Pharmacokinetics And Pharmacodynamics Of Intravenous Anesthetics And Hemorrhagic Shock

 

P. De Paepe, MD, PhD

Emergency Department, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium

 

Critically ill patients with hemorrhagic shock presenting to the emergency department or intensive care unit often need many different drugs. Major analgesics and anesthetics are frequently necessary in these patients and because of the pathophysiological changes, the use of these drugs remains a major challenge. In a 10-year survey of mortality associated with anesthesia, Harrison found that the induction of anesthesia in hypovolemic subjects was the most common cause of death attributed to anesthesia, and of an unknown number of anesthetic-associated complications¹. A dramatic illustration of the challenge of providing general anesthesia to hypovolemic patients is provided by Halford who described in 1943 an increased mortality of wounded military personnel during surgery under thiopental anesthesia at the beginning of World War II². This increased mortality was attributed to increased drug effect in the presence of extensive blood loss. Since then it is common clinical practice to reduce the dose of anesthetic drugs in hemodynamically compromised patients. However, this is mainly an empirically based practice. Indeed, in a recent editorial, Heffner emphasized that most of our knowledge of the pharmacokinetics of sedative drugs derives from short-term studies in normal subjects³. He further remarks that critical illnesses alter the volumes of distribution, availability, and elimination of drugs, essentially converting “short-acting” sedatives to drugs with long-term effects.

Knowledge of the influence of critical illness on the pharmacology of analgesics and anesthetics and correct dosing of these drugs are very important as underdosing may lead to inadequate pain relief and sedation, and overdosing may result in cardiorespiratory depression in patients who are already hemodynamically compromised. No human data about the influence of hemorrhagic shock on the pharmacokinetics and pharmacodynamics of drugs are available. Obviously, the lack of sound clinical studies may be explained by the ethical and practical difficulties associated with studies in critically ill patients. More data about the pharmacology of analgesics and anesthetics during hemorrhage are available for animals. It was only five years ago that the first animal studies were published dealing with newer anesthetics, and focussing on both the pharmacokinetics and the pharmacodynamics. Table 1 gives an overview of animal studies investigating the pharmacokinetics and/or pharmacodynamics of anesthetics and analgesics during hemorrhage, and describes for each study the direction in which hemorrhage changes the pharmacokinetics and/or pharmacodynamics of the drug under investigation compared with simultaneously studied control subjects. When interpreting these animal data in the context of the clinical setting it should be noted that the effect of fluid resuscitation on the pharmacology of anesthetics has not been studied yet. The pharmacological effect of a drug is determined by its free concentration present in the target tissue and by the intrinsic efficacy and end organ sensitivity. The free concentration built up at the site of action is in turn determined by processes like absorption, distribution, biotransformation and excretion of the drug. These processes which constitute the pharmacokinetics of a drug determine the relationship between the administered dose and the concentration of the drug in different tissues. These different processes may be altered during critical illness leading to changes in free concentration at the effect-site, and eventually to alterations in drug effect. Moreover, changes in drug effect may also result from changes in pharmacodynamics, such as changes in end organ sensitivity.

Theoretically, the direction of the pharmacokinetic changes during hemorrhagic shock may be predicted from its pathophysiological mechanisms. Hemorrhagic shock elicits characteristic compensatory hemodynamic adjustments mediated in large part by activation of the sympathetic nervous system. Enhanced sympathetic tone increases cardiac contractility and peripheral vascular resistance both of which serve to maintain arterial blood pressure. The increase in peripheral vascular resistance, however, is not uniform among different vascular beds. Organs with high metabolic requirements such as the heart and brain exhibit autoregulation; despite sympathetic stimulation, the vessels in these organs remain relatively dilated due to the local effects of hypoxia, lactic acid, or other products of anaerobic metabolism that accumulate when organ perfusion is reduced. Therefore, blood flow to the heart and the brain tends to be preserved while vasoconstriction decreases blood flow in other organs such as skin, muscle, and splanchnic organs. Thus, a disproportionate fraction of the available cardiac output is delivered to the heart and brain. These changes are expected to influence one or more of the four classic phases of drug disposition: absorption, distribution, metabolism and elimination.

