Pharmacology & Finding Nemo: The Plasma Protein Binding Story
I’ll admit, I was naïve. As a new paramedic, I was under the impression that when we gave IV medications, we pushed the drug and it just floated upstream in the plasma as a free-floating drug in a solution.
I thought of it a lot like this Finding Nemo gif:
Dory and Marlin (the medicine) just pop into that East Australian Current (our blood vessels) that Crush the Sea Turtle talks about. And they just tumble down the EAC and go find their respective receptor to attach to.
This seems all good in theory but, unfortunately, this isn’t quite the case and of course, it is more complicated than that. The drugs we administer in the field do not just “free float” in the bloodstream like Dory or Marlin do in the EAC. Instead, drugs travel in the blood like this:
Medications we administer are carried around on proteins called plasma proteins! Marlin being the medication and Crush the Sea Turtle being our plasma proteins.
I. More about these plasma proteins…
Plasma proteins are just that: proteins that exist in our plasma. There are a few plasma proteins circulating in our blood at any given time. However, the primary plasma protein I want to focus on is Albumin. A primary role of albumin is to act as a sponge and absorb the medications we administer. Albumin acts a lot like these guys…
Albumin wants, very much, to soak up the medication we administer. When we push an IV drug, much of that drug we administer attaches to albumin and uses the albumin as a transport. However, not all of that drug attaches to the albumin.
Each medication has a unique relationship with albumin; that is, how much it wants to attach to albumin or how much it stays away from albumin. Drugs with plasma protein binding greater than 70% are considered highly protein-bound. Here are some examples of various drugs we carry in EMS and their plasma protein binding profiles:
Breaking down Midazolam, for example, 96% of it attaches onto the albumin. The remaining 4% is considered unbound and free-floating (I was kind of right I suppose in thinking it was just “free-floating” to begin with!!). The same principle applies to the other medications listed above like Succinylcholine: 20% of the Sux attaches to plasma proteins while 80% are unbound and free-floating.
When a drug attaches to albumin, it creates what is known as a Drug Protein Complex. Here is the important point to remember: The drug that is bound to the albumin forming the Drug Protein Complex becomes inactive. Only the unbound drug is available to bind to receptor sites and cause a physiologic change. This is known as the Free Drug Theory. So, the unbound drug is considered the "active" form of the drug, and the bound portion of the drug is "inactive". The inactive form can also be thought of as a reserve collection of the drug to use later when the body needs to increase the active component.
This same concept affects what is known as the drug's "bioavailability" -- Or the amount of drug that is available to reach its intended physiologic destination (i.e. some receptor of some kind on an end-organ). A highly protein-bound drug, like Midazolam, has a low bioavailability simply because it would rather bind to the albumin and therefore less of the "active" form of the drug exists. On the contrary, Succinylcholine has a high bioavailability as it is less protein-bound and more of the "active form" exists. This also helps to explain why Succinylcholine has a short onset of action and short duration. Sux has more active forms immediately available once pushed IV (quick onset), and very little of that drug gets stored onto the albumin (short duration).
II. So what can alter our plasma protein binding properties?
There are several mechanisms that can alter the drug’s binding properties. Clinically speaking the end result is the same: if less albumin is available then the more unbound drug is available. If the more unbound drug is available then it has more of a physiologic effect as more are able to bind to receptor sites. Theoretically, less drug may be required to achieve the desired physiologic response when clinical states of low albumin exist.
Here are 5 clinical examples of how medicine and pharmacology are awesome:
Alteration #1: Albumin is produced and synthesized in the liver and without proper hepatocyte function, less functional albumin is produced leading to hypoalbuminemia. This leads to a reduction in the drug uptake leaving more of the unbound drug available. Overall, patients at risk for chronic hepatic disease include chronic alcohol users, patients with a history of Hepatitis, and diabetics. This is not an all-inclusive list though.
Alteration #2: Another important cause is critically ill patients who are intubated and on mechanical ventilation. These patients have high metabolic demands are may potentially be malnourished and receiving low dietary protein from the nutritional support they are receiving in the ICU. This low protein consumption can lead to states of hypoalbuminemia as well and contribute to the bioavailability of some medications.
Alteration #3: In patients with acidosis or renal impairment, clearance of built-up metabolites (toxins) is reduced and in an effort to stifle the accumulation of waste products, the albumin scoops up the built-up toxins. If the albumin is pre-occupied with waste products, less of the drug we administer is able to bind to albumin leading to once again — more unbound drug available for receptor sites!
