Metabolic Diseases & Drugs

Metabolic Diseases & Drugs

Learning Objectives

• Describe how biomolecules are used to derive energy
• Explain biochemistry of metabolic syndrome
• Discuss normal control of blood glucose and insulin secretion
• Differentiate between various forms of diabetes

Energy Metabolism

• Adenosine triphosphate (ATP)

  • Cellular energy currency
  • Uses: transport, biosynthesis, and various cellular activities

• Carbohydrates

  • Converted to glucose
  • Further converted to CO$_2$ + water, capturing released energy
  • Used for biosynthesis

• Fats

  • Converted to fatty acids
  • Further converted to CO$_2$ + water, capturing released energy
  • Used for biosynthesis

• Proteins

  • Converted to amino acids
  • Used for biosynthesis

Metabolic Syndrome

• Affects over 50 million in the USA.
• Characterized by:
  • Obesity (excessive weight)
  • Waist circumference indicating abdominal obesity
  • Hypertension
  • Elevated blood glucose (hyperglycaemia)
  • Managed by insulin
  • Elevated blood lipids (hyperlipidemia)
  • Glucolipotoxicity

Biochemistry of Metabolic Syndrome

• Inefficient glucose use leads to:
  • Conversion of glucose to fats
  • Lowered insulin sensitivity (insulin resistance)
  • Pancreatic dysfunction and loss of insulin-producing cells (glucolipotoxicity)
  • Blood vessel plaque formation due to inflammation

Diabetes Overview

• Definitions:

  • Fasting blood glucose greater than 12.5 mg/mL indicates hyperglycaemia.

• Types:

  • Type 1 Diabetes
  • Insulin-dependent
  • Insufficient insulin production by pancreas
  • Requires insulin injections for management.
  • Type 2 Diabetes
  • Non-insulin dependent
  • Multifactorial influences including genetics, diet, and physical activity
  • Can lead to Type 1 diabetes.

Cardiovascular Disorders

Learning Objectives

• Understand diagnostic criteria for cardiovascular disease
• Explain biochemical control of the cardiovascular system
• Discuss normal control of cholesterol
• Describe the biochemistry of atherosclerosis.

Cardiovascular Disorders

• Hypertension:

  • Incidence: ~50% in 60-69 year olds
  • Damages blood vessels
  • Blood pressure readings:
  • Systolic: force during heartbeats
  • Diastolic: force between heartbeats
  • Ideal: < 120/80 mmHg, sustained increase > 140/90 mmHg

• Myocardial Infarction (Heart Attack):

  • Loss of blood flow to portions of the heart.

• Congestive Heart Failure:

  • 500,000 deaths/year in the US.
  • Health care costs: $27 billion.
  • Decreased cardiac output and increased sympathetic activation leading to fluid retention, fatigue, and shortness of breath.

• Angina (pectoris):

  • Insufficient oxygen supply leads to myocardial ischaemia, affecting over 9 million Americans.

Normal Cardiovascular Control

• Sympathetic Nervous System:
  • Involved in autonomic control.
  • Primary neurotransmitter: noradrenaline (norepinephrine), akin to adrenaline (epinephrine).
  • Stimulates fight or flight response.

Cholesterol Control

• 80% cholesterol is synthesized in the body.
• Hyperlipidemia (high cholesterol) promotes:
  • Atherosclerosis and plaque formation.
  • Types:
  • "Good" cholesterol: High-Density Lipoproteins (HDL)
  • "Bad" cholesterol: Low-Density Lipoproteins (LDL)
  • Importance of LDL:HDL ratio.

Atherosclerosis

• Fat plaques accumulate on arterial walls.
• Narrows blood vessels, increases blood pressure.
• Plaque rupture can release clotting factors.

Anti-Diabetics

Learning Objectives

• Recognize names of anti-diabetic drugs.
• Compare mechanisms of different diabetes treatments.

Medications

• Metformin (Glucophage):

  • Used for Type 2 diabetes.
  • Introduced in 1979; FDA approved in 1994.
  • Mechanism:
  • Increases AMP-dependent protein kinase activity.
  • Decreases hepatic glucose release.
  • Increases glucose uptake in muscle and fat cells.

• Glipizide (Glucotrol):

  • Introduced in 1984; a sulfonylurea.
  • Mechanism:
  • Blocks ATP-sensitive potassium channels in pancreas.
  • Stimulates insulin release via increased calcium entry.
  • Side effects include weight gain and hypoglycemia.

• Pioglitazone (Actos):

  • Introduced in 1999; activates PPAR-γ.
  • Mechanism:
  • Increases transcription of insulin-responsive genes.
  • Usually activated by fatty acids and other molecules.

• Sitagliptin (Januvia):

  • Introduced in 2006; a DPP-4 inhibitor.
  • Mechanism:
  • Inhibits the breakdown of incretins, increasing insulin release and decreasing hepatic glucose release.

Anti-Cholesterols

Learning Objectives

• Compare pharmacological mechanisms for cholesterol control.

Medications

• Atorvastatin (Lipitor):

  • Introduced in 1997; first synthesized in 1985.
  • Mechanism:
  • Inhibits HMG CoA reductase, an enzyme for cholesterol synthesis.
  • Common side effects include muscle weakness.

• Ezetimibe (Zetia):

  • Introduced in 2002.
  • Mechanism:
  • Inhibits intestinal cholesterol uptake, minimally entering the bloodstream.

Cardiovascular Agents

Learning Objectives

• Describe mechanisms of drugs for cardiovascular disorders.

Medications

• Atenolol (Tenormin):

  • Introduced in 1976; a β-blocker.
  • Mechanism:
  • Blocks (nor)adrenaline action at β-adrenergic receptors,
  • Slows heart rate and decreases contraction force, dilating blood vessels.

• Enalapril (Vasotec):

  • Introduced in 1985; an ACE inhibitor.
  • Mechanism:
  • Converts angiotensin I to angiotensin II, causing vasoconstriction.
  • A pro-drug that is activated in the body.

• Valsartan (Diovan):

  • Introduced in 1998; an angiotensin receptor blocker.
  • Used for hypertension and chronic heart failure.

• Amlodipine (Norvasc):

  • Introduced in 1990; a calcium channel blocker.
  • Mechanism:
  • Reduces the force of heart contractions, dilating arteries, aiding both angina and hypertension.

• Digoxin (Lanoxin):

  • Used for centuries; a cardiac glycoside.
  • Mechanism:
  • Inhibits the sodium-potassium pump, enhancing the heart's contraction force due to increased calcium levels.
  • Very narrow therapeutic window with high arrhythmia risk.

• Nitroglycerin:

  • Introduced in 1878; a vasodilator for angina and heart failure.
  • Decomposes in vivo to produce nitric oxide (NO), a natural vasodilator.