Exam 2 - Endocrinology Flashcards Preview

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1
Q

DIABETES

A

2
Q

Why are oral glucose challenges important for pregnant woman?

A

Check for gestational diabetes

3
Q

A1c

A

Glycosylated hemoglobin; gives you an idea of the average blood glucose level for the body in the last three months.

4
Q

What’s a 1 point increase in A1c equivalent to?

A

35mg/dL increase in sugar

5
Q

Type 1 DM

A
  • Require exogenous insulin for survival.
  • AI condition; beta cells are destroyed and can no longer make insulin.

-If blood glucose is too high for a prolonged period, can have DKA.

6
Q

Type 2 DM

A
  • Insulin resistance
  • Insulin is constantly made due to poor diet and obesity, so receptors are down regulated.

-Beta cells can be worn out and insulin won’t be as effective.

7
Q

Prediabetes (IFG)

A
  • Impaired fasting glucose

- Fasting blood sugars of 110-125; not high enough to be diabetic, but warning sign.

8
Q

Pancreas

A

9
Q

A cells

A

Mobilizes fuel via glucoenogenesis and glycogenolysis in the liver; secretes proglucagon and glucagon.

10
Q

B cells

A

Promote fuel storage and growth by releasing proinsulin, insulin, C-peptide, and amylin.

At time of diagnosis, already lost 50% of beta cell function.

11
Q

Glucagon

A

1 - Increases blood glucose by stimulating the liver to undergo gluconeogenesis. Glucose comes from the glycogen stores in the liver.

2 - Releases LES tone; can use glucagon to loosen the LES to have foreign body pass.

Glycogen => glycogenolysis => gluconeogenesis => blood sugar (stimulated by glucagon).

12
Q

If a patient has a long-standing hypoglycemia, they may not have glycogen stores. How do you treat their hypoglycemia?

A

Glucagon won’t make their glucose go up without glycogen stores.

Prolonged state of hypoglycemia - need sugar.

13
Q

D cell

A

Inhibits secretory cells and secretes somatostatin.

14
Q

Insulin

A
  • Beta cells release proinsulin (prodrug) and C-peptide in response to elevated glucose.
  • Proinsulin is cleaved into insulin (c-peptide is cleaved off).

-Short half-life; longer half-life and hypoglycemia seen when insulin “sticks around longer” - i.e. renal impairment.

15
Q

How is insulin cleared by the body?

A
  • Liver will metabolize insulin.

- Can see longer half-lives for insulin in presence of renal impairment.

16
Q

Insulin Overdose

A
  • Death by insulin overdose = diagnosed by C-peptide levels.

- C-peptide is low; you know insulin was from an exogenous source.

17
Q

Mechanism of insulin release:

A

Pancreas exposed to glucose, binds to glut2 transporters on beta cells, which are internalized and start TCA cycle.

ATP levels go up. In response, closes potassium channels, which causes cells to depolarize and open the calcium channels, which flow into the cell and releasing vesicles of insulin into the bloodstream (where sulfonylurea drugs work).

18
Q

Mechanism of insulin action:

A

Stimulates glucose uptake into target tissues (glut4); causes phosphorylation cascade for glucose to be transported into the cell.

Tyrosine phosphate proteins are phosphorylated when insulin binds, which causes more glut 4 transporters to be put out to take in more glucose.

Important for type two diabetics, because as they get more insulin resistant, more transporters are on cell surface to desensitize the body to insulin.

As they get insulin resistant, you can see less glut4 are on cell surface. Need drugs to RESENSITIZE to insulin.

19
Q

GLUT4

A
  • Transporters in muscle and adipose

- See resistance over time

20
Q

GLUT2

A

-Transporters in B cells of pancreas, liver, and kidney

21
Q

What effect does insulin have on the liver?

A

Insulin STIMULATES liver to store glucose as glycogen. Glycogen is converted to fatty acids, VLDL, and adipose (end prodt.).

Insulin will INHIBIT or slow the liver from doing glycogenolysis and gluconeogenesis, bc glucose supply is adequate (in presence of insulin).

22
Q

How does insulin affect skeletal muscle?

A

Stimulates glycogen storage and store amino acid storage as proteins.

Insulin = anabolic steroid; consumed with protein and sugar to fill the skeletal muscle and stimulate growth.

23
Q

How does insulin affect adipose tissue?

A

Stimulates storage of fatty acids as triglycerides and inhibits the conversion of triglycerides to fatty acids.

24
Q

Insulin Release

A

Insulin is stimulated in the presence of glucose.

Basal insulin released throughout the day with spikes of insulin that occur around mealtime. Try to mimic this during treatment.

25
Q

How do you modify the pharmacokinetics of insulin?

A
  • Varying zinc concentration, e.g. Lente formulations.
  • Adding protamine, e.g. NPH and NPL.
  • Insulin analogs - changing AA sequence to get different actions.

How to make longer-acting insulin

26
Q

Insulin Admin

A

Insulin is a protein, need to give it subQ. Otherwise, stomach acid would destroy it.

27
Q

Pro-insulin

A

Proinsulin = insulin with C-peptide attached to it.

Sulfide bond is cleaved to release insulin only.

28
Q

Where is insulin from?

A
  • Beef, pork, mix
  • Beef no longer available, antigenic.
  • Pork only available by special order; if they have CI to other forms.

