagogues (sulfonylureas, meglitinides)
• Biguanides (metformin)
• Insulin sensitizers (thiazolidinediones)
• Inhibitors of carbohydrate absorption (a-glucosidase
inhibitors)
• Glycosurics (inhibit renal glucose reabsorption)
• amylin (pramlintide)
• incretin mimetics (exenatide, sitiglipin)

Question 2

Sulfonylureas

Prototype name
Brand names (2)
Approved Use
Adverse Effects (2)
Contraindication
Metabolism
Pharmacokinetics
Efficacy and Safety
MOA

Rx for DM II?

Answer 2

Prototype drug: Glyburide (Micronase, Glynase)

Metabolized by liver to agents with low
hypoglycemic potential; excreted by kidney

Half life 4 hours, duration 24 hours

Approved for monotherapy and in a combination tablet with METFORMIN

Can cause hypoglycemia (fairly rare alone) and weight gain

Cardiovascular complications with LONG TERM use (may be due to interaction with CV KATP channels which are sites of action for antianginal drugs).

Contraindicated in patients treated for pulmonary artery hypertension with the endothelin receptor antagonist, BOSENTAN, due to elevated liver enzymes

Metabolized by CytP450

MOA- Inhibit Katp Channels in beta-pancreatic cells.

Do not give to DM II

Question 3

Meglitidine

Prototype name
Brand Name
Mechanism of Action
Pharmacokinetics- include when to consume.
Metabolism
Contraindications
Adverse Effects
Approved Use

Answer 3

Prototype: Repaglinide (Prandin)

• Not a sulfonylurea, but binds to the SUR and
inhibits KATP currents thus causing insulin
secretion

• Primarily used for controlling postprandial blood
glucose elevation (good for patients with normal
fasting but high postprandial glucose)

• Take just before meals,Shorter and faster acting compared to SUs.

Repaglinide pharmacokinetics and adverse
effects:

• Well absorbed; fast onset, peak in 1 hour, half
life is 1 hour =rapid effect limited duration

• Metabolized by the liver (P450) – use with
caution in patients with liver dysfunction

• Risk of hypoglycemia if meal is skipped
• Weight gain
• Monotherapy and with metformin (COMBO TABLET)

Question 4

Biguanides

Prototype and Brand name
Usage and function
MOA- periphery, liver, skeletal muscle
Adverse Effects

Answer 4

• Prototype: Metformin (Glucophage)
• Commonly used; good for obese patients with T2DM
• Monotherapy and in combination with insulin,
SU, meglitanides, thiazolidinediones, aglucosidase
inhibitors, incretin mimetics and
pramilintide
• Lowers fasting glucose levels- because of gluconeogenic control

• Mechanism: Activates AMPK in the periphery
AMPK inhibits cellular processes that use ATP and stimulates those that produce it.

Liver: suppression of hepatic glucose output by
decreasing gluconeogenesis decreases fatty acid synthesis and increases FA beta oxidation (decreasing fatty liver)

Sk. Muscle: translocation of GLUT4

• No hypoglycemia with monotherapy (can occur
in combo or with alcohol)

• Does not cause weight gain, MODERATE LIPID lowering
effect

MOA- Decreases hepatic glucose production, decreasing intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization)

Question 5

Biguanides
• Prototype and Brand Name

Pharmacokinetics
Drug Interactions
Toxicity
Contraindications

Answer 5

Prototype- Metformin (Glucophage)

Metformin: pharmacokinetics
• Rapidly absorbed through the intestine;
peak concentrations in 2 hours
• Half life is 1.5 – 3 hours, excreted
unchanged by kidney
• Drug Interactions:
cimetidine competitively inhibits renal
tubular excretion of metformin

• GI effects (nausea, anorexia, diarrhea,
vomiting) 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- Overwhelmed pyruvate DH thus pushing pyruvate to lactic acid production. Due to increase production of ATP.

