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844 - Therapeutics II > Exam 2 > Flashcards

Exam 2 Flashcards

1
Q

What are the 3 main causes of CKD?

A

Diabetes mellitus - The high glucose concentration causes the blood to be very thick, which impacts the filtering of the glomerulus.

Hypertension - High pressure impacts the autoregulation of the pressure of the blood that enters the glomerulus.

Glomerulonephritis

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2
Q

Why does CrCL overestimate the kidney function of someone with declining kidney function?

What is MDRD?

A

Creatinine clearance is a good estimate when the kidney function is stable. The value reflects filtration but not secretion, which happens more when kidney function is impaired.

MDRD - The most accurate measure of GFR. It takes in rate and gender into consideration.

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3
Q

What are the 5 functions of the kidney and what are their related complications in CKD?

A
  1. Excrete waste products of metabolism from the blood -> Uremia - build up of waste products in the blood
  2. Regulate the body’s concentration of water and salt -> Fluid retention
  3. Maintain acid/base balance of plasma -> electrolyte imbalances
  4. Synthesize calcitriol -> Mineral and bone disorder
  5. Secrete hormones (EPO, rennin, PGAs) -> Anemia
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4
Q

What is uremia and how do patients with uremia present?

A

Uremia - Symptoms due to ESRD caused by the accumulation of waste molecules in the blood that are normally removed by the kidneys.

Symptoms -
- Uremic fetor (ex. urine smelling breath)
- GI symptoms like anorexia, NV, constipation, metallic taste
- Mineral and bone disorder
- Restless less syndrome
- Anemia
- Uremic frost (crystallizes in skin to cause itching)

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5
Q

How does hyperphosphatemia cause mineral and bone disease in CKD patients?

A

Phosphate retention causes increased parathyroid hormone production, which makes the body think it needs more calcium, so it ends up pulling calcium from the bone.

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6
Q

What are the advantages and disadvantages of these phosphate binders:
- Calcium carbonate
- Calcium acetate

A

Calcium carbonate - Cheap, SE is constipation

Calcium acetate - More expensive than Tums, less elemental calcium, may bind calcium better than Tums, SE is constipation

**do not exceed 1500mg of elemental Ca2+

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7
Q

What are the advantages and disadvantages of these phosphate binders:
- Sevelamer carbonate
- Lanthanum carbonate
- Aluminum hydroxide

A

Sevelamer carbonate - Not absorbed which reduces systemic toxicity, decreases uric acid and LDLs, really expensive, no serious ADRs, SE are GI upset, N/V, diarrhea

Lanthanum carbonate - Works over a variety of pHs in the body, SE is mild stomach upset

Aluminum hydroxide - Decent at phosphate binding, can cause aluminum toxicity, horrible

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8
Q

What are the advantages and disadvantages of these phosphate binders:
- Sucroferric oxyhydroxide
- Ferric citrate

A

Sucroferric oxyhydroxide (Velphoro) - No increase in iron concentrations due to such tight binding, SE is darkened stools

Auryxia (ferric citrate) - Iron gets absorbed, seen in increase of TSATs and ferritin, SE is discolored feces

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9
Q

How is secondary hyperparathyroidism caused in CKD patients?

A

Because the kidneys don’t activate Vitamin D anymore, there is a decrease in calcium serum concentrations. This makes the parathyroid gland secrete more parathyroid hormone, which increases calcium mobilization from bone.

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10
Q

What are the Vitamin D compounds that we use in secondary hyperparathyroidism? When do we give one type versus the other?

A

Unactivated vitamin D - Requires activation, good if pt still has kidney function
- Ergocalciferol
- Cholecalciferol

Activated Vit D - for CKD stage 5 pts mainly
- Calcitriol: cheapest, but highest change of hypercalcemic events
- Paricalcitol (Zemplar): most favorable adverse event profile, less calcemic activity compared to calcitriol
- Doxercalciferol: Prohormone that is activated in the liver

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11
Q

What are the calcimimetics we use for secondary hyperparathyroidism in CKD and how do they work? What are the side effects? And what are important counseling points?

A

Cinacalcet (Sensipar) - Minics action of calcium by binding to sensing receptor (CaR), then induces a conformational change to the receptor, which triggers PTH gland to decrease PTH secretion
- Side effects: hypocalcemia

Etelcalcetide (Parsabiv) - IV formulation of cinacalcet

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12
Q

Why does anemia happen in CKD patients?

A
  1. Decreased production of erythropoietin
  2. Uremia causes a decreased life span of red blood cells
  3. Vitamin losses during dialysis
  4. Blood loss through dialysis
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13
Q

What are MCV and RDW and how do we interpret them?