Human, recombinant forms made in E. coli or yeast. Plasmids are injected into yeast/Ecoli for them to produce human insulin themselves.

  • E. Coli - Humulin, *Lilly products
  • Baker’s yeast - Novolin, *Novo Nordisk products
29
Q

Rapid Acting Insulins

A

Humalog (Lispro)
Novolog (Aspart)
Apidra (Glulisine) *super fast acting; marketed to take WITH meals instead of beforehand.

  • Treat acute hyperglycemia from eating meals.
  • Sliding scale regimen: based on blood glucose at that moment, reactionary measure.
30
Q

Short acting insulin (Regular)

A
  • Humulin R (regular) U100
  • Novolin R (regular)

Not as able to titrate as the rapid acting ones, but are short acting in nature.

31
Q

Intermediate acting insulin (N)

A

N = NPH formulation

  • Humulin N
  • Novolin N

Intermediate acting; seen given twice a day to make sure they get good 24hr coverage.

32
Q

Long-acting insulin

A
  • Lantus (Glargine)
  • Levemir (Detemir)
  • Tresiba (Degludec)(new)
  • Ultralente - not used
  • Longer acting form; provides a basal coverage. Once daily.
  • No peak effect.
  • Longer duration of activity; good for 24hr coverage.
  • Supplemented by short acting insulin at meals.
  • Don’t treat acute hyperglycemia.
33
Q

Inhaled insulin

A
  • Afrezza

- Short acting, meal type insulin

34
Q

How do you dose insulin?

A

Units

  • U100
  • U500 for severe diabetics; will have a 5 fold overdose if given to a normal diabetic.
35
Q

Insulin delivery systems

A
  • Injection: most conventional, usually subcutaneous
  • Portable pen injector via cartridge.
  • Continuous subcutaneous infusion (insulin pump)
  • Inhaled insulin - Afrezza (dry powder)

Viruses can affect your blood sugars.

36
Q

IV insulin

A
  • Used in DKA
  • Only do short-acting or regular insulins IV
  • NEVER give long-acting insulin via IV
37
Q

Who are insulin pumps preferred for?

A

T1DM

  • Well maintained on subcutaneous insulin
  • Good at watching sugars, carb counting

-Program the basal rate and boluses needed throughout the day, without doing constant injections

38
Q

What type of insulin do you use in pumps?

A

Fast-acting insulins

  • Novolin
  • Humalin

Don’t use levemir, detemir, or glargine bc they’re long acting and can’t be titrated.

SA forms can be titrated.
X units per hour, X carbs give bolus X for meals.

39
Q

Premixed formulations of insulin:

A
  • Humalog mix 75/25 - Protamine and Lispro.
  • Novolog mix 70/30 - Aspart and protamine.
  • Humalog mix 50/50 - protamine and lispro.
40
Q

Concentrated insulins:

A

Regular insulin (U500)
Humanlog (U200)
Toujeo (U300)

  • U500, be careful.
  • Dosing errors may occur.
41
Q

NPH forms

A

Cloudy

42
Q

How can you mix insulins to minimize injections?

A

To decrease number of injections, patients can mix intermed-acting NPH forms with the short-acting insulins.

Don’t mix long-acting forms with rapid acting forms.

43
Q

Complications of using insulin:

A

U100, U200, U500

  • Hypoglycemia
  • Too much insulin

Immunopathology

  • Insulin allergy (IgE) - rare with use of human insulin.
  • Immune insulin resistance (IgG) - insulin becomes less effective; sugars start rising.
  • Injection reactions may be due to injecting cold insulin (causes vasodilation) - to avoid, roll it in the hands.

Lipodystrophy at injection sites; rotate the sites around the abdomen.

Weight gain (anabolic steroid).

44
Q

How is insulin stored?

A

Should be stored in the fridge; heat will breakdown proteins and render it ineffective.

Mix in hands before injecting avoid injecting cold insulin.

45
Q

Draglutitide

A

Causes weight loss

46
Q

What can make insulin work less effectively?

A

Decrease hypoglycemic effect of insulin.

  • Oral contraceptives
  • Corticosteroids - cause hyperglycemia
  • Dobutamine
  • Epinephrine - catelcholamines stimulate “fight or flight”; will increase blood sugar.
  • Niacin
  • Smoking
  • Thiazides
  • Thyroid hormone
47
Q

What can increase hypoglycemic effect or make insulin work more effectively?

A
  • Alcohol
  • a-blockers
  • Anabolic steroids
  • Beta blockers - Cool, pale, diaphoretic when hypoglycemic - BB will block tremors and masks signs of hypoglycemia so it prolongs hypoglycemic state.
  • MAO inhibitors
48
Q

When do we use insulin for patients?

A
  • T1DM; not producing their own.
  • Pregnant women with type 2 DM or gestational diabetes - needed for hyperglycemia; use human insulin. Preferred in pregnancy.
  • T2DM when not controlled by diet, exercise, and oral meds.
  • DKA (common of T1DM)
  • Hyperglycemic hyperosmolar nonketotic syndrome T2DM with severe hyperglycemia.
  • Hyperkalemia
49
Q

Why do you use insulin for hyperkalemia?