Absorption of drugs from sites with impaired blood flow like e.g. muscles, skin and splanchnic organs is expected to be slow and incomplete. Thus, the oral, transdermal, subcutaneous, and intramuscular routes are not reliable in patients with hemorrhagic shock, and an intravascular route is preferred.

The homeostatic redistribution of blood flow away from less vital organs may result in a decreased drug distribution which together with the decreased blood volume may lead to higher blood concentrations. Due to the higher blood concentrations and the autoregulation of brain and heart blood flow, drug content in these organs is expected to be much higher in early phases explaining why central nervous system and heart toxicity may result when standard doses are administered to patients with hemorrhagic shock.

Changes in the plasma protein binding may also influence drug distribution. Hemorrhagic shock may cause increased concentrations of acute phase reactant proteins like a₁–acid glycoprotein which is a major binding protein for basic drugs like e.g. alfentanil. Increases in the concentration of a₁–acid glycoprotein will decrease the unbound fraction of drugs that bind to this protein in the plasma, and result in a decreased distribution volume. In contrast, reduction in the level of serum albumin during hemorrhagic shock may increase the free drug fraction of drugs that bind to albumin resulting in an increased distribution volume. Reduced organ perfusion causes anaerobic metabolism and metabolic acidosis which may alter the distribution of ionisable drugs. The latter may also result from pH changes due to e.g. respiratory and kidney failure.

Metabolism in the liver is the major route for elimination of a wide variety of drugs. In certain studies, hepatic dysfunction is present in more than 50% of critically ill patients and is associated with hypothermia, hypotension and sepsis. Hepatic clearance of a drug may be defined as the volume of blood perfusing the liver that is cleared of the drug per unit of time. The pharmacokinetic concept of hepatic clearance takes into consideration the anatomical and physiological facts that the drug is transported to the liver via the portal vein and the hepatic artery and leaves the organ by the hepatic vein. It diffuses from plasma water to reach the metabolic enzymes. There are at least three major parameters to consider in quantifying drug elimination by the liver: blood flow through the organ, which reflects transport to the liver; free fraction of drug in blood which affects access of drug to the enzymes; and intrinsic ability of the hepatic enzymes to metabolize the drug, expressed as intrinsic clearance. Intrinsic clearance is the ability of the liver to remove drug in the absence of flow limitations and blood binding. The ratio of the hepatic clearance of a drug to the hepatic blood flow is called the extraction ratio of the drug. Extraction ratio can be generally classified as high (>0.7), intermediate (0.3-0.7) or low (<0.3) according to the fraction of drug removed during one pass through the liver. The effect of critical illness on hepatic clearance depends on these extraction characteristics of the drug as explained below. Table 2 lists the hepatic extraction ratio in humans for some sedative and analgesic drugs.

Drugs with a high hepatic extraction have a high intrinsic hepatic metabolizing capacity and are rapidly and extensively cleared by the liver from the blood. Their clearance depends primarily on hepatic blood flow, and binding to blood components is not an obstacle for extraction; the extraction is said to be non-restrictive or blood flow dependent.  The clearance of high extraction drugs is expected to be decreased during hemorrhagic shock due to a reduction in hepatic blood flow. For high extraction drugs, changes in protein binding do not affect total drug concentrations at steady state whereas unbound drug concentrations at steady state change directly with the free drug fraction.  The latter implies that for high extraction drugs, changes in free drug fraction may result in alterations in drug effect as free drug concentrations determine the drug effect.  

Drugs with a low hepatic extraction have a low intrinsic hepatic metabolizing capacity and are extracted less avidly and incompletely from hepatic blood. Their clearance is relatively independent of hepatic blood flow, and is primarily determined by the intrinsic metabolizing capacity of the liver and by the free drug fraction; the extraction is said to be restrictive or capacity limited. As mentioned above, changes in free fraction may occur during hemorrhagic shock and will result in alterations of clearance of low extraction drugs. For low extraction drugs changes in protein binding are inversely related to total drug concentrations at steady state, but have no effect on unbound drug concentrations at steady state. Hepatocellular enzyme activity is expected to be reduced in hemorrhagic shock leading to decreased clearance of low extraction drugs, and is presumably influenced by factors such as organ perfusion, intracellular oxygen tension and cofactor availability. The cytochrome P-450 (CYP) enzyme system has been shown to be importantly affected in critical illness. Hypoxemia results in reduced enzyme production in the liver, reduced efficiency of the enzyme present and decreased oxygen available for drug oxidation.

