Morgan & Mikhail Chap 7 (Pharmacological Principles) Flashcards
Key Concept 1: Drug Molecules obey the laws of mass action…
Drug molecules obey the law of mass action. When the plasma concentration exceeds the tissue concentration, the drug moves from the plasma into tissue. When the plasma concentration is less than the tissue concentration, the drug moves from the tissue back to plasma.
The rate of rise in drug concentration in an organ is determined by that organ’s perfusion and the relative drug solubility in the organ compared with blood. The equilibrium concentration in an organ relative to blood depends only on the relative solubility of the drug in the organ relative to blood unless the organ is capable of metabolizing the drug.
Key Concept 2: Most drugs that readily cross the…
Most drugs that readily cross the blood–brain barrier (eg, lipophilic drugs like hypnotics and opioids) are avidly taken up in body fat.
Lipophilic molecules can readily transfer between the blood and organs. Charged molecules are able to pass in small quantities into most organs. However, the blood–brain barrier is a special case. Permeation of the central nervous system by ionized drugs is limited by pericapillary glial cells and endothelial cell tight junctions. Most drugs that readily cross the blood–brain barrier (eg, lipophilic drugs like hypnotics and opioids) are avidly taken up in body fat.
Key Concept 3: Biotransformation is the chemical…
Biotransformation is the chemical process by which the drug molecule is altered in the body. The liver is the primary organ of metabolism for drugs.
An exception is the esters, which undergo hydrolysis in the plasma or tissues. The end products of biotransformation are often (but not always) inactive and water soluble. Water solubility allows excretion by the kidneys.
Key Concept 4: Small, unbound molecules…
Small, unbound molecules freely pass from plasma into the glomerular filtrate. The nonionized (uncharged) fraction of drug is reabsorbed in the renal tubules, whereas the ionized (charged) portion is excreted in urine.
Key Concept 5: Elimination half-life is the time…
Elimination half-life is the time required for the drug concentration to fall by 50%. For drugs described by multicompartment pharmacokinetics (eg, all drugs used in anesthesia), there are multiple elimination half-lives.
Key Concept 6: The offset of a drug’s effect…
The offset of a drug’s effect cannot be predicted from half-lives. The context-sensitive half-time is a clinically useful concept to describe the rate of decrease in drug concentration and should be used instead of half-lives to compare the pharmacokinetic properties of intravenous drugs used in anesthesia.
Pharmacokinetics
Pharmacokinetics defines the relationships among drug dosing, drug concentration in body fluids and tissues, and time. It consists of four linked processes: absorption,
distribution, biotransformation, and excretion.
Pharmacokinetics: Absorption
Absorption defines the processes by which a drug moves from the site of administration to the bloodstream. There are many possible routes of drug administration: inhalational, oral, sublingual, transtracheal, rectal, transdermal, transmucosal, subcutaneous, intramuscular, intravenous, perineural, peridural, and intrathecal. Absorption is influenced by the physical characteristics of the drug (solubility, pKa, diluents, binders, formulation), dose, the site of absorption (eg, gut, lung, skin, muscle), and in some cases (eg, perineural or subcutaneous administration of local anesthetics) by additives such as epinephrine.
Pharmacokinetics: Distribution
Once absorbed, a drug is distributed by the bloodstream throughout the body. Highly perfused organs (the so-called vessel-rich group) receive a disproportionate fraction of
the cardiac output (Table 7–1). Therefore, these tissues receive a disproportionate amount of drug in the first minutes following drug administration.
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Half Lives and Emergence Time
The complex process of drug distribution into and out of tissues is one reason that half-lives provide almost no guidance for predicting emergence times.
Pharmacokinetics: Biotransformation
Metabolic biotransformation is frequently divided into phase I and phase II reactions. Phase I reactions convert a parent compound into more polar metabolites through oxidation, reduction, or hydrolysis. Phase II reactions couple (conjugate) a parent drug or a phase I metabolite with an endogenous substrate (eg, glucuronic acid) to form water-soluble metabolites that can be eliminated in the urine or stool.
