Drugs for Diabetes Flashcards by Anika Gouws

What are the main actions of insulin?

Inc glucose uptake

Inc glycogen synthesis

Dec glycogenolysis

Dec gluconeogenesis

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What are the main actions of glucagon?

inc glycogenolysis

Inc gluconeogenesis

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Considering insulin phases, what is the difference between T1DM and T2DM?

T2DM = missing only phase 2 of insulin regulation

T1DM = missing both phases 1 and 2 of insulin regulation

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Summarise the key points of T1DM

Juvenile-onset –> immune mediated

Insulin dependent = little or no insulin produced

Usually non-obese and symptoms appear suddenly

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Summarise the key points of T2DM

Adult onset

Non-insulin dependent diabetes = begins w/ insulin resistance –> eventual beta cell failure

Genetic basis, sx appear slowly

Require oral hypoglycaemic agents

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What are the main symptoms of diabetes?

Hyperglycaemia

Glycosuria

Polyuria

Polydipsia

Insulin def

Diabetic ketoacidosis

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What symptoms are more common in T1DM?

Lethargy

stupor

Weight loss

Kussmaul breathing (hyperventilation)

Smell of acetone

N/V, abdominal pain

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What are the complications of diabetes?

Macrovascular disease = accelerated atheroma

Microangiopathy = retinopathy, nephropathy, neuropathy

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What is HbA1c?

Glycosylated haemoglobin = glucose that is haem/protein bound

Ideal is 7% (53 mmol/mol)

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What amino acids determine the length of action of the insulins?

B-3

B-28-30

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List the different types of insulin

Human insulin

Insulin aspart (asp at B-28_

Insulin lispro (lys B-28, proline B-29)

Insulin glulisine (lysine B-3)

Insulin glargine (glycine A-21)

Insulin detemir (nothing on B-30)

Insulin degludec (nothing on B-30, may have missing B-29 lysine)

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List the ultra short acting insulins

Insulin aspart

Insulin lispro

Insulin glulisine

Faster acting insulin aspart

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List the short acting insulin

neutral insulin (human insulin ?)

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List the long acting insulin

Isophane insulin

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List the long acting insulin analogues

Insulin detemir

Insulin glargine

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Outline the mechanism behind insulin release

Phase 1:
Glucose transported in through the GLUT4 transporter –> inc in ATP –> inhibition of K+ATPase channel –> depolarisation of beta cell –> opening of voltage gated Ca2+ channel –> release of insulin granules

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Describe the mechanism behind diabetic ketoacidosis

Hyperglycaemia –> insufficient glucose uptake –> cells use proteins and fat as energy –> FFA broken down in liver to ketone bodies (kidney - ketonuria) –> acetoacetate converted to acetone in liver (exhaled - fruity breath)

Cont lipolysis –> inc ketogenesis –> exceeds elimination –> ketonaemia –> inc FFA lvls –> worsening acidosis

Initial compensation through Kussmaul breathing and buffering in blood –> blood and breathing no longer able to compensate –> ketoacidosis

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What are some adverse effects of insulin?

Hypoglycaemia

Rebound hyperglycaemia

Insulin resistance

local reactions (lipodystrophy)

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What are the counter regulatory sympathetic stimulation responses seen in diabetes?

Sweating

Anxiety

Palpitations

Tremor

What are the main drug interactions associated with insulin?

B-adrenergic blockers = prolong hypoglycaemia due to inhibition of compensatory mechanisms

Diuretics, corticosteroids, oral contraceptives = inc blood glucose

Alcohol = precipitates hypoglycaemia due to depletion of hepatic glycogen

Salicylates, lithium, theophylline = precipitate hypoglycaemia –> enhance insulin sec and peripheral glucose utilisation

List the oral drug classes used in T2DM

Metformin

SGLT2 inhibitors

DPP-4 inhibitors

Sulfonylureas

thiazolidinedione

Acarbose

List the parenteral drugs used in diabetes

Insulin

GLP-1 analogue

List the relevant sulfonylureas used in DM

*all end in -ide

Glibenclamide (long acting)

Gliclazide

Glipizide (short acting)

Glimepiride (short acting)

What is the MOA of sulfonylureas?

Bind + inhibit K+ATPase channel —> inc insulin release from pancreatic beta cells in response to glucose

Act to inc insulin release

Which sulfonylureas have a lesser affinity for the K+ATPase channel?

glimepride, Gliclazide Augment second phase of insulin, little effect on 1st phase

What are some ADRs of sulfonylureas?

