Part II Part II
Chapter 6 Chapter 6
59
Dosing differences are often necessary to ensure that
bioequivalence is achieved
when two different routes of administration of the same drug are employed.
Absorption following
oral administration
Drugs enter the gastrointestinal (GI) tract and are absorbed through the stom-
ach or small intestine. They travel via the portal vein first to the liver and then through the heart and into general circulation.
Oral administration results in more variable drug absorption and drug bioavail-
ability than other administration routes.
First-pass metabolism
(also known as the first-pass effect) refers to the inactiva- tion of an orally administered drug by liver enzymes immediately following absorption from the GI tract and prior to the drug reaching general circulation.
Enterohepatic recirculation refers to the cyclical movement of orally administered drugs from the GI tract to the liver, then packaged into bile and secreted into the small intestine, and then reabsorbed back into the liver.
Drug dissolution may be protracted up to approximately 8 hours by formulat-
ing sustained-release, extended-release, and controlled-release preparations.
Sustained-release formulations (e.g., controlled-release paroxetine [Paxil CR]) may minimize GI distress, decrease the number of daily dosages, and provide more uniform drug absorption.
Many controlled release (CR) formulations are available only as brand name
medications at a substantially increased price over standard-release formula- tions. CR formulations cannot be crushed or chewed. Only formulations that are scored can be split.
Drugs that are inactivated by gastric acid or that cause gastric irritation may be
prepared with an enteric coating, which permits drug absorption to be delayed until the drug passes through the stomach and enters the intestine. Care should be exercised not to coadminister antacids with enteric-coated products, or the coating will dissolve in the higher pH.
Patients with GI distress may have impaired oral absorption.
Absorption following transdermal administration
Suitable formulation and route of administration for drugs able to permeate intact skin.
Toxic effects may occur during transdermal absorption if drugs are highly lipid
soluble, or when applied to irritated or damaged skin, or if transdermal applica- tion is a patch and previous patch is not removed prior to next dose (or if patch is cut or divided prior to topical application). Exposure to heat can increase drug absorption and thus should be avoided (use of heating blankets, saunas, etc.).
Controlled-release transdermal formulations (e.g., nicotine patches) are becom-
ing increasingly available for various medications.
Absorption following
intramuscular (IM) administration and subcutaneous (SC) administration
Many similarities exist between IM and SC injections. Both provide relatively
rapid absorption of aqueous solutions and relatively slow absorption of lipo- philic solutions.
The rate of absorption and drug bioavailability following an IM or SC injection
are dependent on the lipophilicity of the drug, fat content, and blood flow at the injection site.
Injections may provide even, prolonged absorption. A drug may be prepared in
a depot formulation that is gradually absorbed over time. Coadministration of a vasoconstricting medication may prolong absorption.
SC injections may result in pain if irritant is present.
Pharmacokinetic PrinciPles 61
Administration via
intravenous (IV) injection
Absorption is essentially instantaneous, as the drug is delivered directly into the
circulatory system.
It is useful when rapid drug effect is needed and allows for administration of
poorly lipid-soluble drugs and irritants.
Continued and repeated IV administration requires accessibility to patent veins.
Absorption may involve passive diffusion or active transport.
Passive diffusion
is the movement of a drug across a cell membrane down its concentration gradient.
Drugs that are smaller, less protein bound, and more lipophilic can be more read-
ily absorbed via passive diffusion. Most psychotherapeutic drugs are absorbed via passive diffusion.
Active transport
is the facilitated movement of a drug across a cell membrane.
Drugs unable to be absorbed via passive diffusion—either because of their
chemical properties or the drug concentration gradient—require active transport in order to be absorbed.
Active transport mechanisms include membrane-spanning proteins that facilitate
the movement of drugs across cell membranes and into the circulatory system.
Active transport of drugs is limited to those medications structurally related to endogenous compounds for which active transport mechanisms already exist (e.g., ions, amino acids, and simple carbohydrates).