Question 6

Insulin Sensitizers
Prototype and Brand Name

Function
MOA- describe and illustrate

Answer 6

Thiazolidinediones (TZDs)
• Prototype drug: Pioglitazone (Actos)

• Insulin sensitizers increase glucose uptake and utilization in skeletal muscle and adipocytes

• alter differentiation of preadipocytes (shift from visceral
  “metabolically active” type to less active SC type)

• Mechanism: unclear; ligands for peroxisome proliferator-activated receptor gamma (PPAR-g)

nuclear receptors involved in expression and
modulation of insulin responsive genes. Expression
is much higher in adipocytes than muscle. PPAR-g regulates IRS-1/2 and PI(3)K—>—-> increase GLUT4 translocation.

Mechanism of Action- Thiazolidinedione antidiabetic agent that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a mechanism of action that is dependent on the presence of insulin for activity. Pioglitazone is a potent and selective agonist for peroxisome proliferator-activated receptor-gamma (PPARgamma). Activation of nuclear PPARgamma receptors influences the production of a number of gene products involved in glucose and lipid metabolism.

Question 7

Insulin Sensitizers
Prototype and Brand Name

Type of drug
Usage and as a result influence of an adverse effect
Metabolized.

Answer 7

Thiazolidinediones (TZDs)
• Prototype drug: Pioglitazone (Actos)

• Insulin mimetic but not insulin secretagogue
• May slow the progression of T2DM
• No risk of hypoglycemia when given alone
• Approved as monotherapy and with metformin
• Metabolized by P450

Question 8

Insulin Sensitizers
Prototype and Brand Name

Adverse Effects (5)
Contraindications

Answer 8

Thiazolidinediones (TZDs)
• Prototype drug: Pioglitazone (Actos)

Adverse Effects
• Hepatotoxicity
First TZD (troglitazone) was withdrawn
Premarketing showed no effect with Pio
but several reports of toxicity later
Periodic liver enzyme monitoring recommended
• Cardiovascular problems.
Sept 2010 FDA restricts use of Avandia (rosiglitazone)
and issued a new box warning for Actos
(pioglitazone)
• Bladder cancer may increase with pioglitazone
• Weight gain due to increased total fat mass
• Fluid retention
• Contraindications are liver disease or advanced
congestive heart failure

Question 9

Inhibitors of carbohydrate absorption (a-glucosidase
inhibitors)

Prototype drug and Brand Name
Function
When to consume
Approved usage
Adverse Effects
Contraindication

Answer 9

a-glucosidase inhibitors
• Prototype drug: Acarbose (Precose)
competitve inhibitor of intestinal aglucosidase

• Decrease starch metabolism to glucose; target
postprandial glucose control

Take before every meal

No hypoglycemia when taken alone

• Approved for monotherapy and in combo with
SUs or metformin.

a-glucosidase inhibitors: Adverse
effects
• Adverse effects: flatulence, diarrhea, abdominal
pain. Transient
• Hypoglycemia may occur with SUs – give
dextrose since Acarbose interferes with sucrose
metabolism to glucose

• Contraindicated in patients with chronic or
inflammatory bowel disease or renal impairment.
Can elevate liver enzymes

Question 10

Glycosurics

Prototype
MOA
Route of Administration
Effects
Risk
Approved Usage

Answer 10

Glycosurics
• Prototype drug: Canagliflozin (Approved March 2013)

• Sodium glucose co transporter (SGLT)-2 inhibitors
– SGLT-2 is expressed in the S1/2 segments of renal proximal tubule
– Block glucose reuptake in renal tubules

• Orally active
• Reduces HbA1C as well as body weight and systolic blood pressure
• Low hypoglycemia risk
• Approved for monotherapy

Question 11

Glycosurics

Prototype
Special Pt. Population Consideration
Contraindication
Adverse Effects (4)

Answer 11

Glycosurics
• Prototype drug: Canagliflozin (Approved March 2013)

• Glucose lowering effect is attenuated in patients with
renal impairment

• Contraindicated when glomerular filtration rate

Question 12

Amylin

Prototype and Brand name
Function
MOA
Used for

Approve Use
Time of Consumption
Excretion
Adverse Effects
Adverse Effects
Interactions