GI dist = n/v/diarrhoea/constipation Hypoglycaemia Hypersensitivity reactions blood disorders cardiovascular mortality

What drugs inc the effect of sulfonylureas? (cause hypos)

CYP inducers = azole antifungals, salicylates, sulphonamides Clarithromycin, alcohol, ACE-i Disopyramide, BB, MAO-i

List the important biguanide used to treat diabetes and its MOA

Metformin MOA = inc the activity of AMP-dependent kinase (AMPK) --> dec expression of G6P --> inhibits mitochondrial glycerol-3-phosphate Dec cellular energy stores (ATP & phosphocreatine) --> activates AMPK Facilitates glucose uptake by skeletal muscle and adipocytes, inhibits mitochondrial resp chain oxidation (promote peripheral glucose utilisation)

What does metformin mediated activation of AMPK do?

Inc fatty acid oxidation Inc glucose uptake dec lipogenesis dec gluconeogenesis

What is the effect of metformin on the liver?

dec gluconeogenesis Dec glycogenolysis dec glucose production

What is the effect of metformin on the intestine?

Inc anaerobic glucose metabolism

What is the effect of metformin on the muscle?

Inc insulin-mediated glucose uptake Inc glycogenesis

What are some benefits to metformin?

Suppress appetite = less weight gain than sulfonylureas May be cardioprotective Improves adverse plasma lipid profile - inc FFA oxidation - Inc HDL - Dec plasma triglycerides

What are some notable ADRs of metformin?

Diarrhoea - anorexia, abdominal discomfort, nausea, weight loss Dec Vit B12 absorption Metallic taste Inhibition of pyruvate metabolism --> lactate accumulation --> lactic acidosis

List the relevant thiazolidinediones and their MOA

Pioglitazone = no effect on insulin secretion, "insulin sensitizer" MOA = its a ligand for PPARY (peroxisome proliferation activating receptor gamma) --> involved in regulation of genes involved in glucose and lipid metabolism

What are some general effects of the PPAR-Y agonists used in diabetes?

Dec insulin resistance (both muscle and kidney) ---> inc muscle glucose uptake and dec liver gluconeogenesis (inhibition of fructose-1,6-bisphosphate) Inc glucose utilisation in peripheral tissues and ehances expression of cell glucose transporters (GLUT 1 and 4)

Name a glucosidase inhibitor used in T2DM treatment and its MOA

Acarbose MOA = competes w/ dietary oligosaccharides for alpha-glucosidase enz ---> irreversibly binds to the enzyme --> slow digestion/absorption of glucose --> preprandial peak of glucose is low, BGC is more stable

What are some ADRs for acarbose?

GI effects = flatulence, abdominal discomfort, diarrhoea Abnormal liver function = hepatitis

What are the actions of incretins (generally)?

Enhance glucose-dependent insulin secretion Inhibit glucagon secretion --> dec hepatic glucose production Slow gastric emptying Inc satiety --> less food intake Both GLP-1 and GIP are rapidly cleaved and inactivated by dipeptidyl peptidase 4 (DPP4)

List the drugs that belong to the glucagon-like peptide-1 (GLP-1) analogue class and their overall MOA

* all end in "-glutide" Exenatide Liraglutide Semaglutice Dulaglutide MOA = incretin mimics

How are GLP-1 analogues used in diabetes and what are some of their ADRs?

Good adjuvant w/ metformin and/or sulfonylurea ADRs: - n/v - diarrhoea, constipation, dyspepsia, GORD, abdominal pain - hypoglycaemia, headache, dizziness, injection site reactions - pancreatitis, allergic reactions

What diabetic drugs belong in the Dipeptidyl peptidase-4 (DPP-4) inhibitor class?

* "-gliptin" Aloglipin Linagliptin Saxagliptin Sitagliptin Vildagliptin

How are DPP-4 inhibitors used in diabetes and what are some of their ADRs?

Good adjuvant in dual therapy w/ metformin, a sulfonylurea, or a thiazolidinedione ADRs: - hypoglycaemia, n/c, acute pancreatitis

What diabetic drugs belong in the Na+/glucose co-transporter 2 (SGLT2) inhibitor class?

* "-gliflozin" Canagliflozin Dapagliflozin Empagliflozin ertugliflozin

What is the MOA of SGLT2 inhibitors and what are some of their ADRs?

MOA = inhibit SGLT2 co-transporters in the kidney --> reduce glucose reabsorption ADRs: - genital infections, polyuria, UTI, dyslipidaemia, hypoglycaemia - renal impairment - Hypovolaemia, hypotension, dehydration - euglycemic ketoacidosis