General pharm – Drug metabolism/elimination

1 Old HOR, 2 MAGS (“One old whore, two mags.”) <– Weird-as-fuck mnemonic I created, but it literally does help.

Phase I

• Cytochrome P-450-dependent.
• Geriatrics (Old people) lose phase I ability.
• Hydroxylation, Oxidation, Reduction reactions.

Phase II

• Not P-450-dependent
• Methylation, Acetylation, Glucuronidation, Sulfation
• People who are slow-acetylators (slower Phase II acetylation rate compared to most individuals) can have ↑ side-effects from drugs such as isoniazid because of ↓ rate of metabolism.

1 Old HOR, 2 MAGS (“One old whore, two mags.”) <– Weird-as-fuck mnemonic I created, but it literally does help.

Phase I

• Cytochrome P-450-dependent.
• Geriatrics (Old people) lose phase I ability.
• Hydroxylation, Oxidation, Reduction reactions.

Phase II

• Not P-450-dependent
• Methylation, Acetylation, Glucuronidation, Sulfation
• People who are slow-acetylators (slower Phase II acetylation rate compared to most individuals) can have ↑ side-effects from drugs such as isoniazid because of ↓ rate of metabolism.

Zero-order elimination

• Same amount of drug eliminated per unit time, regardless of dose (e.g., 2mg/hr eliminated always).
• Graph of serum drug concentration (Cp) vs time is a straight line.
• Capacity-limited elimination (i.e., the liver/kidney are saturated/maxed out on how much they can eliminate).
• PEA –> Phenytoin, Ethanol, Aspirin.

People who are slow-acetylators (slower Phase II acetylation rate compared to most individuals) can have ↓ rate of metabolism of certain drugs (e.g., isoniazid).

8 –> 6 units/L after one hour means we have metabolism at a rate of 2 units/hour.

Zero-order means the same amount will be metabolized over the next hour: 6 –> 4 units/L.

4.5 units/L would be the answer for first-order kinetics, where 25% is metabolized per hour. (i.e., 8 –> 6 –> 4.5 units/L).

Zero-order elimination

• Same amount of drug eliminated per unit time, regardless of dose (e.g., 2mg/hr eliminated always).
• Graph of serum drug concentration (Cp) vs time is a straight line.
• Capacity-limited elimination (i.e., the liver/kidney are saturated/maxed out on how much they can eliminate).
• PEA –> Phenytoin, Ethanol, Aspirin.

Answer = 8.1 units/L.

Aspirin is metabolized zero-order. So the same amount of drug is metabolized per unit time. This means at a rate of 5 units/hr, after another hour, the serum concentration would be 5 units/L.

6.67 units/L is the answer for first-order kinetics, where the same fraction of drug is metabolized per unit time. So if 15 –> 10, the rate is 33% per hour, where 10 –> 6.67 units/L would be another 33% by the end of hour-two.

a + b) sodium bicarbonate

c)

42M + consumes bottle of aspirin in suicide attempt; sodium bicarb is administered; what’s the mechanism via which this helps? –> answer = increased excretion through urinary alkalinization.

In contrast,

42M + consumes his TCA medication in suicide attempt; sodium bicarb is administered; what’s the mechanism via which this helps? –> answer = “increased dissociation from myocardial sodium channels.” The wrong answer is “increased excretion through urinary alkalinization,” which refers instead to salicylates.

Drug elimination in relation to urine pH

• Key concept is: ionic species (i.e., -NH3⁺/-COO^–) are poorly reabsorbed; neutral species (i.e., -NH2/-COOH) are readily reabsorbed.
• If a species is a weak acid (i.e., has a -COOH group, where -COOH ↔ -COO^–):
  • ↓pH favors -COOH
  • ↑pH favors -COO^–
  • Salicylates (aspirin) are HY example, where Tx for overdose is sodium bicarbonate –> increases pH of urine –> traps aspirin as -COO^– form in the urine –> decreased reabsorption. USMLE will ask why sodium bicarb is the Tx for aspirin toxicity; answer = “increased excretion through urinary alkalinization.”
• If a species is a weak base (i.e., has an -NH2 group, where -NH3⁺ ↔ -NH2):
• ↓pH favors -NH3⁺
• ↑pH favors -NH2
• Tricyclic antidepressants (TCAs) and barbiturates are HY examples.
• Tx for TCA toxicity is sodium bicarbonate, which paradoxically decreases urinary excretion. Student says, “Wait, well then why the fuck does that make any sense then?” –> It’s because the sodium bicarb functions to induce dissociation of the TCA from myocardial sodium channels to decrease risk of arrhythmia; the purpose isn’t to increase urinary excretion.

Decrease serum levels.

Alkalinization would cause -COOH –> -COO^–.

Since ionic species are less readily reabsorbed by the renal tubules, serum levels would decrease in this setting.

Salicyclates (aspirin) are the HY example of this.