A

MCV - Average size of red blood cells. Normal value is 80-96 um^3

RDW - Red cell distribution width. Normal value is 11.5-14.5%. If not in range, then the distribution is off.

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14
Q

What are TSAT and ferritin? What are the goal values?

A

TSAT - transferrin saturation. Normal range is 20-30%

Ferritin - stored iron in the body. Normal range is 200-500 ng/mL

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15
Q

What are the oral and IV iron treatments that we can use in CKD and ESRD patients? Why can’t we always use oral iron treatments for CKD patients?

A

Iron won’t work for patients on dialysis, so we need to use IV iron in these pts.

Oral iron, heme iron
- Side effects: stomach upset
- Take with food

IV: Preferred for CKD 5D patients
- Iron dextran: test dose due to possible allergy
- Sodium ferric gluconate: 8-10 doses
- Iron sucrose: 10 doses; only one that have non-dialysis pt indication (IV push x 5 doses)

Infused into dialysate: Triferic (ferric pyrophosphate citrate)

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16
Q

What are ESAs? When do we use them, how are they administered, what do we monitor for effectiveness, and what are the 3 types?

A

ESAs - Erythropoiesis stimulating agents. We use them after the correctable causes of anemia have been addressed.
- In CKD 3-5ND pts: Start when Hb < 10g/dL
- In CKD 5D: Start when Hb is between 9-10 g/dL

Don’t use ESA to push Hb above 11.5 g/dL due to risk of cerebrovascular AEs

Epogen - Recombinant human erythropoietin; stimulates erythroid progenitor cells

Aranesp - Darbepopetin alfa; stimulates erythroid progenitor cells, but has 3 fold longer half life than epogen

Mircera - Methoxy polyethylene glycol; Extended half life

Adverse effects: Pure red cell aplasia PRCA, meaning antibodies develop to EPO

Monitor Hb

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17
Q

What are the requirements for protein, energy, and vitamins for pts who have CKD and ESRD?

A

Protein - 0.8g/kg/day if GFR is less than 30mL/min; 1.2g/kg/day if ESRD

Energy - 60-65 kCal/kg/day

Vitamins - Need water soluble vitamin ( Vit B, Vit C) replacement if ESRD
- use Nephrocaps, Nephron FA

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18
Q

What are the indications for renal replacement therapy?

A

Renal replacement therapy -
- Indications: Acid/Base balance, Electrolytes (Na+/K+), Intoxication, Overload of fluid, Uremia
- NOT indicated for mineral and bone disorder, anemia, or phosphate

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19
Q

What’s the difference between intermittent and continuous renal replacement therapies and where is each one used in practice?

A

Intermittent - Sessions last 3-4 hours. Usually MWF or TRS. Used for ESRD patients.
- Initiate when BUN > 100, Scr > 10, and consider signs of uremia

Continuous - Uses the patient’s peritoneal membrane as a dialysis membrane. The patients can carry the solution and drainage bag on their bellies and go about their day. There’s different schedules of when the bags need to be switched.

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20
Q

What’s the difference between AV fistulas and grafts (survival rates, times to maturity, and risk of infection)?

A

AV fistula - The artery and vein is connected, which causes a mass that allows for easy IV access. These have the longest survival rates (~20 years), fewer complications, but takes 1-2 months to “mature” enough to be used. Not very fast

AV graft - Synthetic connection between vein and artery. There’s a shorter survival, higher infection rate, but it only takes 2-3 weeks to be ready, so it’s much faster if something like blood flow is a problem.

fistula:graft:cathether infection -> 1:2:30

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21
Q

How is a hemodialysis session conducted?

A

Blood leaves the body, goes through dialyzer, where the dialysate is flowing through the opposite way. As they flow through the dialzyer, the waste products get removed through the semi-permeable membrane, then the nutrients go through the dialyzer and the blood goes back into the body.

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22
Q

How do we measure hemodialysis efficacy?

A

Kt/V = measure of the function of total body water that is cleared of urea
- Goal = 1.4

K = Cl of urea
V = Vd of urea
t = time

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23
Q

What substances are not removed from the dialyzer

A
  • High Vd
  • High lipophilicity
  • Large molecular weight
  • Highly protein bound
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24
Q

What opportunities are there for pharmacists in the care of older adults?

A

Long term care facilities -
- Support providers when they have medication questions
- consult on medication regimens
- recommendations about initiating/adjusting medications based on clinical data
- Consultant pharmacy services: review med administration, pt charts, medication storage

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25
Q

What medications may result in more adverse events than benefits in older adults? NOT DONE

A

Water soluble drugs: decreased Vd and increased conc. (ex. atenolol)

Lipid soluble drugs: increased Vd and increased t1/2 (ex. rifampin)

Hepatically-cleared drugs: decreased clearance and increased t1/2 (ex. propranolol)

Renally-cleared drugs: decreased clearance and increased t1/2 (ex. atenolol)

Anticholinergic drugs -

Sedatives/meds with CNS effects - falls

Diabetic agents:

Medications that may exacerbate chronic conditions:

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26
Q

What is the role of palliative care and advance care directives supporting end of life care in older adults?

