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Treatment and Prevention of illness > Diabetes Pharmacology > Flashcards

Diabetes Pharmacology Flashcards

1
Q

Hyperglycaemia

A

So much Glucose, not all reabsorbed from urine - sweet
Thirst, frequent urination Headaches, Blurred vision, Fatigue, Dehydation, electrolyte imbalance (Na, K+) Restore fluid volume and electrolyte balance

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2
Q

Hypoglycaemia

A

Dizziness, sweating, indecision, slow thinking, palpitations, hunger, tingling around mouth. Patient needs oral glucose

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3
Q

Antidiabetic medications

A

•Type II Diabetes is a progressive disease caused by the oversupply of calories
– Treat consequences of disease rather than curing disease
• Antihyperglycaemic medicines
– Progressive disease - response to treatment
worsens
– Treatment paradigm -> escalation in number of drugs used
– Many type II diabetics end up using insulin

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4
Q

Summary: the Actions of Diabetic Medicines

A

diagram slide 7 + 8

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5
Q 
Metformin (a biguanide)
Mechanism
Indication
PK
ADR
Caution
CI
Interactions
A

• Mechanism
– Reduction of hepatic glucose output
– increased sensitivity to insulin in muscle cells
• Indications
– Type II diabetes
– not for type I – requires pancreatic β cell function
• PK
– renal excretion
• ADR
– lactic acidosis –increased glycolysis leads to elevated lactic acid, potentially fatal
– rarely causes hypoglycemia – useful in elderly (cf other anti-diabetics)
• Caution
– patients receiving radiological contrast agent may suffer temporary renal impairment – withdraw metformin for 48 hours see ADR !
• Contraindications
– renal insufficiency – risk of lactic acidosis see ADR !
• Interactions
– drug which impair renal function – including NSAIDS – risk of lactic acidosis see ADR !

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6
Q

Metformin Hepatocyte Mechanism of Action

A

• Concentrated in hepatocytes
• Inhibition of mitochondrial respiratory chain complex I
• Alters ATP/AMP Ratio &
activates AMPK (and other mechanisms) –> Metabolic effects & decreased glucose output

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7
Q

AMPK

A
  • AMP dependant Protein Kinase (NOT PKA which is cAMP dependant)
  • Activated by increased intracellular AMP
  • “The cells fuel sensor”
  • activated when depleted of ATP or glucose (poison, exercise)
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8
Q

Type II Diabetes – second line therapy

A

• Three classes of drug which increase Insulin Secretion
– Sulfonylureas and Metglitinides – glucose independent increase in insulin
– GLP-1 analogues (incretins) – increase glucose- stimulated insulin secretion
– DPP-4 inhibitors – increase GLP-1 activity
• Usually given in combination with metformin

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9
Q

Glucose-stimulated insulin secretion

A
  1. Increased intracellular glucose leads to increased ATP production
  2. ATP-sensitive K+ channel closes and membrane depolarises
  3. Voltage-gated Ca++ channel opens
  4. Insulin secretion (and synthesis) triggered
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10
Q

Sulfonylurea-stimulated insulin secretion

A
  1. SU binds to SUR1, a component of ATP-sensitive K+ channel
  2. ATP-sensitive K+ channel closes and membrane depolarises
  3. Voltage-gated Ca++ channel opens
  4. Insulin secretion (and synthesis) triggered
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11
Q

Insulin secretagogues: Sulfonylureas and meglitinides

examples and indication

A

SU: Glibenclamide, Gliclazide, Glipizide, Glimepiride, Tolbutamide

Meglitinides: Nateglinide, Repaglinide

• Indications
– Type II diabetes, not effective in Type I
– combination with diet and exercise
– meglitinides usually given with metformin if need mealtime control

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12
Q

Sulfonylureas (and Meglitinides)
PK
ADR

A

• PK
– sulfonylureas
• hepatic metabolism
• range of t1/2 and more rapidly metabolised drugs preferred initially to reduce risk of hypoglycemia
• highly plasma protein bound
• good Foral
– meglitinides • good Foral
• hepatic metabolism
• ADR
– hypoglycemia –titrate dose
– weight gain (insulin is anabolic) – worsens condition!
– nausea, vomiting, diarrhoea, constipation infrequent
• Repaglinide is clinically effective and cost effective
– frequently used when metformin not tolerated.
– No licensed combination containing repaglinide that can be offered at first intensification