Answer 12

Pramlintide
(Symlin)
• Synthetic amylin
• Amylin is co-secreted with insulin

• Decreases glucagon release, slows gastric
emptying, decreases food intake

• Acts on receptors in the area postrema (lacks
BBB), projections to hypothalamus, c. amygdala

• Improves fasting glucose and decreases body
weight (good for obese patients)

• Monotherapy and in combination with insulin (carefully –
reduce insulin by 50% initially) or metformin
• Use at mealtimes (self-administered injection)
• Cleared through the kidney
• Side effects: nausea, possible hypoglycemia 3 hrs after injection
(when initiating decrease insulin 50% and monitor
closely)
• Contraindications: gastroparesis (decreased stomach
emptying), history of frequent hypoglycemia
• Interactions: drugs that require high threshold activity
may be impaired by decreased gastric emptying

Question 13

Incretin mimetics

In general incretins-

site of production
Action
Function

Answer 13

• Incretins produced by intestine, brain (nu. solitarius)
• GIP-1 and GLP-1 (effect is preserved in T2DM)

• Action:
potentiate glucose induced insulin release
(only increase insulin during high blood sugar but not normal glucose) may delay beta cell apoptosis
inhibit glucagon, inhibit gastric secretion
decrease food intake (CNS mediated, hypothalamus?)
• Decrease fasting and postprandial glucose, HbA1C
and body weight

Question 14

Incretin mimetics- GLP-1 receptor agonist

Name the prototype and Brand name
Route of Administration
Excretion
Adverse Effects 
Contraindications
Interactions
Approved use

Answer 14

Exenatide (Byetta)
• GLP-1 receptor agonist
• Self-injection (pre-filled pen, BID)
• Cleared by kidney
• Side effects: Transient nausea, vomiting, headache,
can cause hypo with SUs
• Contraindication: gastroparesis, renal disease
• Interactions: shouldn’t be taken with drugs that require
rapid absorption due to delayed gastric emptying, warfarin (increased prothrombin time)
• Monotherapy and in combination with insulin

Question 15

Incretin mimetics- Dipeptidyl peptidase (DPP-4) inhibitor

Name prototype and brand name
Route of Administration
Adverse Effects
Compared to the GLP-1 receptor agonist
Excretion
Interactions
Approved Use

Answer 15

Sitagliptin (Januvia)
• Dipeptidyl peptidase (DPP-4) inhibitor (prevents GLP-1 degradation)
• ORALLY administered
• No GI side effects
• Weight neutral
• More modest decrease in glucose/HbA1C compared to exenatide
• Cleared by the kidney (contraindicated in renal disease)
• Interactions: few recorded, increased digoxin concentration
• Monotherapy or in combination with metformin

Question 16

List the drugs that:

1. Improves fasting glucose
2. Improves postprandial glucose
3. No hypoglycemia with mono therapy
4. No weight gain with monotherapy
5. Weight loss due to decreased food intake (CNS)
6. Gestational diabetes

Answer 16

Comparison between hypoglycemic drugs

• Improves fasting glucose:
SUs, metformin, pioglitazone, pramlintide, exenatide,
sitaglipin, canagliflozin

• Improves postprandial glucose:
repaglinide, acarbose, pramlintide, exenatide, sitaglipin

• No hypoglycemia with monotherapy:
metformin, acarbose, pioglitazone

• No weight gain with monotherapy: metformin, acarbose,
pramlintide, exenatide, sitaglipin

• Weight loss due to decreased food intake (CNS): pramlintide, exenatide
• Gestational diabetes: insulin (doesn’t cross placenta)

Question 17

Discuss the current approach for treating DM I

DCCT recommendation
Caution

Answer 17

Current Approach for treating T1DM
INSULIN

Ultra short or short acting for postprandial
glucose control

Plus

Intermediate or long acting for basal glucose
control

DCCT recommends: fasting glucose

Question 18

Tx of diabetic neuropathic pain (3)