A

Palliative and End of Life Care:
- Align medications with goals (if they are appropriate)
- Ensure effective control or bothersome symptoms
- Educate family and providers on medication regimen
- Activate non-standard dosage forms if needed
- Support financial concerns
- Ensure safe and legal disposal of medications

Advanced Care Directives (ACD):
- Helps people make decisions about their health care when they are unfit to

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27
Q

What is the definition of healthy aging? What are the largest contributors to functional decline?

A

Healthy aging - The process of developing and maintaining the functional ability that enables wellbeing in older age. We want the person to engage in activities they value.
- Mental, nutritional, and cognitive health, stable housing, physical health, access to health care

Largest contributors to functional decline: Musculoskeletal & cardiovascular

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28
Q

What are the 3 goals of care for older adults?

A
  1. Maintain independence (daily activities, finances, transportation)
  2. Avoid the need for institutionalization
  3. Maintain quality of life
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29
Q

What classes of medications are known to cause more risk of falls and why?

A

Neuroleptics/antipsychotics
Antidepressants
Opioids

These target sites in the brain which result in increased risk of fall

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30
Q

What are the 3 main medication problems in older adults?

A

Polypharmacy - Medications without indication, medications treating adverse effects, 40% don’t understand medications well

Nonadherance

Altered pharmacokinetics - Lots of changes associated with aging (esp. decreased baroreceptor response/activity and reduced heart rate variability, which is especially apparent when going from standing to sitting)

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31
Q

Beers criteria:
1. How are decisions about recommendations decided?
2. Who is involved in the decision-making process?
3. What types of evidence/literature are evaluated?
4. How does the committee describe quality of evidence and strength of recommendation?

A
  1. 2 years of article searches - A panel of people analyze over a thousand studies to make their decisions. They focused on adverse drug events.
  2. Clinicians that had experience in different settings
  3. Controlled trials, observational studies, systematics reviews, meta-analysis for 65 years old +
  4. Evidence: High - further research probably won’t change confidence in answer due to quality of research. Moderate - further research may change confidence in answer due to limitations in research. Low - further research will most likely change confidence in answer due to bias and limitations.

Strength: Strong - Clear that risks outweigh the benefits. Weak - Not clear that risks really outweigh the benefits.

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32
Q

What are the 4 main considerations when choosing medications for older adults?

A
  • Life expectancy
  • Goals of care
  • Treatment targets
  • Time required to benefit

Less options if the patient has less time and needs palliative treatment; More options if the patient has more time and wants curative treatment.

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33
Q

What is the definition of palliative care?

A

Happens after the diagnosis of a terminal illness, the disease is not responsive to curative treatment or the treatment doesn’t exist.
- Now we focus on medical, psychological, social, and spiritual care for patient and family, optimizing the quality of life of the patient, and stop medications that aren’t improving QOL

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34
Q

What is hospice care?

A

Can be provided at home, a long term care facility, or an independent facility. Used when the life expectancy is 6 months or less (certified by MD). Diagnostic tests, hospitalizations, and labs are no longer covered by insurance.

35
Q

What is an Advanced Care Directive?

A

ACD - Verbal and written instructions about future medical care & treatment.
- Health Care Representative: Names someone to make decisions if you are unable (or prevents someone from making decisions for you)
- Psychiatric Advance Directive: Sets preferences regarding mental illness during periods of incapacity
- Power of Attorney: Financial or health care grants power to others you choose

36
Q

What is a POST?

A

Physician Orders for Scope of Treatment - A legal documentation of preferences for resuscitation, medication interventions, antibiotics, and artificial nutrition
- it’s an agreement between the patient and physician that must be signed and dated to be valid

37
Q

What is the most common type of urinary incontinence?

A

Urge (63% in women, 59% in mens)

38
Q

What is the 3 step process in normal bladder function?

A
  1. Stretch receptors tell the brain that the bladder is full and needs to empty. β3 receptors support relaxation/filling.
  2. Neurologic stimulation initiates contraction. Ach receptors at the top of the bladder, α-adrenergic receptors in the base of the bladder/proximal urethra.
  3. Sphincter in bladder relaxes allowing release of urine.
39
Q

What 3 age-related changes happen to the bladder and urethra and what 2 things may they result in?

A

Changes: decrease in bladder capacity/elasticity, increase of spontaneous detrusor contractions, decrease in sphincter compliance

Result: incomplete bladder emptying and a decrease in the ability to postpone urination

40
Q

What is urge urinary incontinence? What are the symptoms, and what are the causes?