The clearance of drugs with intermediate extraction is dependent of hepatic blood flow, intrinsic metabolising capacity of the liver and free drug fraction.

For many drugs, the kidneys are responsible for the excretion of both the parent drug and metabolites produced by the liver and other tissues. The urinary excretion of a drug is the net result of filtration, secretion and reabsorption. Reductions in blood flow due to e.g. hemorrhagic shock may compromise kidney perfusion as part of the homeostatic mechanisms resulting in a decreased glomerular filtration rate leading to a reduction in renal drug clearance. Clearance of drugs that are only filtered and not secreted or reabsorbed is determined by both glomerular filtration rate and free drug fraction. Urinary drug secretion may also be influenced by protein binding and this will depend on the efficiency of the secretion process and on the contact time at the secretory sites. By analogy with hepatic metabolism, for drugs that are almost completely removed from blood within the time they are in contact with the active transport site, secretion is dependent of blood flow and independent of protein binding, and reduced renal blood flow may be expected to slow elimination. The tubular reabsorption of drugs may be increased as a consequence of decreased urine flow accompanying a decrease in glomerular filtration rate.

Besides the pharmacokinetics the pharmacodynamics may also be influenced during hemorrhagic shock due to changes in the affinity of the receptor for the drug or alterations in the intrinsic activity at the receptor. From table 1 it is clear that only limited data are available about pharmacodynamic changes during hemorrhage.  

 

 

 

 

Table 1 Literature review on the effect of hemorrhagic hypovolemia on the pharmacokinetics and pharmacodynamics of anesthetics and analgesics

Drug             (route of administration)	Species	Model	n	Pharmacokinetics				Pharmacodynamics	Drug effect	Ref.
				Cl	V	t1/2	fu
Phenobarbital (IV)	Rat	Hemorrhage 30%	12	-	-	-	=	increased  sensitivity	reduced dose for loss of righting reflex	4
Desmethyldiazepam (IV)	Rat	Hemorrhage 30%	14	¯	=	­	=	increased sensitivity	reduced dose for loss of righting reflex	5
Midazolam (IV)	Dog	Hemorrhage 30%	8	¯	=	­	-	-	increased CNS depressant effect	6
Ketamine (IV)   Thiopentone (IV)	Pig	Hemorrhage 30%	4   4	-   -	-   -	-   -	-   -	-   -	decreased anesthetic dose requirement for both drugs	7
Fentanyl (IV)	Pig	Hemorrhage 40-45 mmHg	8	¯	¯	-	-	-	-	8
Morphine (IV)	Rat	Hemorrhage 30%	8	=	¯	=	-	-	increased effect as measured by tail-flick test	9
Etomidate (IV)	Rat	Hemorrhage 30%	9	¯	¯	=	=	=	increased effect as measured by EEG and righting reflex	10
Propofol (IV)	Rat	Hemorrhage 30%	9	¯	¯	=	=	increased sensitivity	increased effect as measured by EEG and righting reflex	11
Remifentanil (IV)	Pig	Hemorrhage 40 mmHg	8	¯	¯	=*	-	=	increased effect as measured by EEG	12
Propofol (IV)	Pig	Hemorrhage 50 mmHg	8	¯	¯	-	-	increased sensitivity	increased effect as measured by EEG	13
Etomidate (IV)	Pig	Hemorrhage 50 mmHg	8	=	¯	-	-	=	=	14

 

Hemorrhagic hypovolemia was induced by removing blood using a fixed volume (expressed as percentage of circulating blood) or targeting a blood pressure level (expressed in mmHg).

 

-  : not mentioned or not measured