Pharmacology Chapter on Angiotensin II and Toxicity

Angiotensin II

• At low concentrations, Angiotensin II binds to the Angiotensin II Type 1 receptor (ATR1), leading to vasoconstriction
• At very high concentrations, it binds to the Angiotensin II Type 2 receptor (ATR2), negating the effects of ATR1 activation
• Angiotensin II has a high affinity for ATR1 and a low affinity for ATR2, explaining why it only binds to ATR2 at very high concentrations

Toxicity

• Everything is toxic, the dose determines if it has a beneficial or toxic effect
• Insulin at high concentrations can lead to diabetic hypoglycemia and death
• Paracetamol, an analgesic, at high concentrations can kill liver and kidney cells

LD50 and TD50

• LD50: The amount of a drug needed to kill 50% of test cells or organisms
• TD50: The amount of a drug needed to cause toxicity in 50% of test cells or organisms
• Toxic effect can involve dysfunction or cell death

Therapeutic Index

• Therapeutic index (TI) = LD50 or TD50/ED50, indicating the likelihood of side effects or toxicity
• Drugs with a low TI (blue and red lines close together) require careful dosing as toxicity can occur at therapeutic doses, like Warfarin
• Drugs with a large TI, therapeutic concentrations are much lower than toxic ones, reducing the likelihood of toxicity

Drug Properties

• Three key drug properties determine if a drug works and works safely:
  • Selectivity/Specificity
  • Potency
  • Efficacy

Selectivity/Specificity

• Selectivity describes a drug's ability to produce a particular effect, relating to its molecular structure and receptor specificity
• Receptor specificity is determined by the precise molecular interactions between a drug molecule and a receptor protein
• Some drugs bind to one target (e.g., a receptor), while others interact with multiple targets
• Binding to multiple targets (promiscuity) can be beneficial pharmacologically or lead to off-target/toxic effects

Drug Promiscuity

• Example 1: Statins
  • Inhibit HMG-CoA reductase, reducing cholesterol synthesis in the liver and circulating cholesterol levels
  • Reported to modulate nitric oxide synthase gene expression in vascular endothelial cells (promoting vasodilation), reducing macrophage proliferation (anti-atherosclerosis effects), and inflammatory markers (anti-thrombus formation effects)
• Example 2: Propranolol
  • Blocks beta-adrenoceptor beta 1 in the heart, reducing heart rate and contractive force (clinical effect)
  • Also blocks beta-adrenoceptor beta 2, inhibiting bronchial smooth muscle relaxation, potentially causing bronchospasm in asthmatic and COPD patients (toxic/harmful effect)

Drug Potency

• Relates to the amount of drug needed to elicit an effect
• Depends on the drug's affinity for its target
  • Low affinity: Weak binding, readily dissociates, requires larger amounts of drug for effect
  • High affinity: Strong binding, requires less drug for effect
• Potency is often expressed as EC50, the concentration needed to elicit 50% of the maximum response
• Time of exposure is crucial, especially in cell culture experiments

Drug Efficacy

• Ability of a drug to induce a biological or physiological response
• Drugs can be:
  • Full agonists: Induce a full biological response at specific doses
  • Partial agonists: Cannot induce a full biological response regardless of dose, but can still be effective drugs with reduced overdose risk
• ED50: Dose of drug needed for a therapeutic effect in 50% of test cells or organisms

Agonists and Antagonists

• Agonist: A compound that binds to a target molecule (e.g., a receptor) and activates it, eliciting a response.
• Antagonist: A compound that binds to a target molecule and inhibits its activity.