In the critically ill patient, several studies have noted that the rate of synthesis of albumin is decreased as well. Increased capillary leakage in disease states like sepsis also alters the concentration and distribution of albumin between the intravascular and extravascular compartments leading to hypoalbuminemia.
Alteration #4: The presence of other medications can alter binding capabilities. We will explore a clinical example of this scenario further down in this blog. However, since many medications are protein bound to albumin and many patients take multiple medications, there is logically some “fighting” over who gets to attach to the albumin. And since some drugs have more binding power than others, there is room for potentiating the effects of certain medications just by administering another medication that is more protein-bound than the other.
Alteration #5: The last situation worth noting is hemorrhage. As our patient loses plasma and blood volume into their abdomen or into the street, for example, they also lose their albumin with it. Less albumin means more unbound forms of the drugs we give in acute trauma cases!
III. Clinical Scenarios
Scenario #1: Pain management in the hemorrhagic trauma patient
You are dispatched to a report of a single-vehicle MVA on a rural county road. It has been raining off and on for several days now and the roads are slick. A passerby reported that the patient appeared to hydroplane, then strike a road barrier.
As you arrive, there is significant damage to the front end of the vehicle as well as passenger space intrusion. The patient is alert but you note they are slow to respond to your questioning. You note bilateral, compound femur fractures. You note a significant amount of blood on the floorboard as you gain access to the patient. They are pale and cool and appear to be in hemorrhagic shock.
Albeit, there are many treatment priorities to consider however I wanted to focus on the pharmacological management aspects of this patient — Namely, the pain control.
Recall that Fentanyl is highly protein bound to albumin (85-90%). However, in this patient, much of that albumin within the blood plasma has conveniently relocated itself to the floorboard of his or her vehicle. This means less of it is situated within the intravascular space to soak up the Fentanyl we may give this patient. As a result, the patient may begin to feel analgesic effects from the Fentanyl at a potentially lower dose than anticipated.
But why is this a bad thing?
The difference between a drug and poison is nothing more than the dose! In these patients who have less albumin available to bind drugs (i.e. Fentanyl) the therapeutic window becomes much narrower. It may be wise to consider smaller aliquots of Fentanyl given this understanding of plasma protein binding. On the other hand, starting with a high dose could surpass the therapeutic effects leaving you with more unwanted side effects like altered mentation, hemodynamic changes, etc.
P.S. The same theory could be applied to Midazolam for sedation during extrication! Midazolam is even more protein-bound than Fentanyl. You may want to consider the smaller doses and titrating to the effect rather than just starting with a 5 mg bolus right off the bat.
Scenario #2: Which came first? The chicken or the egg?
You are dispatched out to a residential address for a report of a 60-year-old female who has reportedly had a seizure. The husband was the reporting party and called EMS after witnessing his wife have a 1-minute tonic-clonic seizure from which she is now postictal.
You have completed your primary assessment and determine no immediate life threats. The patient is started on some low flow oxygen via cannula and you inquire about some medical history to the husband. He reports that she has a history of seizures in which she takes Dilantin. She also has a history of atrial fibrillation for which she takes Coumadin. Being the astute clinician you are you also ask about any surgical history (because why not, right?). The husband says she was supposed to have elective surgery in 3 days and she was told to discontinue her Coumadin until the surgery is complete.
So what is the issue here? Coumadin and Dilantin are both highly plasma protein-bound drugs! Coumadin being 97% plasma protein bound and Dilantin being roughly 90%. Since the Coumadin was stopped prior to surgery, this left more albumin available to soak up the remaining Dilantin in our patient’s system.
The Dilantin that was unbound (because Coumadin was occupying the albumin) now became bound to albumin and rendered unusable. This left lower therapeutic levels of the anti-seizure medication, Dilantin, circulating and as a result… SEIZURE!
Now, this rare, great white buffalo of a presentation may present itself maybe once in your career; I do hope that you are able to recognize the interaction! Impress the doctor or maybe your preceptor!
My take-home points:
Bound to albumin = Inactive = No physiological response
Unbound to albumin = Active = Physiological response
Think of disease states in terms of albumin availability, this will help guide your pharmacological decision making (i.e. like hemorrhage and less albumin available)
Annotated References:
Bista, Sudeep Raj, et al. “Protein Binding of Fentanyl and Its Metabolite Nor-Fentanyl in Human Plasma, Albumin and α-1 Acid Glycoprotein.” Xenobiotica; the Fate of Foreign Compounds in Biological Systems, vol. 45, no. 3, 1 Mar. 2015, pp. 207–212, pubmed.ncbi.nlm.nih.gov/25314012/, 10.3109/00498254.2014.971093. Accessed 4 Dec. 2020. PPB of Fentanyl is 85-90%.
