Pharmacology of Ketamine

Pharmacology is the scientific study of how drugs work in the body. Pharmacokinetics examines how quickly a medication is absorbed, distributed, metabolized, and eliminated in the body – what the body does to the drug. Pharmacodynamics is the opposite, that is, what a drug does to the body. How a drug is administered, whether orally (O), intravenously (IV), intramuscularly (IM), or intranasally (IN) will impact both its pharmacokinetics and its pharmacodynamics.

Three factors influence the clinical effect of medications: the route of administration; the patient’s physiology and other drugs that may be in the patient’s system; and the amount or dose of the particular medication. 

The route of administration impacts the absorption of the drug. Two factors play a role in choosing the route of administration: the bioavailability (the fraction that enters the blood when not given intravenously) of the drug and the conditions under which it is given, including the patient’s ability to cooperate. Typically the more controlled hospital environment and its readily available resources allow for more options than the less predictable prehospital setting. Drugs administered through intramuscular injections have a lower bioavailability (albeit some, like ketamine, approach the intravenous route) but can be given in a number of places such as the upper arm, thigh, and buttocks. In situations where the patient is highly agitated, establishing and maintaining IV access can be extremely difficult and IN administration can easily be rejected. Based on these considerations, the panel recommends that a patient who requires chemical restraint be given the medication via intramuscular injection because of the ease of administration and acceptable bioavailability of the drug. If, however, the EMS provider can safely establish an intravenous route, the panel agrees that an IV injection is preferable.

Drug-drug interactions and the individual patient’s physiology influences a medication’s effect. For example, the use of benzodiazepines in a patient on opioids (i.e., morphine) with lung disease increases the risk of respiratory failure and death much more than when the drugs are individually administered in an otherwise healthy patient. Ideally, a medical professional would obtain a medical history, physical exam, and diagnostic studies before deciding what medications to give. An EMS provider trying to assess a highly agitated or delirious patient would lack much of that information. 

Panel members discussed other non-medical factors that may impact patient physiology. For example, in some cases law enforcement is involved with an agitated person before paramedics arrive on scene. Oftentimes there has been a struggle between the police and the person resulting in the application of physical restraints. These actions can cause positional asphyxia that impedes the person’s ability to breathe and restricts blood flow to the brain. In such a situation, any drug that lowers breathing drive – decreasing ventilation – can exacerbate the injury. In these situations, EMS providers must make a rapid determination about whether to administer medication to a respiratory-distressed individual. If medication is necessary, providers must determine the appropriate medication to administer and undertake immediate monitoring.

There are several drugs that can be used to calm agitated patients; no one drug is perfect for addressing every level of agitation. Midazolam, haloperidol, and droperidol are frequently used for chemical restraint or sedation.[28(pp. 5-6)]  For instance, a benzodiazepine such as midazolam can be appropriate for mild to moderate agitation, while haloperidol was suggested by panel members as an alternative for severe agitation. The Colorado EMPAC Ketamine Waiver Guidance that was in effect before June 2021 provides that “treatment of agitation, even severe agitation, should be with benzodiazepines and/or antipsychotics [e.g., haloperidol]…When necessary, ketamine may be used to treat behaviors exhibited in extreme or profound agitation in order to rapidly facilitate patient care management and transport to the hospital.” (See Appendix G.) 

As noted in the table below, however, these alternative drugs are slower acting, have a longer duration of action, and possess significant side effects. For example, haloperidol lowers the seizure threshold and can cause temperature dysregulation leading to heat stroke, drug-induced parkinsonism, fatal arrhythmias, and neuroleptic malignant syndrome.[38]  Benzodiazepines can cause low blood pressures, airway obstruction, apnea, and paradoxical agitation (when underdosed). The ideal chemical restraint for out-of-hospital use would have a wide therapeutic index, be easy to administer, and have a predictable effect with rapid onset and moderate duration, lasting only long enough for patient assessment, preliminary treatment, and handover to a medical facility for care. A chemical restraint that lasts longer may result in medical complications.[28(p. 7)] The panel acknowledges that when the criteria for ketamine set forth in Recommendation A.3 are not met, the other medications may still be appropriate.

The table synopsizes information that the panel’s toxicology expert presented to the KIRP. It compares the onset and duration for IM ketamine to other drugs used in the prehospital setting.

Table 5. Onset and Duration for IM Ketamine Versus Other Drugs