Ion trapping
occurs when a drug classified as a weak acid transfers from a body compartment that is more acidic to one that is more alkaline (e.g., from the stomach to the plasma) or, conversely, when a weak base transfers from a more alkaline to a more basic compartment.
Absorption-related
drug–drug or food–drug interactions should be closely monitored. Antacids, for example, may impair the absorption of orally coadministered psychiatric drugs, leading to subtherapeutic concentrations of the coadministered drug.
distriBUtion Distribution
refers to the movement of a drug from the circulatory system to its site(s) of action. Drugs are distributed to sites in the body responsible for producing both therapeutic effects and adverse effects.
The variables affecting drug distribution—and delivery of the drug to its site of
action—include blood flow to the target tissue, lipid solubility, and plasma protein binding.
Tissues of the body with
high blood flow (e.g., the brain and muscle) will receive higher concentrations of a drug faster than tissues with low blood flow (e.g., adipose tissue).
Drugs with
high lipid solubility (e.g., nonpolar molecules) will more readily cross cell membranes, including the blood–brain barrier and placenta. These drugs will more readily localize in tissues with high lipid content (e.g., brain and adi- pose tissue).
Drugs with a
low level of plasma protein binding (e.g., lithium) have a less encum- bered movement and have generally increased bioavailability than drugs with a high level of plasma protein binding (e.g., valproic acid). Table 6.1 identifies psychiatric drugs with high and low plasma protein binding.
The most abundant plasma protein is
albumin, and the terms plasma protein bind-
ing and albumin binding are often used interchangeably.
The biochemical properties that make a drug more readily absorbed into the cir-
culatory system (e.g., high lipid solubility and low molecular weight) also make the drug more readily distributed throughout the body (Gupta, Hammarlund- Udenaes, Chatelain, Massingham, & Jonsson, 2006).
The total accumulation of lipid-soluble drugs in
adipose tissue is dependent on the
fat content of an individual. Adipose tissue may serve as a drug reservoir, which may result in redistribution during instances of profound weight loss. This increase in adipose tissue is significant for the elderly—loss of muscle and increase in fat can put them at heightened risk.
The
blood–brain barrier results from brain capillary endothelial cells possessing con- tinuous tight junctions, which impede drug movement from the circulatory system into the central nervous system (CNS). Drugs passing into the CNS require specific transporter proteins or high drug lipophilicity.
Variables affecting
in utero drug distribution
For women who are pregnant, special considerations should be given to the
potential for maternal–fetal drug transfer via the placenta.
Similar properties dictate passive diffusion across the placenta as the blood–
brain barrier. Often drugs are able to cross the placenta first.
Drugs that have a high degree of lipid solubility, low molecular weight, and
low serum protein binding cross the placenta more readily than drugs with a low degree of lipid solubility, high molecular weight, and high serum protein binding.
Because fetal plasma is slightly more acidic than maternal plasma, ion trap-
ping of alkaline drugs may result in the increased accumulation of drug in the placenta.
Patients suffering from malnutrition or acute or chronic inflammatory responses
may present with hypoalbuminemia. The decrease in serum protein caused by hypoalbuminemia may result in greater drug bioavailability, particularly for drugs that are highly protein bound, leading to potentially toxic effects.
Distribution-related drug–drug or food–drug interactions should be closely moni-
tored. Warfarin, for example, may compete for albumin binding with other highly protein-bound psychiatric drugs, leading to an increased bioavailable plasma con- centration of either the psychiatric drug or warfarin. These increased drug levels
table 6.1 relative Plasma Protein Binding
HigH Protein-Binding
PsycHiatric drugs Low Protein-Binding PsycHiatric drugs Aripiprazole (>99%) Lithium (0%)
Ziprasidone (>99%) Gabapentin (3%) Atomoxetine (99%) Levetiracetam (10%)
Diazepam (99%) Topiramate (15%)
Sertraline (98%) Methylphenidate (15%)
Buspirone (95%) Clonidine (20%)
Valproic acid (93%) Venlafaxine (28%)
Pharmacokinetic PrinciPles 63
may be toxic and thus require dosage adjustments (Hisaka, Ohno, Yamamoto, &
Suzuki, 2010).
metaBolism Metabolism
refers to the chemical modification of the administered drug by enzymes in the patient’s body. Drug metabolism may take place before or after the drug reaches its site of action.