A

Drags it into the cells, K+

50
Q

When is a basal-bolus insulin regimen most used?

A

Insulin Regimens in T1DM
-Basal-bolus regimen: long acting forms are given 1-2x a day to provide a basal dose throughout the day; short acting forms are used as bolus doses for meals.

51
Q

Insulin administration

  • More often?
  • Less often?
A

Insulin administration

  • More often: will have tighter glycemic control (in range), but increased complexity for pts.
  • Less often: less chance of hypoglycemia, but looser glycemic control (more variations in blood glucose).
52
Q

What affects insulin dosing?

A
  • Carb intake
  • Exercise

Long acting doses are taken in the morning or evening.
Rapid acting are taken around mealtimes.

53
Q

How can insulin scales be given?

A
  • Sliding scale doses

- Carbohydrate counting

54
Q

Sliding Scale Dosing

A
  • Reactionary way to dose insulin.
  • Insulin dose is changed based on what glucose readings are.

Preprandial readings are taken and then insulin amount is corrected to lower glucose. Based on sensitivity, they’ll have a correction factor.

55
Q

When using a sliding scale approach to treating patients, how do you determine their correction factor?

A

More insulin resistant = tissues have a tougher time dealing with insulin; will have smaller changes in blood glucose in response to 1 unit.

Those more sensitive to insulin; 1 unit has a wider change in blood glucose.

56
Q

Carbohydrate counting

A
  • Adjusting the dose based on the carbs ingested; insulin dose is adjusted based on that.
  • Based on insulin sensitivity, they know how 1 unit of insulin will affect them (based on grams of carbs).

Preferred, more proactive method.

57
Q

Why do T2DM need insulin supplementation?

A
  • T2DM take in too many carbohydrates; poor diet.
  • B cells deteriorate in pancreas and are worn out from producing too much insulin.
  • Pancreas tissue becomes resistant to insulin produced.

Skeletal muscle and liver tissue become insulin resistant as well.

58
Q

How does insulin dosing differ in T1 and T2 DM?

A

T1DM
-0.5-0.6 units/kg/day

T2DM

  • 0.7-2.5 units/kg/day
  • Insulin resistance; need higher doses.
59
Q

What is the basal/bolus breakdown of insulin?

A

50% basal (long-acting)

50% as bolus (rapid-acting or regular)

60
Q

If you have a 40kg female diagnosed with T1DM; what’s her total insulin dose per day?

A

0.5 units/kg * 40kg = 20 units per day

50% basal = 10 units
Given as 5 units detemir SC BID

50% bolus = 10 units
20% breakfast = 4 units of lispro
15% lunch = 3 units of lispro
15% dinner = 3 units of lispro

61
Q

When on an insulin pump, how do you determine bolus dose?

A

Patient needs to input mealtime carbs to calculate bolus dose.

  • Pts must be controlled beforehand on SC dosing
  • Need to be trained
  • Pumps can malfunction leading to glucose extremes.
62
Q

What is the biggest complication with insulin?

A

Hypoglycemia

  • BG < 65-70 mg/dL
  • Can be life threatening
  • Severe hypoglycemia leads to seizures, coma, and death.
  • Need to be educated on signs/symptoms
63
Q

What is hypoglycemic unawareness?

A

Longstanding diabetics with insulin resistance have neuropathies that may occur, which blunt the effects of hypoglycemia resulting in hypoglycemic unawareness.

64
Q

What’s a patient issue with hypoglycemia?

A

They feel terrible, over eat, and it leads to hyperglycemia.

Rule of 15 helps with management.

65
Q

Rule of 15

A

Used to manage hypoglycemia.

“Do 15g of simple carbohydrates”.

  • Can find in 8oz OJ/milk or 4 glucose tablets.
  • Recheck glucose in 15mins.
  • If BG <70mg/dL, repeat.
66
Q

If a patient has severe hypoglycemia, but they’re unconscious and unable to manage hypoglycemia.

How can you raise their glucose?

A
  1. Glucagon PRN
    - Used as an injection; stimulates glycogenolysis/ gluconeogenesesis in the liver to raise BG.
    - ADR: N/V, may need Zofran.
    - Can also be used to relax LES and smooth muscle tone.
  2. Dextrose IV: D10, D25, D50
    If a patient has long-standing hypoglycemia and they’ve depleted their glycogen stores, may need to use dextrose therapy.
    Glucagon won’t work if you don’t have glycogen stores.
67
Q

Why don’t you shake glucagon syringe?

A

Don’t shake; can cause foaming, which will denature protein.

Need to roll it to put the powder back into the solution before injecting glucagon IM.

68
Q

If glucagon isn’t going to work, how do you treat a patients hypoglycemia?

A

Dextrose IV
-Used when they can’t tolerate glucose PO

  • D10, D25, D50
  • D25 in infants/peds
  • D50 for adults (50mg for 100ml, 50%)

Usually 0.5-1g/kg ~25 grams
D50 are 50ml = 25g

69
Q

What risks are there when administering D50 through a peripheral vein in a pediatric patient?

A

Thrombophlebitis, tissue necrosis

Use lower concentrations in pediatric patients.

70
Q

Treatment goals of diabetes:

A

American Diabetes Assoc.