Although this is usually a sequential process, phase I metabolites may be excreted without undergoing phase II biotransformation, and a phase II reaction can precede or occur without a phase I reaction.
Pharmacokinetics: Excretion
Some drugs and many drug metabolites are excreted by the kidneys. Renal clearance is the rate of elimination of a drug from the body by kidney excretion. This concept is analogous to hepatic clearance, and similarly, renal clearance can be expressed as the renal blood flow times the renal extraction ratio.
Small, unbound drugs freely pass from plasma into the glomerular filtrate. The nonionized (uncharged) fraction of drug is reabsorbed in the renal tubules, whereas the ionized (charged) portion remains and is excreted in urine. The fraction of drug ionized depends on the pH; thus, renal elimination of drugs that exist in ionized and nonionized forms depends in part on urinary pH. The kidney actively secretes some drugs into the renal tubules.
Many drugs and drug metabolites pass from the liver into the intestine via the biliary system. Some drugs excreted into the bile are then reabsorbed in the intestine, a process
called enterohepatic recirculation. Occasionally metabolites excreted in bile are subsequently converted back to the parent drug. For example, lorazepam is converted by the liver to lorazepam glucuronide. In the intestine, β-glucuronidase breaks the ester linkage, converting lorazepam glucuronide back to lorazepam.
Compartment Models
Multicompartment models provide a mathematical framework that can be used to relate drug dose to changes in drug concentrations over time.
Conceptually, the compartments in these models are tissues with a similar distribution time course. For example, the plasma and lungs are components of the central compartment. The organs and muscles, sometimes called the vessel-rich group, could be the second, or rapidly equilibrating, compartment. Fat and skin have the capacity to bind large quantities of lipophilic drug but are poorly perfused.
These could represent the third, or slowly equilibrating, compartment. This is an intuitive definition of compartments, but it is important to recognize that the compartments of a pharmacokinetic model are mathematical abstractions that relate dose to observed concentration. A one-to-one relationship does not exist between any “mathematically identified” compartment and any organ or tissue in the body.
Many drugs used in anesthesia are well described by two-compartment models.
Two Compartment Model
As previously noted, in compartmental models the instantaneous concentration at the time of a bolus injection is assumed to be the amount of the bolus divided by the central compartment volume. This is not correct. If the bolus is given over a few seconds, the instantaneous concentration is 0 because the drug is all in the vein, still flowing to the heart. It takes a minute or two for the drug to mix in the central compartment volume.
This misspecification is common to conventional pharmacokinetic models.
Elimination Half-Time
Elimination half-time is the time required for the drug concentration to fall by 50%. For drugs described by multicompartment pharmacokinetics (eg, fentanyl, sufentanil), there are multiple elimination half-times, in other words, the elimination half-time is context dependent. The offset of a drug’s effect cannot be predicted from half-lives alone.
Moreover, one cannot easily determine how rapidly a drug effect will disappear simply by looking at coefficients, exponents, and half-lives. For example, the terminal half-life of sufentanil is about 10 h, whereas that of alfentanil is 2 h. This does not mean that recovery from alfentanil will be faster because clinical recovery from clinical dosing will be influenced by all half-lives, not just the terminal one.
Pharmacodynamics
Pharmacodynamics, the study of how drugs affect the body, involves the concepts of potency, efficacy, and therapeutic window. The fundamental pharmacodynamic concepts
are captured in the relationship between exposure to a drug and physiological response to the drug, often called the dose–response or concentration–response relationship.
Exposure-Response Relationship
The shape of the relationship is typically sigmoidal, as shown in Figure 7–2. The sigmoidal shape reflects the observation that often a certain minimal amount of drug must be present before there is any measurable physiological response. Thus, the left side of the curve is flat until the drug concentration reaches a threshold.
The right side is also flat, reflecting the maximum physiological response of the body, beyond which the body simply cannot respond to additional drug. Thus, the curve is flat on both the left and right sides. A sigmoidal curve is required to connect the baseline to the asymptote, which is why sigmoidal curves are ubiquitous when modeling pharmacodynamics.