Answer 18

Pregabalin, Duloxetine, Tapentadol

Question 19

Prolactinoma Rx and Side effects

Answer 19

Bromocriptine, Cabergoline (long-acting)
– Side effects differ between drugs: heart valve fibrosis
– Rapid reduction of Prolactin levels
– Tumor shrinkage in 70-90%

Question 20

Drug treatment for Cushing’s Disease

Answer 20

↓ ACTH
– Dopamine agonists: small number of responders
– Cyproheptadine, Valproate
– Lanreotide; pasreotide: Somatostatin Receptor
antagonists

• ↓ steroid synthesis
– Ketoconazole, aminoglutethimide, metyrapone
– Mitotane (o,p’-DDD)
– Korlym (mifepristone) just approved last month

Question 21

Tx for Hyperthyroidism

Answer 21

• METHIMAZOLE or PROPYLTHIURACIL
• Under treatment is better than over treatment in the
outpatient setting unless you are concerned about thyroid
storm (Treat to target)
• M is 10X more potent then PTU and longer acting, thus 30 mg
of M = 300 PTU
• PTU preferred in pregnant 1st trimester and M in 2nd & 3rd
trimester
• Other Therapy
• 1) RAI- easy, goal is hypothyroidism 1st dose 75%, 2nd dose 90%,
3rd dose 95%
• 2) Surgery- subtotal thyroidectomy usually reserved for big goiters
• 3) Maintain lower dose methimazole (or PTU) for 1 year
• 40-50% of patients stay in long term remission

Question 22

HYPERTHYROIDISM SECONDARY TO THYROIDITIS

“HASHITOXICOSIS” Rx

Answer 22

Thionamides

Question 23

Subclinical Hyperthyroidism when to Tx.

Answer 23

if patient > 60 yrs, treat

patient < 60 probably should not treat

Question 24

Treatment of acute Hypercalcemia

Answer 24

• Fluid resuscitation with isotonic saline
• Loop diuretic such as furosemide (also bumetanide, torsemide)
• Calcitonin

Question 25

Treatment of acute Hypocalcemia

Answer 25

• Direct intravenous administration of calcium (eg. calcium gluconate)
• Vitamin D analogs
• Dietary calcium as calcium citrate or calcium carbonate
• Hyperphosphatemia can be reduced by interfering with intestinal phosphate availability with calcium carbonate or calcium acetate (complex with phosphate)

Question 26

Vitamin D and therapeutic analogs

Clinical Forms of Vitamin D (5) & Adverse Effects

Use

Answer 26

• Calcitriol (1,25-(OH)2D3; CALCIJEX, ROCALTROL).
Oral administration or injection. High does intravenous calcitriol (or derivatives) used in chronic and end-stage kidney disease.

• Vitamin D3 supplements available over the counter.

• Ergocalciferol (calciferol; DRISDOL).This is Vitamin D2.
Available for oral administration or injection, used in vitamin D deficiency, hypoparathyroidism, familial hypophosphatemia.

• Alphacalcidol (1α-Hydroxycholecalciferol ONE-ALPHA).
Prodrug of Calcitriol that is already hydroxylated at 1α position, but must be activated by 25-hydroxylase in liver to form 1,25-(OH)2D3.

• Doxercalciferol (1α-hydroxyvitamin D2, HECTOROL).
Prodrug of Ergocalciferol that is already hydroxylated at 1α position.

Also used for secondary hyperparathyroidism.

Adverse effects of Vitamin D therapy can include hypercalcemia, renal calculi.

Question 27

Vitamin D and therapeutic analogs
Pharmacological analogs of Vitamin D (2) & Adverse Effects

MOA, Use, Half-life

Answer 27

Vitamin D and therapeutic analogs
Pharmacological analogs of Vitamin D:

• Paricalcitol (1,25-dihydroxy-19-norvitamin D2, ZEMPLAR).
Synthetic calcitriol derivative that has a short half-life. Reduces PTH under hypocalcemic conditions without causing hypercalcemia or altering serum phosphate because it has minimal effects on intestinal uptake or bone.

Used for treating secondary hyperparathyroidism.

