Diabetes Pharmacology Flashcards
Hyperglycaemia
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
Hypoglycaemia
Dizziness, sweating, indecision, slow thinking, palpitations, hunger, tingling around mouth. Patient needs oral glucose
Antidiabetic medications
•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
Summary: the Actions of Diabetic Medicines
diagram slide 7 + 8
Metformin (a biguanide) Mechanism Indication PK ADR Caution CI Interactions
• 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 !
Metformin Hepatocyte Mechanism of Action
• Concentrated in hepatocytes
• Inhibition of mitochondrial respiratory chain complex I
• Alters ATP/AMP Ratio &
activates AMPK (and other mechanisms) –> Metabolic effects & decreased glucose output
AMPK
- 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)
Type II Diabetes – second line therapy
• 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
Glucose-stimulated insulin secretion
- Increased intracellular glucose leads to increased ATP production
- ATP-sensitive K+ channel closes and membrane depolarises
- Voltage-gated Ca++ channel opens
- Insulin secretion (and synthesis) triggered
Sulfonylurea-stimulated insulin secretion
- SU binds to SUR1, a component of ATP-sensitive K+ channel
- ATP-sensitive K+ channel closes and membrane depolarises
- Voltage-gated Ca++ channel opens
- Insulin secretion (and synthesis) triggered
Insulin secretagogues: Sulfonylureas and meglitinides
examples and indication
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
Sulfonylureas (and Meglitinides)
PK
ADR
• 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
Insulin secretagogues
Caution
CI
Interactions
• 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)
Incretins
• 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)
DPP-IV inhibitor Mechanism of Action
• 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
Incretin medicines
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
Incretins
PK
ADR
• 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
Why is GLP-1 Agonists use so restricted?
• 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)
Insulin sensitizers: Pioglitazone
Mechanism
Indication
• 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
Pioglitazone PK ADR Caution CI Interactions
• 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
SGLT-2 inhibitors
• 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)
Gliflozins
PK ADR Caution CI Interactions
• 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
SGLT2 inhibitors and Euglycemic DKA
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
Insulin different forms
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
Insulin • ADR
• ADR
– hypoglycemia if adminstrated with inadequate carbohydrate
– acute symptoms of hypoglycemia - tachycardia, confusion, vertigo, sweating
• Interactions
– with sulphonylureas -risk of hypoglycaemia
Inhibition of glucose uptake (class not on NICE paradigm)
• 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
TIID Treatment Paradigm Problems
• 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
Diabetes and Multi-morbidity
• 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