Drugs may be metabolized (a) from active to inactive compounds, (b) from inac-
tive to active compounds, or (c) from an active compound to a slightly less active compound (or vice versa).
Most commonly, drug metabolism leads to the
biotransformation of a more lipo-
philic parent drug to a more hydrophilic metabolite, which is often essential to increase the rate of excretion from the body.
The chemically modified variant of the administered drug is referred to as a
metabolite.
Metabolites of several commonly administered drugs are therapeutically active
at the same sites as their parent drug (e.g., s-desmethylcitalopram, the metabo- lite of escitalopram).
Metabolites of other drugs produce effects different from their parent drug
(e.g., desipramine, the metabolite of imipramine, blocks noradrenaline uptake, whereas imipramine itself inhibits serotonin reuptake).
Cytochrome P450 (CYP)
refers to the large family of enzymes, found primarily in the liver, responsible for facilitating the majority of drug metabolism in the body.
Each CYP family member has a unique collection of substrates (i.e., drugs and
other exogenous compounds) that it metabolizes.
Metabolism of one psychotherapeutic drug may increase or decrease the
metabolism of a second medication (Azzaro, Ziemniak, Kemper, Campbell, &
VanDenBerg, 2007). This is often a consequence of alterations in CYP activity.
Identification of a drug’s CYP metabolism is routinely established in preclinical
and clinical testing. This information is generally included in the pharmacoki- netics sections of printed drug guides or online/mobile device–based clinical management software (e.g., Lexi-Comp or ePocrates).
Individual drug effects on or by P450s may also be included as drug side effects
or as drug–drug or food–drug interactions.
The standard nomenclature for specific CYP isozymes includes a three- to four-
digit number–letter–number sequence, which identifies each isoform’s sequence homologies.
The primary CYP isozymes present in humans and involved in metabolizing
psychiatric drugs are CYP1A2, 2B6, 2C19, 2D6, and 3A4.
In addition to being substrates for specific CYPs, drugs may induce or inhibit
P450 activity. Grapefruit juice, for example, specifically inhibits the drug metabo- lizing activity of CYP3A4. This leads to an increase in plasma concentration of other drugs that would have normally been metabolized by CYP3A4.
The majority of drug metabolism occurs via P450s in the liver; however, in addition
to hepatic P450s, notable amounts of drug metabolism also take place in the small intestine, kidney, and lungs.
Patients with impaired liver function, such as those suffering from hepatitis or
cirrhosis, are at risk of having impaired drug metabolizing activity. This may lead to an increase in bioactive drug concentrations and require a decrease in dosing in order to avoid drug toxicity.
Metabolism-related drug–drug or food–drug interactions should be closely moni-
tored. Grapefruit juice inhibits the metabolism of buspirone and other CYP 3A4 metabolites, leading to an increased plasma concentration of buspirone.
Therapeutic drug monitoring
improves the quality and safety of psychiatric drug therapy. Valid specimens must be collected during a specific time window; for example, many psychiatric medications such as lithium and valproic acid are drawn as “trough” concentrations just prior to the next dose is due. Appropriate pharmacokinetic interpretation of monitoring data can decrease costs and improve therapeutic outcomes (Llorente Fernández, et al., 2010).
The term
half-life (t½) refers to the amount of time necessary to decrease the concen- tration of the drug in the patient by 50%. The term plateau refers to the steady-state drug levels achieved in the body with continual drug administration.
Due to the unique pharmacodynamic properties of psychiatric drugs (e.g.,
antidepressants), it is possible for there to be a significant delay in therapeutic response even after a plateau drug level has been reached.
Since psychoactive drugs often have delayed neurochemical effects (e.g., recep-
tor remodeling), it is possible that physiological changes will be observed even after most of the medication has been removed from the body.