• Calcipotriol (calcipotriene, DOVONEX).
Derivative of calcitriol with similar affinity to calcitriol for vitamin D receptor but little effect on calcium metabolism. Also has short half-life. Topical cream used as a treatment for psoriasis.

Adverse effects include GI symptoms.

Question 28

A calcium sensing receptor sensitizer

MOA, Use, Dose, Metabolism, Adverse Effects

Answer 28

Cinacalcet (SENSIPAR)

• Modifies the calcium sensitivity of the Calcium-Sensing Receptor (CaSR) by making it more sensitive to Ca2+. As a result, PTH secretion is inhibited at lower levels of serum free Ca2+.

• Used to treat Primary and Secondary Hyperparathyroidism.
Primarily for treatment of hyperparathyroidism in chronic renal failure.

• Oral dosing, long half life of 30-40
hours.

• Metabolized by CYP3A4 and CYP1A2, and inhibits CYP2D6. Therefore contraindicated in hepatic dysfunction.
• Adverse effects include hypocalcemia, GI tract (nausea).

Question 29

Osteoporosis - Pharmacological Treatments
• Estrogen Hormone Replacement Therapy (HRT)
• Selective Estrogen Receptor Modulators (SERMs) - Raloxifene
• Targeting RANK-Ligand - Denosumab
• Targeting the osteoclast - Bisphosphonates
• Calcitonin
• An anabolic approach using PTH analogs - Teriparatide

Answer 29

Informational

Question 30

Estrogen Hormone Replacement Therapy (HRT)

Benefits/Risks

Answer 30

• Shown to be effective in conservation of bone and protection from osteoporotic fracture.
• Largely abandoned when long-term studies showed increased risks of heart disease and breast cancer.

Question 31

Selective Estrogen Receptor Modulators (SERMs)

Sites of action (tissue)
MOA
Benefit/Risk

Answer 31

Raloxifene (EVISTA)

• Raloxifene has tissue-specific effects, acting as an estrogen agonist in bone (and liver), but not in uterus or breast tissue.
• Raloxifene acts as an estrogen antagonist on the breast, and actually reduces the risk of breast cancer.
• Shown to increase BMD and reduce vertebral fractures.
• Does not increase risk of heart disease, but does increase the risk of venous thromboses.

Question 32

Denosumab, Estrogen

MOA on reducing the risk of bone loss.

Interval of DOSE, caution,benefit for Denosumab

Answer 32

Denosumab (PROLIA, XGEVAIS) is a humanized monoclonal antibody with high affinity for RANKL.

Estrogen suppresses RANKL and increase OPG (Osteoprotegerin).

It mimics the effect of OPG to reduce the availability of RANKL to bind to its receptor on the osteoclast.

• Subcutaneous injection every 6 months.
• Reduces vertebral and non vertebral fractures (including hip).
• Should not be given to patients with hypocalcemia, need to monitor serum calcium levels.

Question 33

Structure-activity of Bisphosphonates

MOA, 1-3 generation bisphosphonates.

Answer 33

• Pyrophosphate analogs that link the two phosphonates with a geminal (central) carbon.
• Like pyrophosphate, they form complexes that chelate free Ca2+ and have a high affinity for bone (especially during remodeling).
• Bisphosphonates become incorporated into the mineralized matrix of newly formed bone, and may remain in bone for years.
• Primary mechanism of action is to inhibit osteoclast-mediated bone resorption.
• First-generation bisphosphonates have small side chains (eg. methyl group in etidronate) and are the least potent.
• Second-generation are aminobisphosphonates (eg. pamidronate, alendronate, ibandronate) that contain longer nitrogen-containing side chain and are up to 100 times more potent.
• Third-generation bisphosphonates (e.g., risedronate, zoledronate) have a nitrogen-containing heterocyclic ring and are up to 10,000 times more potent than first-generation bisphosphonates.

Mechanism of action:
• Previously incorporated bisphosphonates are released during bone resorption due to acidic environment and release of proteolytic enzymes.
• Bisphosphonates act directly on the osteoclasts, at least partially by being taken up into the cell.
• Bisphosphonates inhibit the proton pump responsible for acid secretion and induce apoptosis of the mature osteoclasts.
• Aminobisphosphonates also interfere with the mevalonate pathway, which is required for cholesterol synthesis, and also protein prenylation.

