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Pharmacokinetics and Pharmacodynamics

Phillip Lerche and Jeffrey Lakritz

Introduction

Pharmacokinetic studies describe the time course of drugs from administration to removal from the body, and pharmacodynamics evaluates the effects drugs have on the various body systems. The basic concepts of pharmacokinetics and pharmacodynamics with reference to drugs commonly used in the peri-anesthetic period will be reviewed in this chapter. The unique aspects of inhalant anesthetic pharmacokinetics are discussed in Chapter 10.

Pharmacokinetics

Drug disposition refers to the processes of absorption, distribution, metabolism and excretion within the body after the drug is administered. In order for drugs to exert their effects when given by routes other than intravenous administration (IV), they must first be absorbed into the central compartment (i.e. the systemic circulation), from where they are distributed to the site of action. Distribution is followed by metabolism (biotransformation) and, finally, the drug and/or its metabolites are eliminated from the body (Caldwell et al. 1995).

Absorption and Bioavailability

Absorption refers to the movement of a drug from its site of administration into the central compartment. Most anesthetic and other drugs given in the peri-anesthetic period are given IV, thus bypassing the absorption phase. Advantages to this include the ability to have an almost immediate effect, (e.g. IV induction of anesthesia with propofol allows for rapid tracheal intubation, thus protecting the airway), to titrate the dosage to effect, to administer large volumes, and for emergency treatment. A disadvantage is that an overdose can rapidly lead to serious side effects.

In order to be absorbed, drugs must cross cell membranes. Drugs that are weak acids or weak bases are typically ionizable. That is, in solution, they exist in two forms: the non-ionized form which is lipid soluble and readily diffusible, and the ionized form which has lower lipid solubility and is poorly diffusible. Distribution of ionizable drugs across cell membranes is related to the drug's pKa, which is the pH at which 50% of the drug is ionized, and 50% is non-ionized. In the presence of a pH higher than a weak acidic drug's pKa, dissociation will be favored, and in the presence of a pH lower than that drug's pKa, non-ionization will be favored. The opposite is true for weak bases - at a pH below the pKa, the drug will be more ionized, while a pH above the pKa will result in more non-ionized drug (see Table 1.1). As an example, a weakly acidic drug will be readily absorbed in the highly acidic environment of the stomach as the pH favors non-ionization, whereas a weakly basic drug will be more non-ionized and readily absorbed in the alkaline environment of the small intestine.

Absorption can be a passive process (e.g. diffusion), or an active process (via active transporters). Most anesthetic drugs move across cell membranes by passive diffusion along a concentration gradient. The family of ABC transporters actively removes some drugs from cells and includes the P-glycoprotein (P-gp) transporter that is coded by the ABCB1 (MDR1) gene. In dogs that have homozygous mutations of this gene, P-gp transporters are nonfunctional. This can result in toxicity with some drugs (e.g. ivermectin in Collies), as well as prolonged activity of acepromazine and opioids (Deshpande et al. 2016; Martinez et al. 2008).

Bioavailability is the fraction (F) of a drug that reaches the central compartment after administration, and can be expressed as follows:

Table 1.1 Impact of pH on ionization of weak acids and weak bases as it relates to a drug's pKa, and the impact on absorption.

pKa is the pH at which the drug is in equilibrium between the non-ionized and ionized form. The non-ionized form of the drug is more lipophilic and therefore more readily absorbed.

? indicates that non-ionized and ionized forms are in equilibrium.

Bioavailability therefore ranges from 0 to 1, depending on route of administration. F =?1 after IV administration of drugs. Drugs given by the subcutaneous (SC) and intramuscular (IM) routes typically result in bioavailability above 0.75. Bioavailability after oral administration is highly variable, and dependent on multiple factors (e.g. impact of gastric enzymes on the drug, incomplete absorption in the presence of food, rate of gastric emptying, presence of enteric coating). Drugs absorbed in the gastrointestinal tract (GI) enter the hepatic portal circulation and can undergo first-pass biotransformation and elimination in the liver prior to entering the central compartment.

Drugs that can be absorbed via the oral mucosal surface (oral trans-mucosal, OTM), e.g. dexmedetomidine, buprenorphine, enter the central compartment via venous drainage from the head and neck to the cranial vena cava (Dent et al. 2019; Enomoto et al. 2022). Giving medication by this route has the advantage of being technically less challenging than giving injections, and therefore useful in minimizing stress in patients who are uncooperative for IM, IV, or SC administration. Absorption via the OTM route is determined by the Fick principle of diffusion, where the amount absorbed is directly proportional to drug concentration, drug lipophilicity, the surface area of and duration of contact with the tissue and is indirectly proportional to thickness of the tissue. The presence in the oral mucosa of enzymes that break down peptides can also limit drug absorption via this route (Zhang et al. 2002). Drugs delivered by this route can also be lost to the GI tract due to swallowing, which is likely to result in decreased bioavailability.

Intranasal (IN) administration offers similar advantages to the OTM route in that a large surface area with good blood supply is available for absorption. Naloxone given IN to dogs, for example, was rapidly absorbed with F = 0.32, and buprenorphine administered using a nasal atomization device had F = 0.57 (Wahler et al. 2019; Enomoto et al. 2022). Drawbacks to this route of administration include the drug being lost due to sneezing, head shaking or swallowing. Some animals actively resist placement of nasal drugs, making administration difficult. The presence of excess mucus in the nasal cavity may also decrease absorption.

Absorption of topical and transdermal formulations of drugs (e.g. the topical formulation of buprenorphine Zorbium®, fentanyl patches) occurs via the skin and, as a general rule, is determined by the lipid solubility of the drug and the surface area available (Kukanich and Clark 2012). In the case of fentanyl patches, other factors also play a role (location, body fat composition at the site of placement, body temperature). Damage to the skin surface can enhance absorption of drugs.

The formulation of a drug can impact its absorption. Several drugs with analgesic properties are available in sustained-release formulations that extend the period of absorption over time (e.g. fentanyl patch, liposome encapsulated bupivacaine) (Bartholomew and Smith 2023).

Distribution

After a drug is absorbed into the central compartment, it is distributed to the tissues. Distribution is impacted by regional blood flow and the tissue groups with high blood flow (the vessel rich group) such as the brain, heart, liver, and kidneys initially receive most of the drug. Delivery to the other tissues of the body (muscle, other viscera, skin, fat) takes longer.

Many drugs bind to plasma proteins. Acidic drugs typically bind to albumin, and basic drugs to a1-acid glycoprotein. Plasma protein binding decreases free drug available for absorption. Decreases in plasma protein binding due to decreased number of binding sites, e.g. with hypoproteinemia, will result in increased drug being unbound in plasma. Many anesthetic drugs are given to effect, e.g. propofol which is highly protein bound (97%), thus, decreased protein binding has limited relevance clinically. The impact of decreased protein binding resulting in an increase in unbound drug may have relevance when the therapeutic index is narrow, e.g. IV lidocaine.

Drugs can accumulate in tissues through tissue binding. The tissue will then act as a reservoir for the drug. Commonly, lipophilic drugs accumulate in adipose tissue.

The endothelial cells of the brain have tight endothelial junctions, thus forming part of the blood-brain barrier. The more lipid soluble a drug is in its unbound, non-ionized form, the more likely it is to cross the blood-brain barrier. Similarly, highly lipid soluble drugs can cross the placenta. Ion...