Bohnert, Tonika, and Liang-Shang Gan. “Plasma Protein Binding: From Discovery to Development.” Journal of Pharmaceutical Sciences, vol. 102, no. 9, Sept. 2013, pp. 2953–2994, 10.1002/jps.23614. Free Drug Theory: States that in the absence of other biochemical processes, the amount of free drug attempts to reach equilibrium between the plasma and the tissues. Only the free drug in the tissues is available to bind to receptor sites. If the plasma concentration is equal to the tissue concentration, then measuring our plasma concentration of unbound drug should give an indication to our unbound concentration in the tissues.
de Vries, J. X., et al. “The Determination of Total and Unbound Midazolam in Human Plasma. A Comparison of High Performance Liquid Chromatography, Gas Chromatography and Gas Chromatography/Mass Spectrometry.” Biomedical Chromatography, vol. 4, no. 1, Jan. 1990, pp. 28–33, 10.1002/bmc.1130040105. Accessed 4 Dec. 2020. PPB Midazolam: 96%.
Farmer, Steven. Plasma Protein Binding. 11 Sept. 2017, youtu.be/HjYUKQvmpIQ. Accessed 30 Nov. 2020. Once drug enters the body, it exists into two states: Bound to plasma proteins or unbound to Plasma proteins.
Gounden, Verena, and Ishwarlal Jialal. “Hypoalbuminemia.” Nih.gov, StatPearls Publishing, 27 Oct. 2018, www.ncbi.nlm.nih.gov/books/NBK526080/. Loss of albumin causes.
Greenblatt, David J. “Clinical Pharmacokinetics of Oxazepam and Lorazepam.” Clinical Pharmacokinetics, vol. 6, no. 2, 1981, pp. 89–105, 10.2165/00003088-198106020-00001. Accessed 4 Dec. 2020. PPB Lorazepam: 88-92%.
Hijazi, Youssef, and Roselyne Boulieu. “Protein Binding of Ketamine and Its Active Metabolites to Human Serum.” European Journal of Clinical Pharmacology, vol. 58, no. 1, 1 Apr. 2002, pp. 37–40, pubmed.ncbi.nlm.nih.gov/11956671/, 10.1007/s00228-002-0439-4. Accessed 4 Dec. 2020. PPB Ketamine: 60-65%.
Lindup, W. E., and M. C. L’E Orme. “Clinical Pharmacology: Plasma Protein Binding of Drugs.” British Medical Journal (Clinical Research Edition), vol. 282, no. 6259, 1981, pp. 212–214, www.jstor.org/stable/29500310?seq=3#metadata_info_tab_contents. Accessed 3 Dec. 2020. Drugs with PPB Binding greater than 70% are considered “highly protein bound” and affect their pharmacokinetics Two major factors affecting drug binding include: Disease states and Presence of other highly protein bound drugs.
Roy, JJ, and F Varin. “Physicochemical Properties of Neuromuscular Blocking Agents and Their Impact on the Pharmacokinetic–Pharmacodynamic Relationship.” British Journal of Anaesthesia, vol. 93, no. 2, 28 May 2004, pp. 241–8, 10.1093/bja/aeh181. PPB Succ: 20%.
Smith, Dennis A., et al. “The Effect of Plasma Protein Binding on in Vivo Efficacy: Misconceptions in Drug Discovery.” Nature Reviews Drug Discovery, vol. 9, no. 12, 1 Dec. 2010, pp. 929–939, www.nature.com/articles/nrd3287, 10.1038/nrd3287. Accessed 1 Dec. 2020. The physiologic actions of a drug are executed by the drug that is unbound to plasma proteins. This holds true for IV medications that may not undergo first pass metabolism. After FPM, biological factors such as membrane permeation and drug clearance and metabolism work to equal out the amount of free drug.
Wallace, S. M., and R. K. Verbeeck. “Plasma Protein Binding of Drugs in the Elderly.” Clinical Pharmacokinetics, vol. 12, no. 1, 1 Jan. 1987, pp. 41–72, pubmed.ncbi.nlm.nih.gov/3545616/#:~:text=Age%20is%20one%20of%20many, 10.2165/00003088-198712010-00004. Accessed 7 Dec. 2020. Age is not a clinical factor in plasma protein binding profiles of most medications.