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13
Q

Insulin secretagogues
Caution
CI
Interactions

A

• Caution
– Elderly, debilitated and malnourished patients at greater risk of hypoglycemia
– hepatic impairment– increased risk of hypoglycemia see PK

• Contraindication
– sulfonylurea
• Acute porphyria
• Ketoacidosis

• Interactions
– activity reduced by corticosteroids and thiazide diuretics
• Glucocorticoids – counteract effects of insulin by increasing expression of enzymes
involved in gluconeogenesis
• Thiazides – hypokalemia causes β cell hyperpolarization so less insulin secretion
– do not combine meglitinide and sulfonylurea (same mechanism – no advantage)

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14
Q

Incretins

A

• Hormones (GLP-1, GIP) secreted by gut in response to meals
• Potentiate glucose-stimulated insulin secretion
– Oral glucose load stimulates 2-3 fold greater insulin response cf intravenous load
• Peptide hormones both short acting
– Inactivated by peptide truncation by dipeptidyl peptidase IV (DPPIV)
• Incretin mimetics & inactivation form basis of drug mechanisms
– GLP-1 agonists (Exenatide, Liraglutide)
– DPP-IV antagonists (Sitagliptin,Vildagliptin)

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15
Q

DPP-IV inhibitor Mechanism of Action

A

• GLP-1 has short plasma half-life
– Peptide hormone (36 amino acids)
– Inactivated by cleavage between a a’s 2&3
– Cleavage catalysed by dipeptidyl peptidase IV (DPP-IV)
• Inhibition of DPP-IV increases plasma GLP-1 concentration
– Increases amount of insulin secreted in response to a meal

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16
Q

Incretin medicines

A

GLP-1 agonists
• Liraglutide
• Lixisenatide
• Exenatide (available as long-acting (once weekly) treatments)
• Albiglutide (available as long-acting (once weekly) treatments)
• Dulaglutide (available as long-acting (once weekly) treatments)

DPP-IV Inhibitors
• Alogliptin
• Linagliptin 
•Saxagliptin 
• Sitagliptin
• Vildagliptin
17
Q

Incretins

PK
ADR

A

• PK
– DPP-IV’s
• Different chemical structures!range of PK
properties
• All have good Foral and PK supporting once daily tablet dosing
– GLP-1’s
• Peptides – no oral bioavailability - injection
• Short acting (bid) and long acting (once weekly) forms
• Cleared by proteolytic degradation
• ADR
– DPP-IV considered very safe – low incidence of hypoglycemia
• Some GI side effects
– GLP-1 analogues – major side effects nausea & vomitting
• Discontinuation in~5-10%
– GLP-1 – Significant weight loss in many patients
• generally seen as additional benefit
– Pancreatitis & kidney failure rare ADR for both

18
Q

Why is GLP-1 Agonists use so restricted?

A

• Better efficacy cf DPP-IV
– HbA1c, weight loss, lipids, blood pressure
• Several disadvantages
– Side effects (nausea and vomitting can affect
compliance; several rare but serious side effects)
– Convenience (bid vs qd; injection vs oral)
– Cost (~2x more expensive (£70 vs £35 per month)
• (Cf metformin - £5/month)

19
Q

Insulin sensitizers: Pioglitazone
Mechanism
Indication

A

• Mechanism
– Act as ligands for transcription factor PPARg (peroxisome proliferator activated receptor)
– Improve insulin resistance, probably by decreasing ectopic fat storage
• Thiazolidinediones – Pioglitazone
– (Rosiglitazone, Troglitazone – withdrawn/suspended)
• Indications
– Second line treatment; and for those who don’t tolerate metformin
– not for type I diabetes
– can take several months to become effective

