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First-Pass Effect
Definition/Introduction
The first-pass effect is a pharmacological phenomenon in which a medication undergoes metabolism at a specific location in the body. The first-pass effect decreases the active drug's concentration upon reaching systemic circulation or its site of action. The first-pass effect is often associated with the liver, a major site of drug metabolism. However, the first-pass effect can also occur in the body's lungs, vasculature, gastrointestinal tract, and other metabolically active tissues. This effect can be increased by various factors such as plasma protein concentrations, gastrointestinal motility, and enzymatic activity.[1][2][3] The extent to which a patient may undergo the first-pass effect differs from patient to patient, and this must also be considered when determining appropriate dosing.[4][5] If the first-pass effect is significantly prominent in a patient, the medication may require administration via a different route or formulation to bypass the first-pass effect.[6]
Issues of Concern
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Issues of Concern
A significant issue of concern with the first-pass effect is considering its variability among different individual patients. It is essential that pharmacological dosing considers these natural variations in human metabolism to ensure patients remain within the therapeutic window of the appropriate drug.[4] Also, differences in the first-pass effect have been noted based on gender and age.[7][8]
Clinical Significance
The clinical significance of the first-pass effect is crucial to the proper administration and maintenance of pharmacological therapy. Some drugs that undergo considerable first-pass metabolism include alprenolol, 5-fluorouracil, morphine, pentazocine, and mercaptopurine. When given orally, these drugs are quickly metabolized via the first-pass effect, requiring their oral dosages to be much larger than their intravenous dosages. The first-pass effect also impacts peak drug concentrations, which may result in drug concentration peaks occurring much earlier than they would in a parenteral dose.[5][9]
Sublingual nitroglycerin quickly relieves symptoms of angina due to its high lipid solubility and bypassing the first-pass effect before entering the systemic circulation.[10] Isosorbide mononitrate differs from nitroglycerin. ISMN undergoes minimal first-pass metabolism, leading to high bioavailability after oral administration. However, its onset of action is too slow for the acute treatment of angina.[11] Administering diazepam rectally in children with febrile seizures significantly bypasses first-pass metabolism, ensuring a rapid onset of anticonvulsant effects, which is particularly important in prehospital settings.[12][13]
Research has shown that monitoring blood concentrations of drugs that experience the first-pass effect is the most viable way to maintain therapeutic concentrations of these drugs.[14] Dextromethorphan, acting as a substrate for CYP2D6 and undergoing significant first-pass bioinactivation, exhibits potential in treating the pseudobulbar-affect. The co-administration of dextromethorphan with a minimal dose of quinidine effectively inhibits first-pass metabolism, resulting in increased systemic concentrations compared to monotherapy. This combination therapy is now FDA-approved for managing the pseudobulbar-affect.[15]
Nursing, Allied Health, and Interprofessional Team Interventions
The interprofessional healthcare team (eg, physicians, advanced practitioners, nurses, and pharmacists) must work together to ensure the safety and efficacy of pharmacotherapy. The healthcare team should monitor for signs of adverse drug reactions. The pharmacist should verify the dosing, perform medication reconciliation, and perform a drug interaction check.[16] Nurses can monitor adverse events and assess treatment effectiveness on subsequent visits. Applying basic pharmacokinetic concepts, eg, the first pass effect, can ensure the appropriate drug route of administration and dosing of the patient. Open communication among nurses, pharmacists, and the prescribing physician is crucial for reporting and discussing any concerns regarding pharmacotherapy. An interprofessional team approach with open communication is essential to optimize patient outcomes with minimal adverse events.
Nursing, Allied Health, and Interprofessional Team Monitoring
When monitoring patients taking drugs that experience the first-pass effect, it is critical to monitor the blood concentrations of these drugs to ensure that the patient's serum drug concentrations remain within their therapeutic windows. Implementing this approach will optimize the effectiveness of the treatment and enhance patient safety.[14]
References
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Level 3 (low-level) evidenceWang X, Zheng M, Liu J, Huang Z, Bai Y, Ren Z, Wang Z, Tian Y, Qiao Z, Liu W, Feng F. Differences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in rats. Journal of ethnopharmacology. 2017 Sep 14:209():175-183. doi: 10.1016/j.jep.2017.07.039. Epub 2017 Jul 26 [PubMed PMID: 28755970]
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Mattes RD, Shaw LM, Edling-Owens J, Engelman K, Elsohly MA. Bypassing the first-pass effect for the therapeutic use of cannabinoids. Pharmacology, biochemistry, and behavior. 1993 Mar:44(3):745-7 [PubMed PMID: 8383856]
Baraona E, Abittan CS, Dohmen K, Moretti M, Pozzato G, Chayes ZW, Schaefer C, Lieber CS. Gender differences in pharmacokinetics of alcohol. Alcoholism, clinical and experimental research. 2001 Apr:25(4):502-7 [PubMed PMID: 11329488]
Wynne H. Drug metabolism and ageing. The journal of the British Menopause Society. 2005 Jun:11(2):51-6 [PubMed PMID: 15970015]
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Level 3 (low-level) evidenceDivakaran S, Loscalzo J. The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics. Journal of the American College of Cardiology. 2017 Nov 7:70(19):2393-2410. doi: 10.1016/j.jacc.2017.09.1064. Epub [PubMed PMID: 29096811]
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Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, Bare M, Bleck T, Dodson WE, Garrity L, Jagoda A, Lowenstein D, Pellock J, Riviello J, Sloan E, Treiman DM. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy currents. 2016 Jan-Feb:16(1):48-61. doi: 10.5698/1535-7597-16.1.48. Epub [PubMed PMID: 26900382]
Level 1 (high-level) evidenceEilbert W, Chan C. Febrile seizures: A review. Journal of the American College of Emergency Physicians open. 2022 Aug:3(4):e12769. doi: 10.1002/emp2.12769. Epub 2022 Aug 23 [PubMed PMID: 36016968]
Wargin WA, Sawchuk RJ, McBride JW, McCoy HG, Rylander ML. Variable first-pass elimination of propranolol following single and multiple oral doses in hypertensive patients. European journal of drug metabolism and pharmacokinetics. 1982:7(3):183-9 [PubMed PMID: 7173272]
Fralick M, Sacks CA, Kesselheim AS. Assessment of Use of Combined Dextromethorphan and Quinidine in Patients With Dementia or Parkinson Disease After US Food and Drug Administration Approval for Pseudobulbar Affect. JAMA internal medicine. 2019 Feb 1:179(2):224-230. doi: 10.1001/jamainternmed.2018.6112. Epub [PubMed PMID: 30615021]
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