  • A1c < 7%
  • Preprandial glucose 80-130
  • Postprandial < 180

AACE:

  • A1c < 6.5%
  • Prepandial glucose < 110mg/dL
  • Postprandial < 140
71
Q

Type 2 Diabetic Goals

A

1 - Restore insulin sensitivity

2 - Make more insulin

72
Q

Type 2 and Glucagon

A

Glucagon stimulate gluconeogenesis in the liver; after mealtime you don’t need glucagon.

When insulin is released, it inhibits glucagon breakdown. Patients iwth normal glucose tolerance will have high glucagon, but it’ll drop when it hits normal levels. T2DM has higher levels of glucagon; less control so we need to manage it better.

73
Q

What drugs stimulate the pancreas to make more insulin?

A

Sulfonylureas

Meglitinides

74
Q

What drugs sensitize the body to insulin and control hepatic glucose production?

A

Thiazolinediones (TZDs)

Biguanides

75
Q

What drugs slow absorption of starches?

A

Alpha-glucosidase inhibitors

76
Q

What drugs suppress glucagon, decrease gastric emptying, and decrease food intake?

A

Incretins (glucagon-like peptides)

  • Supress glucagon, slow gastric emptying, and increase satiety.
  • Decreases food intake; causes weight loss.
77
Q

What decrease reabsorption of glucose from renal tubules?

A

SLGT2 inhibitors

-Decreasing the reabsorption of glucose, so you just pee it out.

78
Q

Most benefit:

A

Biguanide, sulfonylurea, and thiazolidinedione

79
Q

Sulfonylureas List

A
1st generation:
Acetohexamide (Dymelor)
Chlorpropamide (Diabinese)
Tolazamide  (Tolinase)
Tolbutamide  (Orinase)

2nd Generation: (~100 x more potent, less SE’s)
Glimepiride (Amaryl)
Glipizide (Glucotrol, Glucotrol XL)
Glyburide (DiaBeta, Glynase, Micronase)

80
Q

Sulfonylureas (used):

A
1st gen: Chlorpropamide (Diabinese)
2nd Gen: 
Glimepiride (Amaryl)
Glipizide (Glucotrol, XL)
Glyburide (DiaBeta, Glynase, Micronase)
-More potent. Less SE.
  • Metabolized in liver; some active metabolites.
  • Excreted in urine.
  • Highly protein bound.
  • Use CAUTIOUSLY with renal or hepatic insufficiency!

-Cross placenta, may deplete insulin from fetal pancreas. DONT USE IN PREGNANCY.

81
Q

MOA: Sulfonylureas

A

Block ATP-dependent K+ channel on beta-cells in pancreas. Depolarization induced ↑ Insulin release.

↓ Basal hepatic glucose production -↓ gluconeogenesis and glycogenolysis
↑ Insulin receptor sensitivity, ↑ receptor #
↓ Glucagon levels (secondary to ↑ insulin and Somatostatin release)

82
Q

Chlorpropamide

A

1st generation sulfonylurea

  • Avoid in elderly
  • Long acting duration (48hrs)
  • Disulfram-like reaction with alchohol. “Don’t drink Chlorpropamide with your cocktails”

-Chlorpropamide and Glyburide most likely to produce HYPOGLYCEMIA.

83
Q

Glimepiride (Amaryl)

A
  • Increases sensitivity of peripheral tissues to insulin
  • Used in combination with exogenous insulin; will decrease dose of insulin needed.
  • Rapid glucose control, but could cause hypoglycemia.
84
Q

Glyburide (Diabeta, Glynase, Micronase)

A
  • Once daily dosing; long-acting

- Frequent hypoglycemia: problematic

85
Q

Glipizide (Glucotrol or G XL)

A
  • XL: Once daily dosing.
  • 30 mins before meals.
  • Short half life, LESS hypoglycemia.

Works better when given before meals

86
Q

ADR: Sulfonylureas

A
  • Hypoglycemia
  • Weight gain

Pretty well tolerated, may see:

  • Constipation, nausea, diarrhea
  • Rash, pruritis
  • Leucopenia, thrombocytopenia, aplastic anemia

Resistance may develop over time! Due to beta cells becoming “burnt out” due to the added pressure from the drug.

87
Q

When are sulfonylureas CI?

A
  • Diabetic ketoacidosis (with or without coma) - treat with exogenous insulin.
  • Type 1 diabetes - will not help them, bc they lack beta cell function.
  • Pregnancy, breastfeeding - depletes fetus of insulin; don’t use!
88
Q

What are sulfonylurea drug interactions?

A
  • Hyperglycemic drugs decrease effectiveness.
  • Disulfiram like reactions, i.e. Chlorpropamide
  • Protein binding - If something competes for protein binding, you’ll have increased activity iwth more insulin release and hypoglycemia.
89
Q

Meglitinides MOA

A
  • Repaglinide (Prandin)
  • Nateglinidie (Starlix)

MOA: Block ATP-dependent K+ channel in Beta cells ↑ insulin secretion.
Insulin release relative to glucose level***

If you take drugs when there’s no glucose increase (food intake), they won’t have the pancreas release a lot of insulin. Helps pancreas stimulate insulin release at meal times. Otherwise, ineffective.