Drugs of the same pharmacological class may have very different half-lives
(Table 6.2).
eXcretion Excretion
refers to the removal of the drug and any drug metabolites from the patient’s body. Of particular concern is the excretion of (a) a therapeutically active parent drug, (b) any bioactive metabolites, and (c) any toxic metabolites.
The primary organs facilitating drug excretion are the kidneys. Renal excretion
includes (a) glomerular filtration, (b) active tubular secretion, and (c) passive tubular reabsorption.
table 6.2 comparison of half-lives of commonly administered ssris and atypical antipsychotics
ssris atyPicaL antiPsycHotics Paroxetine (t½ = 17 hr) Ziprasidone (t½ = 3 hr) Fluvoxamine (t½ = 15 hr) Risperidone (t½ = 3 hr) Sertraline (t½ = 23 hr) Quetiapine (t½ =6 hr) Citalopram (t½ = 33 hr) Clozapine (t½ = 23 hr) Escitalopram (t½ = 33 hr) Olanzapine (t½ = 33 hr) Fluoxetine (t½ = 53 hr) Aripiprazole (t½ = 47 hr) SSRIs, selective serotonin reuptake inhibitors.
Pharmacodynamic PrinciPles 65
Nonprotein-bound drug is filtered through the glomerulus. Transporter proteins
facilitate active reabsorption.
Drugs may also be excreted through the
GI tract via sequestration in bile or directly
into the intestines. Drugs may also be excreted through the skin (e.g., sweat), oral mucosa (e.g., saliva), breast (e.g., lactation), and lungs (e.g., expiration).
Enterohepatic recirculation may impede excretion. Patients with impaired kidney
function may have impaired drug excretion.
Although most drugs undergo hepatic metabolism, some drugs (e.g., lithium) are
excreted in their active form.
Pharmacodynamics refers to the effects of the drug on the patient. Pharmacodynamic effects can be observed at the molecular and cellular levels, as well as at the tissue and organ system levels.
mechanisms of drUG action or molecUlar drUG tarGets
Drugs most commonly produce their physiological effects through interactions
with cellular drug targets, known as receptors. Receptors are most typically proteins and are expressed on a variety of tissues.
The term
ligand refers to drugs and endogenous molecules (e.g., neurohormones).
Drug–receptor interactions account for the majority of
drug side effects as well as
therapeutic effects. A drug may interact with one or more receptors.
The drug–receptor interaction responsible for the therapeutic drug effect may be
the same or different from the drug–receptor interaction responsible for specific drug side effects.
An example of therapeutic and adverse drug reactions being caused by the same
drug–receptor interaction is illustrated by morphine: Both analgesia (therapeutic effect) and respiratory sedation (drug side effect) are caused by the binding of morphine to the mu opioid receptor.
An example of therapeutic and adverse drug reactions being caused by differ-
ent drug–receptor interactions is illustrated by imipramine: The antidepressant effects result from interactions with serotonin and norepinephrine transporters and receptors; its side effects result from binding to cholinergic receptors (dry mouth, blurred vision, constipation) and histamine receptors (weight gain).
Drug receptors can be classified into five classes based on their cellular location and
general function. The five classes are G protein-coupled receptors (GPCRs), ligand- gated ion channels, cell membrane–embedded enzymes and transporters, intracel- lular enzymes and signaling proteins, and nuclear transcription factors.
GPCRs
comprise a superfamily of proteins, each containing seven membrane-span- ning alpha helices and coupled to a guanosine triphosphate (GTP)-binding protein, which alters the activity of a cellular enzyme or ion channel.
Examples of GPCRs include muscarinic acetylcholine receptors, histamine recep-
tors, serotonin receptors, and dopamine receptors.
Ligand-gated ion channels
are located across cell membranes and permit a specific ion to cross into or out of a cell, down its concentration gradient.
Pharmacodynamic Principles
Examples of ligand-gated ion channels include nicotinic acetylcholine receptors
and gamma-aminobutyric acid receptors.
Cell membrane–embedded enzymes and transporters
span the cell membrane and have
catalytic activity. Examples include the insulin receptor and neurotransmitter reuptake pumps.