A

Urge (aka Overactive bladder) - hyperactivity of the detrusor muscle causes sudden and poorly predictable voiding, which may cause large or small volume accidents.

Symptoms - Urgency, frequency

Causes - Neurologic, medications (ex. acetylcholinesterase inhibitors for alzheimer’s disease)

41
Q

What is stress incontinence? What are the risk factors? What class of drugs can exacerbate the symptoms?

A

Stress - Outlet incompetence, meaning the external urethral sphincter is weak + abdominal pressure or from detrusor muscle. This happens in women more than men. Seen with a small volume of accidents (ex. when coughing, laughing, drinking, caffeine).

Risk factors - Multiple childbirths, estrogen deficiency

Exacerbate symptoms - alpha-antagonists

42
Q

What is overflow incontinence? What are the symptoms? What are the common causes?

A

Overflow - outlet obstruction or inability to or uncoordinated detrusor constriction.

Symptoms - Abdominal discomfort or pain, frequency, feeling the need to void shortly after voiding

Causes - BPH, prostatic blocking of urethra

43
Q

What is neurogenic (atonic) bladder? What are the potential causes? What are the symptoms? What does it increase the risk of?

A

Happens when there is disruption in neurologic innervation of the bladder. It leads to inability or uncoordinated detrusor constriction.

Causes - Atony of bladder muscle due to stroke, neuropathy (ex. due to diabetes), or spinal cord injury

Symptoms - Small urine volume during voiding, small volume accidents, loss of feeling that bladder is full, dribbling of urine, frequency, urgency

Risks increased - UTI, kidney stones

44
Q

What is functional incontinence? What are the causes?

A

Functional - Physical inability to get to the bathroom in a timely fashion

Causes - Physical impairment (mobility), change in mental status (demetia), UTI, medications (sedating)

45
Q

What are the common medication causes for frequency, urgency, and overflow incontinence?

A

Frequency - diuretics, alpha antagonists

Urgency - Acetylcholine esterase inhibitors

Overflow - Alpha antagonists, antihistamines

46
Q

What are the 5 non-pharm treatments we should try for urinary incontinence?

A
  1. Scheduled/times voiding
  2. Pelvic floor muscle strengthening (Kegel): 30-60x/day
  3. Avoiding irritants (coffee, alcohol, caffeine, avoid water before bed)
  4. Absorbent products (pads, shields, adult diapers)
  5. Catheters
47
Q

What pharmacologic options do we have for urge UI management? What are counseling points for these drug classes?

A

Anticholinergics/antimuscarinics - (ex. oxybutynin, tolterodine) May cause dry mouth, constipation, fatigue, confusion, and may induce overflow incontinence, constipation; first line because they are cheaper

β3-agonist - (ex. Mirabegron, vibegron) May cause minor increase in BP, UTI; more effective, but $$$

counseling - do not crush/split long-acting formulations unless scored, max benefit takes at least 4 weeks to achieve, stopping too quickly may cause recurrence of symptoms that is worse than baseline

48
Q

What are some clinical pearls about urge UI management?

A

Clinical -
- Time to benefit of medications is approximately 4 weeks
- Active drug shows 50% reduction, the placebo is 30% reduction
- About 65% experience an adverse event
- Stopping medication abruptly may result in accidents/episodes that are worse than baseline

Administration -
- Do not split or crush oral tablets
- Patch is applied twice weekly, rotating sites (remove prior patch)

49
Q

What are the 5 steps of stress UI management?

A
  1. Non-pharmacologic management -> Kegel
  2. Duloxetine 40mg twice daily (adrenergic activity increases sphincter tone to prevent leaks)
  3. Topical estrogen (vaginal atrophy) like estrogen vaginal cream, intravaginal cream, 21 days on and 7 days off
  4. Alpha-agonists
  5. Vaginal pessaries or surgery
50
Q

What are the 3 steps of overflow UI management?

A
  1. Address the obstruction
  2. Alpha-adrenergic blockers (if BPH)
    - Doxazosin 1-4mg once daily, Tamsulosin 0.4mg once daily (less hypotension, slightly more selective for bladder neck)
  3. Catheterization
51
Q

What are the options for neurogenic UI management?

A

No pharmacologic management routinely effective, so we focus on non-pharmacologic management like scheduled voiding.
- Intermittent catheterization (thin, flexible tubes collecting urine)
- Botox injections into bladder or urinary sphincter
- Surgery like augmentation cystoplasty

52
Q

What types of catheters are there?

A

Intermittent straight - Rubber latex, silicone, PVC
Indwelling (Foley) - Chronic
Condom
Suprapubic

53
Q

What are the causes of diabetes and what are the manifestations of diabetes?

