Pharmacology and Toxicology: Excretion and Clearance

Mammary Excretion

• Benzoic acid, salicylic acid, alcohol, and heavy metals like lead, mercury, and arsenic can be excreted into milk
• Chloramphenicol, lithium, tetracycline, benzodiazepines, and nicotine can also be excreted into milk

Total Body Clearance

• Total body clearance (CLtotal) is the sum of all clearances from the drug-metabolizing and drug-eliminating organs
• Clearance is the proportionality factor used to determine the rate of elimination
• Rate of elimination = CL x Concentration

Half-Life (t1/2) of a Drug

• Half-life (t1/2) refers to the time required for plasma concentration of a drug to decrease by 50%
• Low half-life: Frequent administration
• High half-life: Should be given once or twice daily

Elimination Kinetics

• Rate of elimination is the rate of disappearance of active molecules from the bloodstream or body
• Rate of elimination and dosage determine the duration of action of a drug
• There are two types of elimination kinetics:
  • First-order kinetics (linear): rate of elimination is proportional to drug concentration
  • Zero-order kinetics (non-linear): rate of elimination is constant, regardless of drug concentration

First-Order Kinetics

• Rate of elimination = k.C1
• Plasma drug concentration (Cp) decreases exponentially with time
• Half-life is constant

Zero-Order Kinetics

• Elimination rate = k
• Drug concentration in plasma (Cp) decreases linearly with time
• Examples: phenytoin, alcohol, heparin, aspirin at high dose

Fat Necrosis

• Fat necrosis is seen in adipose tissue
• Types of fat necrosis:
  • Enzymatic fat necrosis: occurs in the surrounding adipose tissue under the action of pancreatic lipases
  • Traumatic fat necrosis: occurs in breast and subcutaneous fat tissues
• Grossly, fat necrosis appears as white, chalky areas (fat saponification)
• Histologically, there are vague cell outlines and calcium deposition

Fibrinoid Necrosis

• Fibrinoid necrosis is a pathologic pattern resulting from antigen-antibody (immune complex) deposition in blood vessels
• Microscopically, there is bright-pink amorphous material (protein deposition) in arterial walls, often with associated inflammation and thrombosis
• Example: polyarteritis nodosa

Pharmacodynamics

• Pharmacodynamics is concerned with the actions, interactions, and mechanisms of action of drugs
• Table 9.2 summarizes the chemical mediators involved in the three main stages of acute inflammation:
  • Vascular dilatation: histamine, prostaglandins, PGE2/I2, VIP, nitric oxide, PAF
  • Increased vascular permeability: transient phase—histamine, prolonged phase—bradykinin, nitric oxide, C5a, leucotriene B4, PAF, potentiated by prostaglandins
  • Adhesion of leucocytes to endothelium: upregulation of adhesion molecules on endothelium, principally by IL-8, C5a, leucotriene B4, PAF, IL-1, and TNF-alpha

Role of Tissue Macrophages

• Macrophages secrete numerous chemical mediators when stimulated by local infection or injury
• Lysosomes (membrane-bound packets containing toxic compounds) fuse with phagosomes to form phagolysosomes
• Intracellular killing of microorganisms occurs

Role of Neutrophils

• Neutrophils are highly specialized cells, containing microbicidal agents
• Microbicidal agents may be classified as:
  • Oxygen-dependent mechanisms: hydrogen peroxide, myeloperoxidase, halide, Cl-, peroxide anions, hydroxyl radicals, singlet oxygen
  • Oxygen-independent mechanisms: lysozyme, lactoferrin, cationic proteins, low pH inside phagocytic vacuoles

Role of Mast Cells

• Mast cells have an important role in acute inflammation
• On stimulation by the C3a/C5a complement components, they release preformed inflammatory mediators stored in their granules and metabolize arachidonic acid into newly synthesized inflammatory mediators

Adverse Effects of Rifampin

• Red-orange discoloration of body secretions (urine, sweat, tears)
• Hepatotoxicity (hepatitis most serious) (mainly in patients having preexisting liver disease)
• Allergic reactions (fever, skin rash)
• Gastrointestinal upset; nausea, vomiting, and diarrhea
• Hematologic effects; hemolytic anemia, thrombocytopenia

Ethambutol

• Inhibits arabinosyl transferase (gene names = embA, embB, and embC)—important for the synthesis of the mycobacterial arabinogalactan cell wall
• Bacteriostatic
• Targets the enzyme arabinosyl transferase, leading to incomplete and defective cell wall formation
• Can be used in combination with other anti-TB drugs

Mechanisms of Resistance to Rifampin

• Mutations in the embB gene, reducing its affinity for ethambutol

Adverse Effects of Ethambutol

• Optic neuritis; causing loss of visual acuity and red-green color blindness