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PR3152 Pharmacology > Endocrine disorders > Flashcards

Endocrine disorders Flashcards

1
Q

MOA of Metformin

A

Inhibitis gluconeogensis in liver –> increase AMP-activated protein kinase

May also enhances tissue sensitivity to insulin

Outcome: ↑ glucose uptake into tissues

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2
Q

Describe the PK properties of Metformin

A

A: Oral
F~ 40-60%
Duration of action 8-12hr

D: Rapidly distributed
Minimal plasma protein binding
T1/2 3hr

M: NA

E: excreted unchanged in urine (avoid patients with renal insufficiency)

Does not result in hyperinsulinemia or hypoglycemia
Can help with weight loss and in improving lipid levels

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3
Q

Clinical uses of Metformin

A
  • T2DM (alone or with other oral hypoglycemic
    agents)
  • Useful in obese patients
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4
Q

Adverse effects of Metformin

A
  • Anorexia
  • GI disturbances (diarrhea increased weight loss; vomiting,
    indigestion)(take with or after meal)
  • ↑ risk of Vit B12 malabsorption –> Vit B12 deficiency
  • Use with caution in patients with renal problems or lactic
    acidosis (hepatic disease and cardiovascular problem)
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5
Q

What is Glipizide?

A

A sulfonylurea, Insulin secretagogues (2nd generation) – get the pancreatic β-cells to secrete insulin

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6
Q

MOA of Glipizide

A
  • Lowers blood glucose acutely by ⊕ the
    release of insulin from the pancreas –> dependent upon functioning β cells in the pancreas islets
  • Principal target of sulfonylureas is the
    pancreatic β-cell ATP-sensitive potassium
    (KATP) channel, which plays a major role in
    controlling the β-cell membrane potential.
  • Sulphonylureas (SU) bind to the SU receptor
    proteins, subunits of the KATP channels.
  • Drug binding inhibits KATP channel mediated
    K+ efflux, triggering a calcium dependent
    exocytosis of insulin granules from the
    pancreatic β cells.
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7
Q

List the PK properties of Glipizide

A

A: Oral
F >95% (delayed with food intake)
Onset of action 0.5hr
Duration of action: 12-24hr

D: Binds extensively (~99%) to plasma proteins
(primarily albumin)
T1/2 4h

M: Liver (90%); hydroxylation

E: <10% excreted unchanged in urine and feces metabolites are excreted in urine and feces
(action prolonged in patients with renal disease)

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8
Q

What is the clinical use of Glipizide?

A

Lower risk of hypoglycemia as compared to
other sulphonylureas
(advise patients to monitor blood glucose closely)

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9
Q

What are the adverse effects of Glipizide?

A
  • Hypoglycemia (more likely in elderly)
  • Weight gain
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10
Q

What are incretins?

A

Incretins are a group of metabolic hormones, which are released after eating and they augment the secretion of insulin released from pancreatic β cells of the islets of Langerhans in a glucose-dependent manner (ie. only in the presence of hyperglycemia).

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11
Q

What is Sitagliptin?

A
  • Incretin-based therapy
  • Dipeptidyl peptidase-4 inhibitor (DPP-4i)
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12
Q

MOA of Sitagliptin

A
  • Binds and inhibits DPP-4 -↓ enzymatic degradation of GLP-1
  • prolongs the action of endogenous incretins
  • Increase β cells
  • ↑ glucose-stimulated insulin release
  • suppress α-cell mediated glucagon release and hepatic glucose production
  • ↓ blood glucose level
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13
Q

ADME of Sitagliptin

A

A: Oral
F 87%

D: T1/2 10-12h

M: Low Liver metabolism

E: 80% excreted unchanged in urine;
rest in feces

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14
Q

Adverse effects of Sitagliptin

A
  • GI disturbances
  • Flu-like symptoms (headache, running nose,
    sore throat)
  • Skin reactions
  • Use with caution in patients with a history of
    pancreatitis
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15
Q

What are the clinical uses of Liraglutide?

A

Results in initial rapid release of endogenous insulin, suppression of
glucagon release by the pancreas, delay gastric emptying and reduces appetite (weight loss)

Indicated for adjunct therapy in patients not achieving glycemic
control with oral anti-hyperglycemic agents

  • Since it reduces appetite, it can result in weight loss.
    It has been utilized in the management of obese patients.
  • Clinical trials suggest liraglutide reduces risks of cardiovascular death, non-fatal MI and heart failure among T2DM patients
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16
Q

What is the MOA of Liraglutide?

A
  • Activates GLP-1 receptor (membrane GPCR)
    on pancreatic β-cells–> ⊕ adenylate cyclase
    –> ↑ cAMP –> ⊕ PKA –> ↑ insulin secretion &
    ↓ glucagon release.
  • This insulin secretion subsides as blood
    glucose concentrations ↓ and approach euglycemia.
  • Long acting peptide (DPP-4-resistant form of
    GLP-1*)
17
Q

PK properties of Liraglutide

A

A: given SC
Once-daily dose (a possible dose regime see below) – 3mg maintenance dose
(this 4-2wk regime helps reduce GI symptoms)
F = 55%

D: C16 fatty acid binds to plasma proteins (eg. albumin)
T1/2 13hr (extended due to plasma protein binding)

M: endogenously metabolized in a similar manner to polypeptides without a specific organ as a major route of elimination

E: little or none excreted unchanged

18
Q

What are the side effects of Liraglutide?

