Drug Interactions and Synergism

Drug Synergism

• Aspirin and caffeine are a good example of synergism
• Combining aspirin and caffeine provides greater efficacy and pain relief compared to using them alone
• Efficacy and pain relief are not as high without the combination

Drug-Food Interactions

• Food or beverages can affect medications in the body
• Food can affect how a medication works
• Food can alter the medication's side effects
• The drug can also change how the body uses food

Coca-Cola and NSAIDs

• Drinking Coca-Cola with NSAIDs like ibuprofen significantly increases ibuprofen's concentration in the blood
• Increased absorption is observed
• Daily dosage and frequency of NSAIDs should be carefully monitored when taken with Coca-Cola

Green Vegetables and Warfarin

• Spinach is rich in vitamin K
• Vitamin K is essential for blood clotting
• Warfarin is an anticoagulant that inhibits vitamin K
• Increased spinach intake may reduce the effectiveness of warfarin

Milk and Tetracyclines

• Milk, a dairy product, is rich in calcium
• Calcium can interact with tetracyclines, certain antibiotics
• This interaction can form insoluble substances
• Tetracyclines' bioavailability might be affected by milk

Matured Cheese and Phenelzine

• Matured cheese undergoes a ripening process
• Aging affects cheese flavor, texture, and moisture levels
• Mature cheese contains tyramine
• Tyramine interacts with phenelzine, a medication for depression
• Combining mature cheese with phenelzine can dangerously raise blood pressure
• Potential complications include cardiac arrhythmias, cardiac failure, pulmonary edema, and death

Grapefruit and Statins

• Grapefruit and grapefruit juice should be avoided when taking cholesterol-lowering agents like statins
• Grapefruit contains furanocoumarins that increase statin potency
• Increased statin levels can lead to more severe side effects, including leg pain and muscle weakness

Mechanisms of Drug Toxicity

• Major drug toxicities can be categorized by their underlying mechanisms:
  • On-target
  • Hypersensitivity and immunological
  • Off-target
  • Biological activation
  • Idiosyncratic

Classifications of Drug Toxicity

• On-target: Statins (cholesterol-lowering drugs), Penicillins (antibiotics)
• Hypersensitivity and immunological: Penicillins (antibiotics)
• Off-target: Terfenadine (antihistamine)
• Biological activation: Acetaminophen (pain reliever), Halothane (anesthetic)
• Idiosyncratic: Halothane

Mitochondrial Toxicity

• Inhibition of Protein Complexes: Certain drugs inhibit mitochondrial protein complexes I, II, III, IV, and V, disrupting ATP production
• Inhibition of Mitochondrial Membrane Transporters: Drugs may inhibit mitochondrial transporters, leading to water influx and osmotic swelling, causing mitochondrial damage
• Inhibition of Krebs Cycle Enzymes and Fatty Acid Metabolism: Drugs can inhibit enzymes involved in the Krebs cycle (e.g., fluoroacetate) or fatty acid β-oxidation (e.g., tetracyclines), impacting ATP production
• Inhibition of mtDNA replication and mtDNA-encoded protein synthesis: Certain drugs can inhibit mtDNA replication or protein synthesis, impairing mitochondrial function
• Oxidative stress: An imbalance of free radicals and antioxidants leads to cell damage and apoptosis
• Mitochondrial Permeability Transition Pore: Some drugs can cause irreversible opening of the pore leading to osmotic swelling and mitochondrial toxicity

Targets of Oxidative Stress

• Lipid membranes
• DNA
• Proteins

Cell Cycle Mediated Toxicity

• Cell cycle has four phases:
  • G1 phase (first growth phase)
  • S phase (synthesis phase)
  • G2 phase (second growth phase)
  • M phase (mitosis phase)

Apoptosis

• Mitochondria play a role in apoptosis
• Mitochondrial stress initiates or enhances cell death signaling.
• Induction of the outer mitochondrial membrane permeabilization.
• Swelling and rupture of membrane.
• Release of pro-apoptotic factors.
• Apoptosis by caspase activation and DNA fragmentation

Organ and Tissue Toxicity

• Drug toxicity can affect various organs and tissues, including the liver, kidneys, hematopoietic system, skin, gastrointestinal tract, nervous system, cardiovascular system, lungs, and eyes.

Drugs Affecting Renal Toxicity

• Certain antibiotics (aminoglycosides, antifungals, beta-lactams, quinolones)
• Rifampin
• Vancomycin
• Drug-induced acute renal failure is a potential consequence

Symptoms of Neurotoxicity

• Dysfunction relating to the nervous system, including confusion, poor concentration, memory loss, personality changes, loss of sensation, and muscle weakness.