  • Highly protein bound
  • Hepatic metabolism
  • Take before meals (Repaglinide 30 min, Nateglinide 1-10 min)
  • Peak effectiveness 1 hour, duration 3-4 hours
  • May be combined with Metformin, but not other oral agents (too similar).
  • If meal missed , skip dose!!!!
90
Q

If you miss a meal, how do you dose meglitinides?

A

Skip a dose

91
Q

ADR Meglitinides

A

Hypoglycemia
Weight gain

Small risk for:

  • Headache
  • Nausea
  • Joint pain
  • Use with caution in liver problems
92
Q

Biguanides:

A

Metformin (Glucophage ,Glucophage XL)
XL: increases duration of activity.

  • Buformin (Europe)
  • Phenformin (removed due to FATAL lactic acidosis)
  • Metformin/Glyburide (Glucovance)
  • Metformin/Glipizide (Metaglip)
  • Metformin/Rosiglitazone (Avandamet)

Combined drugs decrease pill burned.

93
Q

Metformin MOA

Biguanides

A

Mechanism:

  • ↓ Hepatic glucose production
  • ↑ Peripheral glucose uptake and utilization
  • ↑ tissue insulin sensitivity
  • ↓ Glucose absorption from GI tract
  • Limited hypoglycemia

Helps body use insulin better! Does not increase insulin release.

May see weight loss.

94
Q

Biguanides and Metformin PK

A

Not metabolized in liver, (hepatic disease contraindicated because of lactic acid being processed in liver - hepatic disease could lead to acidosis)

Not bound to proteins

Excreted unchanged by kidneys via renal tubular excretion (not used in renal impairment)

May be useful in obese patients with insulin resistance and hyperlipidemia.

No weight gain!!

95
Q

Biguanides and Metformin PK

A
  • Not metabolized in liver, but can’t use in hepatic disease, bc liver needs to be able to process lactic acid.
  • Excreted unchanged in kidneys; will have build up of lactic acidosis in renal impairment. :/
  • Good for obese patients and those with resistance.
  • NO WEIGHT GAIN.
96
Q

ADR Biguanides and Metformin

A
  • Metallic taste, N/V/D
  • Lactic acidosis can occur if patient has poor renal clearance.
  • Can occur after surgery if the kidneys had poor perfusion.
  • Rash
  • Megaloblastic anemia due to B12 absorption being inhibited; could supplement with a vitamin.
97
Q

CI: Biguanides and Metformin

A
  • Renal disease: CI if GFR < 30 mL/min
  • Metabolic acidosis or hypoxia
  • Hepatic disease
  • Cationic drugs compete for tubular excretion (it inhibits renal release).
98
Q

If a patient on a biguanide is going in for surgery, what do you do?

A

Should be stopped before surgery (withhold drug for 48 hrs after surgery due to ↑ lactic acid risk).

Reinitiate drug afterwards.
OK to stop for a few days.

99
Q

Thiazolidinediones (TZD) MOA

A
  • Pioglitazone (Actos)
  • Rosiglitazone (Avandia)

MOA:
Potent agonist for Peroxisome Proliferator Activated Receptor Gamma (PPAR - g); product that regulates transcription of insulin responsive genes. Increase transcription of genes to have better lipid and glucose metabolism.

  • ↑ peripheral glucose uptake and utilization
  • ↑ tissue insulin sensitivity, ~ 60%
  • ↓ Hepatic glucose production
  • Takes 6 to 12 weeks to see maximal effects, because gene transcription takes TIME.
  • Metabolized in liver
100
Q

What drug was removed from the market for liver toxicity?

A

TZD:

Troglitazone (Rezulin) (removed from market due to liver toxicity)

101
Q

ADR TZDs

A
  • Expanded blood volume and edema
  • Worsens heart failure
  • Increase HDL, LDL, or TG
  • Weight gain
  • Monitor liver FXC Q2months.
102
Q

If a patient on a TZD has ALT increase of 3x normal value, what do you do?

A
  • Stop the drug, metabolized by liver

- Biggest issue with Troglitazone (Rezulin)

103
Q

What TZD causes increased risk of CV death?

A

Occurs with Rosiglitazone (Avandia) - increase in risk ~43%.

No risk with PO form.

104
Q

Alpha-glucosidase inhibitors

A
  • Acarbose (Precose)
  • Miglitol (Glyset)

MOA:

  • Competitive inhibitors for a-amylase and a-glucosidase enzymes in intestinal brush border
  • Decrease glucose absorption; will have less glucose in blood stream and lower BG levels.
  • Not absorbed systemically
  • Metabolized by intestinal bacteria
  • Take with first bite of each meal.
  • Added onto other agents or insulin.
105
Q

ADR: Alpha-glucosidase inhibitors

A
  • Abdominal pain
  • Diarrhea
  • Flatulence - undigested carbohydrates, bacteria in colon will digest and produce gas.
106
Q

When are alpha-glucosidase inhibitors contraindicated?

A

IBD
GI obstruction
GI ulcer
Intestinal disease

107
Q

Incretins

A

GLP-1

  • Product released during meal time increases in glucose.
  • Only oral glucose will increase incretin (Not IV admin).