A
  • Nausea/vomiting (improves when body adjusts to treatment)
  • Diarrhea/constipation
  • Headache/tiredness
19
Q

In which population should Liraglutide not be used?

A

Pregnant mothers

20
Q

What is a disadvantage of Liraglutide?

A

Expensive (~S$700/mth)

21
Q

MOA of Empagliflozin

A
  • Inhibits sodium-glucose co-transporter-2 (SGLT2)
    –> ↓ reabsorption of filtered glucose
    –> ↓ renal threshold for glucose and thereby ↑
    urinary glucose excretion
22
Q

ADME of Empagliflozin

A

A: Oral
F 60-80%
Cmax 1-2h

D: T1/2 12h (once daily)
Highly plasma protein bound (~90%)

M: undergoes minimal metabolism
Metabolized in Liver (glucuronidation)

E: ~40% unchanged in feces
~27% unchanged in urine

23
Q

What are the adverse effects of Empagliflozin?

A
  • Urinary tract infection (UTI)
  • ↑ urination
  • Female genital mycotic (fungal) infection
  • Diabetic ketoacidosis
24
Q

What are the clinical benefits of Empaglifozin?

A
  • Reduced risk of a major cardiac event (by 11%
    in patients with atherosclerotic CVD)
  • Reduced risk for a composite endpoint of
    worsening renal function, renal failure, or renal
    death with a similar benefit in those with and without atherosclerotic CVD.
25
Q

When is Carbimazole used?

A

In hyperthyroidism ; to control the disease before surgery

26
Q

MOA of Carbimazole

A
  • Decrease thyroid hormones synthesis
  • ↓ thyroid hormones (T4 & T3) output –> reduces signs & symptoms of thyrotoxicosis*

Reduces the synthesis of thyroid hormones by inhibiting thyroid peroxidase which
normally iodinates tyrosyl residues in thyroglobulin to give the precursor of T3 and T4.

27
Q

ADME of Carbimazole

A

A: Oral (once daily dosing^)
Carbimazole is converted into active methimazole
in serum after absorption

D: Methimazole T1/2 4-6hr (^ clinical effect lasts a day because concentrated in thyroid)
Methimazole – no binding to plasma proteins
produces >90% inhibition of thyroid organification
of iodine within 12hr*

M: CYP450 and FMO enzymes

E: >90% orally administered carbimazole excreted in urine as
methimazole or its metabolites; rest in feces
(enterohepatic circulation)
~7% methimazole excreted unchanged in urine

28
Q

Adverse effects of Carbimazole

A
  • Rashes
  • Joint pains
  • Nausea
  • Jaundice
  • Agranulocytosis (rare)
  • Hypothyroidism (due to over treatment) – monitor thyroid size and serum TSH level; once reduced thyroid size and achieved normal TSH level,
    carbimazole dose should be titrated (reduced) to
    avoid hypothyroidism.
29
Q

How long is the clinical response of Carbimazole?

A

Clinical response may take several weeks(3-6wks) after initiating treatment because T4 has a long half-life and the thyroid stores of hormone need to be depleted.

30
Q

ADME of Levothyroxine

A

A: Oral (take on empty stomach with water;
30min before meal); dietary fiber can cause erratic absorption; fasting ↑absorption
F 70-80%
Onset 3-5 days (6-8h IV)
Mainly absorbed in duodenum & jejunum
but affected by gastric pH

D: T1/2 7 days! (once a day dosing)
Highly plasma protein bound (>99%)

M: ~80% T3 is derived peripherally from T4
Liver – major site for degradation of T4 & T3
T3 & T4 metabolized by glucuronidation and
sulphation)
Deiodinated T4 to T3 can happen in kidney

E: kidneys primarily excrete T3 and T4
Metabolites in urine and feces

31
Q

Adverse effects of Levothyroxine

A
  • Reduced appetite
  • Anxiety
  • Diarrhea
  • Difficulty sleeping
  • Hair loss

Rare and Serious:
* Heart issues
(eg. arrhythmias, high BP, pain, failure)
* Seizures

32
Q

Contraindication of Levothyroxine

A

Hyperthyroidism, heart problems, epilepsy

33
Q

When does Myxoedema coma happen with the use of Levothyroxine?

A
  • A severe form of hypothyroidism
  • Reduced blood flow to GI –> affects gut absorption
    of oral levothyroxine
  • IV Liothyronine (synthetic T3) or IV Levothyroxine
34
Q

How should thyroid function be monitored after the use of Levothyroxine?

A

1: When initiating levothyroxine therapy, serum TSH should be measured to monitor for adequate replacement

2: TSH should be measured 6-8 weeks after initiation of, or a change in levothyroxine dose

3: Persistently elevated TSH levels may happen due to inadequate dosing, poor compliance,
malabsorption, drug or food interaction

PR3152 Pharmacology (3 decks)

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