A

Type 1/Insulin dependent: Caused by lack of functioning pancreatic beta cells, usually due to antibodies destroying them. Early age onset around 12 yo. Family history is probably negative.

Type 2/Non-insulin dependent: Seen in 80% of obese population, usually over the age of 35

  • Hyperglycemia: decreased glucose uptake in insulin-dependent glucose uptake cells, decreased glycogen synthesis (normally insulin promotes glycogen production), increased conversion of amino acids to glucose
  • Glucosuria due to high blood glucose
  • Hyperlipidemia: Can’t get glucose out of the blood stream, so there’s increased fatty acid mobilization from fat cells and increased fatty acid oxidation (leading to ketoacidosis)
  • Uninhibited glucagon: Usually, insulin inhibits glucagon in presence of glucose, but here, glucagon keeps getting secreted.
54
Q

What are the types of diabetes and how do they differ?

A

Type 1 - Insulin-dependent diabetes mellitus. The person no longer has functioning insulin-secreting pancreatic beta cells (maybe caused by antibodies that destroy them). They depend on exogenous insulin. Ketoacidosis is common because insulin-dependent glucose absorption is altered, so fatty acids are oxidized for fuel, producing ketones.

Type 2 - Non-insulin dependent diabetes mellitus. Seen in 80% of obese people, onset is later in life compared to Type 1. There is a diminished first phase in insulin release. No glucose reduction in liver after a meal, slower glucose utilization in skeletal muscle, muted suppression of lipolysis in adipose tissue.

55
Q

What are the effects of insulin, glucagon, somatostatin, and amylin on the metabolic defects of diabetes?

A

Insulin - Stimulates uptake and utilization of glucose

Glucagon - Stimulates glycogen breakdown and increases blood glucose

Somatostatin - General inhibitor of secretion of α and β cells, meaning it inhibits secretion of insulin and glucagon

Amylin - Co-secreted with insulin. Slows gastric emptying, decreases food intake, and inhibits glucagon secretion

56
Q

What is the mechanism of insulin release by pancreatic beta cells?

A

Insulin is synthesized in the beta cell as a single peptide, then is cleaved (prodrug) into α and β chain (and C peptide) in the secretory granule by proconvertases.

In a high glucose state, glucose enters the beta cell through GLUT2 transporter. Glucokinase phosphorylates glucose into G6P. The metabolism of this causes ATP to go up and ADP to go down. ATP binds to the K+/ATP channel, closing it. This causes depolarization of the cell, which causes Ca2+ channels to open to balance the cell. The opening of the Ca2+ channel causes release of insulin from the insulin granules inside the beta cell.

57
Q

What are the roles of α and β subunits of the insulin receptor and what is the effect of the tyrosine kinase activity of the receptor?

A

α subunits - these are the regulatory units. They repress the catalytic activity of the beta subunit. This repression is relieved by insulin binding

β subunits - contain tyrosine kinase catalytic domains that are autophosphorylated when insulin binds.

Tyrosine kinase activity - autophosphoylation of the receptor leads to recruitment of insulin receptor substrate (IRS): Increased glycogen synthesis and decreased gluconeogenesis (esp. in the liver)!!
1. Stimulation of MAPK pathway that increases storage of fatty acids as lipids (lipogenesis) and stimulates the use of glucose for cell growth and proliferation
2. PI3K is recruited, which recruits PIP2 -> PIP3, which then recruits PDK1 to the membrane. This leads to a downstream effect of increased breakdown of glucose (glycolysis) and transport of GLUT4 to the surface to promote glucose uptake (esp. in the muscle and fat).

58
Q

What are the rates of onset, duration of action, and what modifications do these insulins have: Regular, Lispro, Degludec, Glargine, Aspart, NPH, Glulisine, Detemir

A

Ultra rapid onset/very short action:
- Lispro (Humalog): Human, switched Proline (P28) and Lysine (K29) on insulin beta chain, resulting in decreased self-association, 5-15min onset
- Aspart (Novolog): Human, switched Proline (P28) to Aspartate on beta chain, resulting in decreased self-association, 5-15min onset
- Glulisine (Apidra): Human, Asparagine (Asn3) and Lysine (K29) switched to Lysine and Glutamine, resulting in decreased self-association, 5-15min onset

Rapid onset/short action:
- Regular (R)

Intermediate onset/action:
- NPH (N): Protamine binds the insulin tightly, tissue proteases release the insulin, resulting in slow absorption and long duration of action.