20
Q 
Pioglitazone
PK
ADR
Caution
CI
Interactions
A

• PK
– good oral bioavailability
– metabolism by Cyp2c8
– highly protein bound
• ADR
– relatively new drugs – still being defined
• rosiglitazone Sept 2010 suspended – link to heart attack & stroke
• troglitazone withdrawn - liver toxicity
– withdraw drug if patient becomes jaundiced
• Cautions
– “Incidence of heart failure is increased when pioglitazone is combined with insulin, especially in patients with predisposing factors…Patients should be closely monitored for signs of heart failure” MHRA/CRM advice December 2007, January 2011
– “…there is a small increase in the risk of bladder cancer, but for patients who respond the benefits outweigh the risks” EMA July 2011
• Contraindications
– avoid in hepatic insufficiency see PK
– History of heart failure
– Active bladder cancer, or a history of same, or uninvestigated haematuria
• Drug interactions
– Clopidogrel and fibrates can increase level of pioglitazone
– Pioglitazone can reduce plasma levels of oral contraceptives

21
Q

SGLT-2 inhibitors

A

• Sodium Glucose Transporter 2
– Symport responsible for reabsorption of glucose in the proximal renal tubule
• Inhibition leads to reduced reabsorption, and increased loss of glucose in urine
– Reduces glucose levels in plasma
• Three drugs available in UK – Dapagliflozin (Forxiga)
– Canagliflozin (Invokana)
– Empagliflozin (Jardiance)

22
Q

Gliflozins

PK
ADR
Caution
CI
Interactions
A

• PK
– good oral bioavailability, long half-life, highly protein bound
– Renal clearance

• ADR
– relatively new drugs – still being defined
– Increased risk of urinary tract infections
– Dapagliflozin clinical trials showed minimally increased risk of breast and bladder cancer
– Minor risk of euglycaemic diabetic ketoacidosis
• Cautions
– Increased urination, -> risk of hypovolaemia or hypotension.
– Reduced efficacy in patients with impaired renal function
• Contraindications
– avoid in hepatic insufficiency can cause fluid retention and subsequent heart failure – avoid in patients with history of this or impaired left ventricular function
• Drug interactions
– Enhances activity of diuretics

23
Q

SGLT2 inhibitors and Euglycemic DKA

A

DKA normally only seen in type I diabetes
– Ketone body production driven by uncontrolled lipolysis in fat tissue
– In presence of high glucose, ketone bodies not used as fuel
– Leads to accumulation in plasma & acidification of blood
• Diabetic ketoacidosis (DKA) reported at low incidence in people treated with SGLT-2 inhibitors
– <1/1000 patient years
– Often in patients on insulin therapy,
• associated with reduced insulin dose
– Delayed diagnosis due to (comparatively) low
plasma glucose
– Important area for patient counselling

24
Q

Insulin different forms

A

Different forms with different onset of action and duration of action
• Differ in formulation and some amino-acids replaced (recombinant)
• Rapidly acting for use with meals or acute hyperglycemia
– Insulin Lispro
– Insulin Aspart
• Long-acting for setting baseline and overnight control – Insulin Glargine
• Biphasic used twice daily –mixed fast and intermediate acting components patients may need snack mid-morning and evening

25
Q

Insulin • ADR

A

• ADR
– hypoglycemia if adminstrated with inadequate carbohydrate
– acute symptoms of hypoglycemia - tachycardia, confusion, vertigo, sweating
• Interactions
– with sulphonylureas -risk of hypoglycaemia

26
Q

Inhibition of glucose uptake (class not on NICE paradigm)

A

• Indication – TIID inadequately controlled by diet or other oral antidiabetic drugs
• Mechanism
– inhibit α-glucosidase (liberates glucose from carbohydrates in GI tract)
– delays uptake (still absorbed from small intestine)
– reduces peak Glc
– only effective when used with meals
• Acarbose – little Foral
• ADR
– few because not absorbed – flatulence

27
Q

TIID Treatment Paradigm Problems

A

• Glycemic targets often not met
– When a new diabetic patient comes in, you can expect to meet them many more times
• Monotherapy not effective long- term
– Step-wise approach tends to perpetuate “failure”
• Goals (for HbA1c) should be individualised
– Hypoglycemia awareness
– Microvascular vs Macrovascular benefits

28
Q

Diabetes and Multi-morbidity

A

• The “Metabolic Syndrome”
• Diabetic patients likely to have hypertension and atherosclerosis as well -> High risk for heart disease
• Causally related? Much debate!
– Independent risk factors
– All should be treated
• Leads to high polypharmacy load in TIID patients
– Up to 3 antihyperglycaemics
– Statin; antihypertensive; other CV drugs

Treatment and Prevention of illness (32 decks)

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