GLP1 MOA:

  • When BG > 90, releases L cells from intestine. GLP1 release increases glucose dependent insulin release from pancreas.
  • Increase insulin
  • Decrease glucagon
  • Will decrease gastric emptying and stimulate satiety.
  • Slows peak absorption of glucose and makes patient ingest less carbs.
  • GLP1 is reduced in patients with T2DM over time.
  • Metabolized by dipeptidyl peptidase - DDP-IV (a drug will inhibit this process later).
108
Q

GLP1 Summary

A
  • Secreted upon the ingestion of food
  • Helps with insulin secretion
  • Regulates gastric emptying time
  • Liver make less glucagon
  • Brain promotes satiety and reduces appetite
  • Cause pancreatitis (DDP4 cause SJS).
109
Q

Exenatide (Byetta)

A
  • Incretin mimetic (GLP1)
  • Isolated from Gila Monster

Indications:

  • Type 2 diabetics taking metformin and sulfonylureas
  • Good effects on weight loss; less caloric intake.
  • Protein-based drug; need to be administered SC.
  • Inject pre-filled pen 60min before meals.
  • Byetta has a greater spike in insulin release after meals; similar to a pt with no insulin resistance.
110
Q

ADR: Exenatide (Byetta)

A
  • N/V
  • Decreased gastric emptying
  • Tolerant to it over time though
  • Hypoglycemia; but more pronounced when on a sulfonylurea too
  • Delay absorption of other meds due to decreased gastric emptying
  • Weight loss is seen.
  • Can cause PANCREATITIS.
111
Q

Liraglutide (Victoza)

A

Incretins

Liraglutide (Victoza) – human GLP-1 analog linked to fatty acid binds albumin to be released slowly (t1/2 12 hrs)

Slower release = needs to be given less frequently; better for patient to not have to inject 2x daily; 1x/week preferred.

112
Q

Dulaglutide (Trulicity)

A

Incretins

Dulaglutide (Trulicity) – administered once weekly SQ

113
Q

Albiglutide (Tanzeum)

A

Incretins

Albiglutide (Tanzeum) – administered once weekly SQ

114
Q

Dipeptidyl Peptidase-4 inhibitors (DDP4)

A

Alogliptin (Nesina)
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Tradjenta)

Inhibit DDP4 to increase activity of GLP1 released.

ADR:

  • Diarrhea, HA
  • Angioedema
  • Anaphylaxis
  • Skin rash (Stevens Johnson)
115
Q

Sitagliptin

A

Synergism when given with metformin. Benefit.

116
Q

Metformin has a lot of GI side effects, what will combine with it best?

A

GLP1 best effects on satiety and gastric emptying. Has more GI side effecst than DP4.

DPP4 is better to combine iwth metformin; less GI effects.

Antibodies can be formed to GLP1 and they’re injectable, which makes htem less tolerable then oral meds in DPP4 inhibition.

DDP4 = SJS
GLP1 = Pancreatitis
117
Q

Sodium-glucose transporter 2 inhibitors MOA

A

Canagliflozin (Invokana)
Dapagliflozin (Farxiga)
Empagliflozin (Jardiance)
Combination products available

MOA: inhibits SGLT2 in proximal renal tubules, inhibits reabsorption of filtered glucose – increased renal elimination of glucose
Lowers blood glucose and body weight.

118
Q

Sodium-glucose transporter 2 inhibitors ADR

A

ADR:

  • UTI - fungal (cipro failed, sign of fungal UTI).
  • Hypotension
  • Raise serum potassium
  • Decreased kidney function
  • Bone resorption or bone fracture risk with canagliflozin
  • Risk for DKA (euglycemia) - normally happens when hyperglycemic. But here you pee out the sugar, with lack of insulin, so you have euglycemic DKA.
119
Q

ADR: canagliflozin

A

-Bone resorption or bone fracture risk

120
Q

Metformin

Efficacy
Hypoglycemia risk
Weight affect
SE
Cost
A
  • Reduces HbA1c
  • Low hypoglycemic risk
  • No weight change or weight loss
  • N/V/D
  • Risk of lactic acidosis in those with poor renal function.
  • Affordable
121
Q

Why won’t sulfonylureas work in T1DM?

A

Sulfonylurea increase insulin release from pancreas and type 1s cannot make their own insulin.

122
Q

If you can’t reach A1c with Metformin, what do you do?

A

Add on another drug.

123
Q

Metformin and sulfonylurea

Efficacy
Hypoglycemia risk
Weight affect
SE
Cost
A
  • High reduction of HbA1c
  • Hypoglycemia risk is moderate
  • See weight gain
  • SD hypoglycemia
  • Low cost
124
Q

Metformin and TZD

Efficacy
Hypoglycemia risk
Weight affect
SE
Cost
A

-High reduction HbA1c
-Low hypoglycemic risk
Weight gain
-Edema, HF worsen, bone
-Moderate cost

125
Q

Metformin w/ DPP4 inhibitor, SGLT2 inhibitor, GLP1

Efficacy
Hypoglycemia risk
Weight affect
SE
Cost
A

DDP4, SGLT2, and GLP1

  • Intermediate drop in A1c; high drop with GLP1
  • Low risk for hypoglycemia (all 3)
  • GLT2 and GLP1 agonist have weight loss
SGLT2 = Fungal UTI 
DPP4 = SJS
GLP1 = GI SE - pancreatitis
126
Q

Metformin and Insulin

Efficacy
Hypoglycemia risk
Weight affect
SE
Cost
A
  • Best ability to drop A1c, esp with sliding scale
  • High risk of hypoglycemia
  • Weight gain
  • SE hypoglycemia
  • Variable cost
127
Q

When is it apropriate to do a 3 drug regimen?