Slow onset/long action:
- Glargine (Lantus): Human, Asn21 of alpha chain is changed to glycine, which alters solubility of insulin. 2 Arginine added to end of beta chain. Post-injection, it precipitates due to the pH, and is then slowly released from the injection site over 24 hours.
- Detemir (Levemir): Human, Thr30 of beta chain is deleted, Lys29 is myristylated, so it binds to serum albumin extensively and slowly disassociates over time.
- Degludec (Tresiba): Human, Thr30 is replaced by g-Glu/C16 fatty acid, so it binds to serum albumin extensively and slowly disassociates over time.

59
Q

How are insulins utilized to effect tight glycemic control?

A

Goals of therapy: keep blood glucose below 150mg/dL to prevent/delay onset of complications; also want to reduce symptoms of polyuria, dehydration, and ketoacidosis

Lispro, Aspart, Glulisine - Injected immediately before meals due to its rapid onset.

Glargine, Degludec - Once daily injection, has no pronounced peak.

Detemir - Injected once or twice daily

60
Q

What is the clinical significance of HbA1c levels and how could it relate to other long-term complications of diabetes?

A

HbA1c: We want the HbA1c to be below 6. Once it’s over 6 there is an increased risk for retinopathy.

Long-term complications of high glucose:
- Cardiovascular: micro and macro angiopathies
- Neuropathy: More glucose in the blood leads to increased utilization of the polyol pathway (aldose reductase), which leads to consuming reducing equivalents that make the neurons more susceptible to oxidative damage and increased cytosolic water in neural cells.
- Nephropathy: Excess glucose leads to changes in renal vasculature and the glomerular basement membrane
- Ocular: Cataracts, retinal microaneurysms, hemorrhage
- Increased susceptibility to infections

61
Q

What are the mechanisms of actions, adverse effects, and drug interactions of sulfonylureas?

A

Sulfonylureas -
-MOA: Enhance insulin secretion from beta cells. Binds to sulfonylurea receptors on the K+/ATP channel, which inactivates the K+ channel and depolarized the cell, making Ca2+ channels open, resulting in insulin release
- AE: includes hypoglycemia, GI problems, weight gain, secondary failures (eventual loss of b-cell function)
- DI: drugs that increase risk of hypoglycemia (alcohol, high dose salicylates), things that displace sulfonylureas from plasma protein binding (salicylates, phenylbutazone, sulonamides, clofirate), drugs that cause hyperglycemia
- Ex. 1st gen: Tolbutamine, Chlorpropamide; 2nd gen: Glimepiride, Glyburide

62
Q

What is the mechanism of action of metformin? What advantages does it have over sulfonylureas? What contraindications does it have?

A

Metformin - Decreases blood glucose concentration in non-insulin dependent diabetes mellitus without the concentration falling below normal. It sensitizes target tissues to insulin. It activates AMP-activated kinase, which most importantly inhibits FBPase step in gluconeogenesis, thus inhibiting export of glucose from the liver. It also increases glycolysis and glucose uptake in muscle and fat cells through rab pathway that translocates GLUT4.

Advantages over sulfonylureas - rarely causes hypoglycemia or weight gain

Contraindicated - In patients with disorders that increase the tendency toward lactic acidosis.

  • It also decreases serum triglycerides, serum LDLs, and reduces risk of CV events
63
Q

What is the role of α-glucosidase and SGLT2 inhibitors in diabetic therapy? What are the mechanism of actions and differences between them?

A

α-glucosidase inhibitors: Acarbose, Miglitol
- These decrease the absorption of carbs from the intestine by inhibing the gut α-glucosidases, so disaccharides don’t get metabolized into monosaccharides. However, they can cause GI issues because bacteria in the gut like to feed on the left over disaccharides.

SGLT2 inhibitors: Canagliflozin, empagliflozin, dapagliflozin, ertugliflozin
- These decrease the threshold for glucose excretion in urine, so we inhibit reabsorption of glucose in the PCT, resulting in more excretion of glucose in urine (and sodium)
- We see significant weight loss with these, partly because of diuretic effect and because we are peeing out carbs we used to be absorbing.
- See more genital infections and it’s contraindicated if pt has renal impairment

64
Q

What is the role of adipokines in the development of type 2 diabetes?

A

Adiponectin increases sensitivity of fat and muscle to insulin, but it’s usually decreased in type 2 diabetics. Adiponectin is activated by PPAR-g

65
Q

What is the incretin effect? What is the physiological and molecular basis for GLP-1 analogs and amylin therapy in the treatment of diabetes?

A

Incretin effect - Oral glucose stimulates a larger insulin response than IV glucose. This is because GLP-1 stimulates excitation secretion and transcription coupling in the beta-cell in response to glucose, leading to increase in insulin secretion through the cAMP pathway.
needs glucose already there (amplifies, doesn’t create)

GLP-1 levels may be decreased in type 2 diabetes, so we can provide a long-lasting GLP-1 analog, prevent degradation of endogenous GLP-1, and/or use positive allosteric modulators for the GLP-1 receptor.