Question 34

Bisphosphonates
Administration and Pharmacokinetics:

Route of Administration, half-life, excretion, Term of Tx, Special Population consideration.

Answer 34

• Bisphosphonates are very poorly absorbed.
• Taken orally but must do so without food and with plenty of water. Patient should remain and keep upright for at least 30 minutes.
• Can be given intravenously (pamidronate, zoledronate).
• Bisphosphonates have a short half life in blood, but can stay in bone for years.
• Excreted primarily by the kidney (dose must be decreased for patients with impaired renal function).
• Treatment with oral bisphosphonates can be maintained for 5 years or more.
• Since bisphosphonates incorporate into growing bone, they are not generally used in children.

Question 35

Bisphosphonates
Clinical Applications: Use
Adverse effects:

Answer 35

Clinical Applications:
• Postmenopausal osteoporosis.
• Hypercalcemia of malignancy (usually treated with injected bisphosphonates).
• Osteolytic lesions caused by bone metastases or lymphoma.
• Paget’s disease.

Adverse effects:
• Gastroesophageal pain, especially when oral medication is not taken correctly.

• Osteonecrosis of the jaw, typically associated with oral surgery. Occurs rarely with oral bisphosphonates but may be more common with IV administration.
• Hypocalcemia, usually only associated with IV administration of potent bisphosphonates (eg. Zoledronate).

Question 36

Calcitonin
Clinical Applications: Use
Administration and Pharmacokinetics:
Rx Prep, half life, Route, special population consideration

Answer 36

Calcitonin
Clinical Applications:
• Can be used in severe hypercalcemia as fast acting (but does not substitute for fluid resuscitation).
• Treatment of Paget’s disease of bone (caused by excessive and disorganized bone remodeling).
• Limited usefulness for osteoporosis due to tachyphylaxis.
• Not physiologically important but high doses useful therapeutically.

Administration and Pharmacokinetics:
• Pharmacological preparation is recombinant salmon calcitonin as this has a longer half-life.
• Typically given parentally (subcutaneous injection).
• Can also be given as a nasal spray, but lower bioavailability.
• May have an analgesic effect in Paget’s disease.
Adverse effects include nausea, uticaria, diarrhea, intestinal cramping.

Question 37

Use of PTH analogs - Teriparatide
Concept:
Administration and Pharmacokinetics:
Route, time of Peak, half life, total clearance time.

Answer 37

Use of PTH analogs - Teriparatide
Concept:
• An anabolic approach - all the pharmacological agents discussed so were directed to reduce catabolic degradation of bone by osteoclasts.
• Stimulate bone remodeling by intermittent treatment with PTH can paradoxically increase net bone formation.
• Uses the 34 amino acid N-terminal human PTH fragment referred to as teriparatide (FORTEO) for use in treating severe osteoporosis.

Administration and Pharmacokinetics:
• Administered by daily subcutaneous injection (human form).
• Can be self-administered.
• Serum teriparatide levels peak at 30 minutes and have a half-life of about 1 hour (due to subcutaneous delivery). Total clearance in 3 hours.

Question 38

Use of PTH analogs - Teriparatide
Clinical Applications: Term of Use
Adverse Effects: Special Population Consideration

Answer 38

Use of PTH analogs - Teriparatide
Clinical Applications:
• Teriparatide is primarily used for severe osteoporosis where there is high risk of fracture.
• The most effective treatment in terms of increased vertebral BMD.
• Shown to significantly reduce vertebral and nonvertebral fracture risk in men and women.
• Should not be continued for more than 2 years due to concerns about long-term effects (but can rebuild bone that is then maintained by other treatments, eg. bisphosphonates).

Adverse Effects:
• Animal studies suggest increased incidence of osteosarcoma.
• Should not be used for patients with Paget’s disease of bone.
• Should not be used for patients with open epiphyses, or prior radiation therapy involving the skeleton.
• Nausea and leg cramps.