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.