  • Agents that enhance the incretin effect: GLP-1R agonist, GLP-1 and GIP dual agonists, DPP-IV inhibitors (inhibits the enzyme that degrades GLP-1)

Amylin analogs slow gastric emptying, decrease food intake, and inhibit glucagon secretion, which blunts the postprandial rise in blood glucose. This is useful in Type 1 and 2 diabetes

66
Q

What are the important structural features of sulfonylureas, SGLT2 inhibitors that determine their mechanisms of action?

A

sulfonylureas - sulfonyl group that binds to sulfonylurea receptor

SGLT2 inhibitors - glucose moiety is what blocks the transporter that would otherwise reabsorb glucose.

67
Q

What drug class can effect blood glucose levels (particularly in diabetics)? What differentiates them? (Exenatide, liraglutide, dulaglutide, lixisenatide, semaglutide, soliqua, xultophy) What are the common adverse effects?

A

Glucagon-Like Peptide 1 Analogs - Lower BG
- Exenatide (from Gila monster saliva) - co administered with other diabetes meds
- Liraglutide (Victoza) - co administered with other diabetes meds
- Dulaglutide (Trulicity): disulfide bonds cause slow release of GLP-1 peptides
- Lixisenatide (Adlyxin)
- Semaglutide (Ozempic) - Extensively bound to serum albumin, thus resulting in once a week injection
- Semaglutide (Rybelsus) - Orally available due to hydrophilic spacer
- Soliqua - glargine + lixisenatide
- Xultophy - degludec + liraglutide

**N/V, pancreatitis, risk of thyroid C-cell tumors (avoid if in family history)

68
Q

What are the mechanisms of insulin resistance in pregnancy? What hormones could possibly cause this? How can we treat this?

A

In early pregnancy, when the placenta is growing and the mother’s fat storage increases, there is an increased insulin response. In late pregnancy, there is reduced insulin sensitivity due to the growth of the fetus. Normally, this should be compensated by an increase in insulin secretion.

Around week 24, we can see if the woman may have gestational diabetes. It can lead to the fetus producing high levels of insulin and having excess storage of fat due to the excess glucose.

CRH-Cortisol, Progesterone, Placental GH, and Placental lactogens all increase throughout pregnancy and are thought to increase insulin resistance.

Placental lactogen activates prolactin and GH receptors, and the GH receptors are what’s thought to lead to insulin resistance. Mutations in prolactin receptor are associated with GDM.

Treatment:
- Diet: complex carbs, small meals
- Insulin is gold standard because it doesn’t cross placenta.
- Glyburide works but may cause harm to fetus, metformin works and doesn’t cause harm to fetus, don’t use thiazoladinediones!

69
Q

Why is glucose so toxic?

A
  1. Covalent modifications of proteins. The aldehyde in glucose is reactive and can react with amino groups on proteins. The oxidation products (Glyoxal, Methylglyoxal) of this reaction form Advanced Glycation End-products (AGEs), which bind to RAGE and promote inflammation.
    - Methylglyoxal has been linked to HTN due to inhibition of vasorelaxation.
  2. Stimulation of other pathways. With a greater quantity of glucose, small pathways get activated more than they should. Glucose -> Aldose reductase pathway may cause neuropathy. F6P -> Hexosamine pathway leads to protein modifications. G3P -> AGE pathway and protein kinase C pathway lead to protein modications.
70
Q

What are the effects of insulin at the liver, skeletal muscle, and adipose tissue?

A

Liver - Stimulation of glycogen synthesis and triglyceride synthesis (remember MAPK pathway); inhibition of glycogenolysis, ketogenesis, gluconeogenesis (remember PDK1)

Skeletal muscle - Stimuation of glucose and amino acid transport (GLUT4)

Adipose tissue - Stimulation of triglyceride storage and glucose transport (GLUT4 and MAPK)

71
Q

What is significant about GLUT1-4?

A

GLUT1 - Low Km, seen in beta cells

GLUT2 - Highest Km, which is important because it mainly works when glucose is in excess. It’s a predominant glucose transporter in beta bells and the liver

GLUT3 - Lowest Km, seen in neurons

GLUT4 - Only one that is insulin-induced, seen in skeletal muscle and adipocytes

72
Q

What are “lente” insulins?

A

Zinc is important for complexing insulin the granule of the beta cell.

These insulins use zinc to complex the insulin (trimer of dimers) to make it absorbed slower. Lente (L) means that there are small amorphous (non-crystalline) and large crystalline complexes.

73
Q

What are the benefits to mixed insulins (ex. Humulin 70/30 or NPL) and Afrezza?