A

A1c not in check after 3 months of treatment.

Combine mechanisms that aren’t identical. Don’t mix GP1 inhibitor with DPP4 inhibitor.

128
Q

HYPERPROLACTINEMIA

A

….

129
Q

Hyperprolacintemia

A
  • Secondary to prolactin secreting tumors
  • Galactorrhea, amenorrhea, impotence, infertility

Tx with dopamine agonist decreases prolactin levels!!

Bromocriptine (Parlodel)
Ergotamine used in Parkinson’s disease
ADR: Dizziness, fatigue, HA, nausea
Used for ovulation induction in hyperprolactinemia as well.

Carbergoline (Dostinex)
ADR: HA, dizziness, nausea
Monitor BP

May need surgery for tumor.

130
Q

ANDROGENS

A

….

131
Q

Natural Steroids

A

Cholesterol helps produce other naturally occurring steroids like cortisol, aldosterone, progesterone, estradiol, and testosterone.

132
Q

Testosterone

A
  • Most important androgen; 8mg produced daily in men.
  • Made by testes
  • Converted to DHT by 5-a-reductase.
  • Converted to estradiol by aromatase.
  • Metabolized in liver.
  • Bound to intracellular androgen receptors affecting gene transcription.
133
Q

Hypothalamus-Pituitary-Gonad Axis

A

Hypothalamus releases GnRH, stimulates pituitary to release LH and FSH to act on testes to make testosterone.

Negative feedback loops. Enough product shuts down process. Don’t need anymore.

134
Q

Testosterone Androgens

A

Naturally occurring in humans:

Testosterone: AndroGel, depoAndro, Depo-Testosterone, Androderm, Striant, Testoderm, Testoderm TTS, Testopel, Andro-L.A., Depandrateo, Durathate, Testa Span, Testerone, Testim, Testone CYP 200, TestroAQ, Testro LA,Tostrelle, Tostrex, Virilon

Dihydrotestosterone: Testosterone converted to DHT by 5 a reductase.

135
Q

Synthetic testosterone: mainly esters or alkylated

A

Methyltestosterone (PO): Android, Testred, Virilon, Methitest

Fluoxymesterone (PO): Halotestin, Android-F, Hysterone, Ora-Testryl

Oxandrolone (PO): Oxandrin

  • Not used as much
  • Hard effects on the liver
136
Q

What happens when androgen react with tissues?

A

Testosterone:
Development of internal genitalia, skeletal muscle effects, erythropoiesis, hair follicles .

DHT:
External genitalia and hair follicles

Estrogen receptor mediated:
Closing of epiphyses, libido effects

137
Q

When are androgens used?

A
  • Male infertility
  • loss of gonadal function (orchidectomy)
  • Prevent osteoporosis
  • In HRT combined with estrogens (MT only)
T = testosterone
MT = methyltestosterone

All use both, except those indicated.

138
Q

When are anti-androgens indicated?

A

Metastatic prostate cancer

Tx hirsutism in women; anti androgen will block effect.

139
Q

What androgen is used to treat inoperable breast cancer?

A

-Inoperable breast Ca (Fluoxymesterone)

140
Q

What androgen is used for its anabolic properties in muscle wasting conditions?

A

-Offset weight loss due to burns, trauma, AIDS, COPD, other chronic diseases (Oxandrolone)

141
Q

Formulations of Androgens: ORAL

A

Oral formulation

  • Metabolized in liver
  • Not useful in oral administration, need MT or other preps to bypass liver metabolism.
142
Q

Formulations of Androgens: INJECTION

A

Injection

  • Oil based products have long-lasting effects
  • Depo Testosterone
  • Andriol
  • Delatestryl
143
Q

Formulations of Androgens: TRANSDERMAL

A

Transdermal

  • Androderm
  • Testoderm
144
Q

Anti-androgens

A

-Androgen receptor antagonists: Flu

145
Q

Anti-androgen receptor antagonists

A

AR antagonists:
-Flutamide (Evlexin)
-Bicalutamide (Casodex)
Used for advanced prostate cancer.

Mixed AR, MR antagonist:
-Spironolactone (Aldactone)
Causes gynecomastia due to antagonist effects.

Mixed PR agonist, AR antagonist: cyproterone acetate

5a reductase inhibitors; block conversion to DHT:
-Finasteride (Proscar)
Used for prevention of growth of prostate tissue

146
Q

Side effects of androgens

A
  • Prostatic enlargement/ prostate cancer
  • Testicular atrophy, azoospermia
  • Gynecomastia, acne
  • Erythrocytosis – not in most men
  • Increased sodium/water retention: problem in patients with CHF
  • 17 alkylated androgens have hepatic effects- cholestasis, reduced HDLs, possibly hepatitis (esp a problem with oral administration)
  • Masculinization in women: hair growth, deep voice
147
Q

What is used to treat BPH?

A

DHT inhibitor (competitive inhibition of 5a reductase)
-Finasteride (Proscar, Propecia)
-Dutasteride (Avodart)
TERATOGENIC; don’t let women handle these drugs, bc will hurt developing fetal hormones.

GnRH analogue: GnRH analogue given SC or IM:
Lowers testosterone production
-GOSERELIN, LEUPROLIDE
Decrease release of LH, FSH, and testosterone.

148
Q

ADRENOCORTICAL INSUFFICIENCY

A

..

149
Q

Corticosteroids

A

Affect gene transcription by binding to receptors in nucleus.

  • Glucocorticoid receptor - work on inflammation
  • Mineral corticoid receptor (aldosterone) - important to maintain water balance and BP. Lead to reabsorption of sodium from DCT to retain water/salt.

Too little MC activity leads to hypotension, leaky vessels.

150
Q

How do you treat a mineralocorticoid insufficiency?

A

Cortisol (hydrocortisone)

  • 10-20mg secreted daily
  • Followed circadian rhythm.
  • Increased stress increases release of it.

Cortisol spikes in severe infection and sepsis.

151
Q

Chronic Addison’s Disease

A

Chronic cortisol insufficiency

  • Hypotension, weakness, fatigue, weight loss
  • Inability to maintain glucose levels
  • Acute stress or colds can cause acute adrenal insufficiency, which leads to circulatory shock from not maintaing BP which leads to death.

Tx: Hydrocrotisone daily; preffered acti

152
Q

Chronic (Addison’s disease)

A
  • Weakness, fatigue, weight loss, hypotension
  • Inability to maintain glucose
  • Minor events can cause acute adrenal insufficiency (stress, colds, etc.).
  • Circulatory shock > death
  • Circ shock: can’t maintain BP.
  • Tx: 20-30 mg hydrocortisone given daily
  • Preffered activity at mineralocorticoid receptors.
  • Increased amounts during stress to supplement!
  • Must also use salt-retaining hormone (fludrocortisone)
  • Long acting, NON-salt retaining should be avoided.
153
Q

Fludrocortisone

A

used for patients with severe adrenal insufficiency to maintain BP

154
Q

THYROID

A

155
Q

How do you treat hypothyroidism?

A
Levothyroxine (T4)
Levothroid, Synthroid
-Drug of choice
-Long duration of action
-Oral (parenteral for pts undergoing organ harvest)

T4 can be bound by iron, calcium, and aluminum interfere with absorption. Need to separate out.

Antibiotics also affect absorption.

Drugs that induce hepatic P450 enzymes enhance excretion of drug.

Used for suppressive therapy

156
Q

When is Liothyronine used to treat hypothyroidism?

A

Liothyronine (T3)
Cytomel, Triostat

  • Oral and parenteral (oral absorption > 95%)
  • Used when a FASTER onset of action is desired.
  • Requires more frequent dosing (1/2 life 1 day)
  • Higher cost
157
Q

Liotrix (Thyrolar)

A
  • Combination of T3 and T4
  • Oral only
  • More natural ratio of T4:T3.
158
Q

Clinical uses for thyroid hormone replacement therapy

A
  • Hashimotos thyroiditis
  • Myxedema
  • Subtotal thyroidectomy
  • Radioiodine ablation of thyroid

DRUGS

Levothyroxine (T4)
Levothroid, Synthroid

Liothyronine (T3)
Cytomel, Triostat

Liotrix (Thyrolar)

159
Q

MOA of thyroid hormones

A

Free TH enters target cell, T4 converted to active T3. Enters nucleus, binds to receptor and starts to regulate gene transcription to have normal thyroid function.

160
Q

What drugs are used to treat hyperthyroidism?

A
Antithyroid drugs (Thioureylenes)
-Propylthiouracil (PTU)
  • Methimazole (Tapazole)
  • More potent that PTU
  • CI liver dysfunction (decreased metabolism)

MOA:

  • Interfere with the oxidation of iodide ion by inhibition of the peroxidase enzyme
  • Interferes with organification of iodine (Iodine added to precursor). Depletes thyroid hormone from being produced.

USES:
Grave’s disease, multinodular goiter to shrink before surgery

ADR: agranulocytosis (RARE)

161
Q

Radioactive Iodine

A
  • Radioactive iodine is used for scanning thyroid or doing ablation of gland.
  • Radioactive effect destroys tissue.

Useful for thyroid cancer. Can cause delayed hypothyroidism.

162
Q

Iodides (Sat. soln. of K iodide in Lugol soln.).

A
  • Treats hyperthyroidism.
  • Used in addition to PTU or methimazole.
  • Improves thyrotoxic symptoms in 2-7 days.

ADR: rash, swollen salivary glands

Can be used prophylactic when at risk of radiation exposure - load up on iodine to prevent uptake of the radioactive formulation.

163
Q

Iodide MOA

A

Trapped, converted iodide > iodine. High levels of iodine inhibits process and decreases amount of thyroid hormone being released.

Organification - produces iodide added onto tyrosine molecules forming MIT and DIT.

MIT and DIT add together to form T3 and T4; can be blocked by high levels iodine as well.

1 MIT + 1 DIT = T3 active form
2 DIT = T4

5 times more T4 than T3 released normally.

Thyroxine - remove iodine = T3
Otherwise, reverse T3 happens, inactive.

164
Q

What is used to treat thyroid storm?

A

Iodinated contrast media (Ipodate)

Emergency treatment of thyroid storm.