A

Mixed insulins - Give preprandial bolus and prolonged basal level in a single injection instead of needing multiple injections.

Afrezza - Inhaled insulin for people who won’t inject themselves. It’s used as preprandial insulin, but contraindicated in people with asthma and COPD.

74
Q

What are the 3 types of patients using insulin? What are the modes of action of insulin in a diabetic?

A

Patients:
1. Type 1 diabetics
2. Pts with ketosis and hyperosmolar coma
3. Some type 2 diabetics

Mode of action
1. Decreased liver glucose output
2. Increased fat storage
3. Increased glucose uptake

75
Q

What are the adverse reactions to insulin?

A

Hypoglycemia - Symptoms include weakness, sweating, hunger, tachycardia, blurred vision, etc. Treated with glucose or glucagon.

Lipodystrophy - Lump of fat at over used injection site

Lipoatrophy - Concavities in subcutaneous tissue

Insulin resistance - Immune response to insulin

76
Q

What are some factors that may alter insulin action? Which ones increase absorption of blood glucose? Which ones increase risk of insulin hypoglycemia?

A

Increase blood glucose: Catecholamines, glucocorticoids, contraceptics, etc.

Increase risk of insulin hypoglycemia: Ethanol (inhibits gluconeogenesis), beta blockers

77
Q

What is the order of treatment for type 1 and type 2 diabetics?

A

Type 1 - Insulin, then diet, then exercise

Type 2 - diet + exercise, then diet + exercise + antidiabetic drugs, then diet + exercise + insulin

78
Q

What is Mounjaro?

A

Mounjaro (Tirzepatide) - Full GIP receptor agonist, biased toward GLP-1, resulting in preferential coupling to cAMP over b-arrestin. This reduces internalization (aka desensitization) of GLP-1 receptor, thus maintaining GLP-1 effect.

Said to reduce A1c and body weight more effectively than GLP-1 receptor agonists

79
Q

What drug class are these: Sitagliptin, Linagliptan, Saxafliptin, Alogliptin. What are the advantages of using these drugs in diabetics? Common side effects and concerns?

A

DPP-4 inhibitors: Block the enzyme dipeptidyl peptidase 4 from degrading GLP-1.
- Sitagliptan (Januvia)
- Saxagliptin (Onglyza)
- Linagliptin (Tradjenta)
- Alogliptin (Nesina)

Pros: these are small molecules, so they can be given orally. There’s a low risk of hypoglycemia because they are glucose dependent. They reduce hyperglycemia and A1c and are weight neutral.

Side effects - Pancreatitis, Joint pain, HF

Concern: DPP-4 is also present on immune cells, so we may see reduced white blood cell count infections and maybe increased risk of cancers

80
Q

What is the effect of insulin resistance on the skeletal muscle, adipose tissue, and liver?

A

Skeletal muscle - impaired glucose uptake

Adipose tissue - Impaired glucose uptake, impaired inhibition of lipolysis, mobilization of FAs to other tissues

Liver - Impaired inhibition of glucose output

81
Q

Why does obesity cause insulin resistance?

A

Obese people have increased free fatty acid levels. Acutely raising FFA levels causes insulin resistance, mainly because of the insulin-stimulated glucose transport. In the same way, acute lowering of plasma FFAs reduces chronic insulin resistance.

At the molecular level, there is Serine phosphorylation (instead of Tyrosine) on insulin receptor and insulin receptor substrate proteins, which inhibits the signaling. This messed up phosphorylation is due to fatty acid uptake, lipid by-products, and inflammatory mediators.

82
Q

What are the mechanisms of actions, adverse effects, and drug interactions of glinides?

A

Glinides -
- MOA: Enhance insulin secretion from beta cells. Inhibits K+/ATP channels.
- AE: includes hypoglycemia, CV events
- Ex. Repaglinide (Prandin), preprandial; Nateglinide (Starlix), shorter t1/2 than prandin

83
Q

What are the mechanisms of actions, adverse effects, and drug interactions of thiazolidinediones? What are the 3 factors regulated by PPAR-g?

A

Thiazolidinediones - Decrease insulin resistance by improving target cell response to insulin through activation of PPAR-g (transcription factor). The main target is adipocytes, but also affects the liver and skeletal muscle.
- Resistin: Simulates resistance: Usually elevated in T2DM, decreases in response
- Adiponectin: Reduces resistance: Usually decreased in T2DM, increases in response
- TNF-a: Stimulates lipolysis. Usually increased in T2DM, decreases in response
- AE: increased risk of bladder cancer, some hepatotoxicity, HF, edema, bone fractures
- Contraindicated in heart failure
- Ex. Pioglitazone, Rosiglitazone

844 - Therapeutics II (7 decks)

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