Intracellular enzymes and signaling proteins
, such as monoamine oxidase, alter the
cellular environment by catalyzing chemical reactions or conveying chemical messages.
Nuclear transcription factors
, such as the glucocorticoid receptor and thyroid hor- mone receptor, bind to DNA and alter the transcription rates of specific gene families.
drUG–recePtor interactions
A drug or endogenous chemical that activates a receptor is referred to as an
agonist. Agonists may be classified as producing maximal receptor activation (full agonist) or less than that (partial agonist). A partial agonist may impede the actions of a full agonist, thus diminishing receptor activity.
A drug or endogenous chemical that inhibits a receptor from being activated is
referred to as an antagonist. Antagonists block the actions of both drugs and endog- enous chemicals (e.g., neurotransmitters).
While the effects of
competitive antagonists can be overcome by the increased con- centration of an agonist, the effects of other antagonists, referred to as noncom- petitive antagonists, will persist even if more agonist is present.
Drugs often act on more than one receptor, causing a multitude of both therapeutic
and adverse drug effects.
The description of a drug binding to a receptor simply indicates a physical interac-
tion. This may lead to either receptor agonism or antagonism.
Prolonged stimulation of a receptor may result in
desensitization, in which the same
concentration of a drug produces diminished therapeutic effects.
The amount of observed therapeutic effect produced by a drug is a measure of
efficacy. Maximal efficacy is the greatest response produced.
The amount of effect a drug produces at a specific drug concentration is a measure
of potency. High-potency drugs produce effects even when a small dose is given.
Low-potency drugs may be nonetheless efficacious; however, they may require a greater dose to be administered.
The difference between high-potency and low-potency psychiatric drugs are exem-
plified by first-generation antipsychotics (FGAs), where high-potency FGAs such as haloperidol produce their therapeutic effects at 1/10 to 1/100 the dose of low- potency FGAs (e.g., chlorpromazine).
Pharmacodynamic drUG–drUG interactions and side effects
Pharmacodynamic drug–drug interactions occur when one drug affects the physi-
ological activity of another drug unrelated to a direct chemical interaction or phar- macokinetic process. Most pharmacodynamic drug–drug interactions occur at the cellular or receptor level.
interPatient VariaBility 67
An example of a pharmacodynamic drug–drug interaction is serotonin syndrome,
which is produced by the coadministration of a monoamine oxidase inhibitor (e.g., phenelzine) and a selective serotonin reuptake inhibitor (e.g., fluoxetine). Both drugs contribute to a toxic accumulation of serotonin because of their actions on their respective drug targets.
Pharmacokinetic and Pharmacodynamic chanGes across the life sPan
Life span considerations affect both pharmacokinetic and pharmacodynamic drug
properties.
In general, pediatric and geriatric patients are more at risk of experiencing
increased sensitivity to therapeutic and adverse drug actions.
Pregnancy causes alterations in the pharmacokinetic actions of certain drugs, pri-
marily by altering the rates of drug absorption and excretion.
PharmacoGenetic imPlications to Pharmacokinetics and Pharmacodynamics
Pharmacogenetics
refers to the effect a patient’s genetic profile has on the patient's response to drug therapy.
Slight changes in the genetic code, referred to as
polymorphisms, have been identi-
fied in DNA that direct the production of proteins that affect drug metabolism, leading to pharmacokinetic variability. Polymorphisms that direct the production of drug receptors have also been identified in DNA, leading to pharmacodynamic drug variability.
An example of a genetic alteration affecting psychiatric drug pharmacokinetics is
a polymorphism in CYP 3A4, leading to the rapid or delayed metabolism of CYP substrates.
An example of a genetic alteration affecting pharmacodynamics is referred
to as the short allele polymorphism of the serotonin (5-HT) transporter.
Patients with short allele 5-HT transporter-experienced insomnia and agitation at higher rates during treatment with fluoxetine (Perlis et al., 2010).
references
Azzaro, A. J., Ziemniak, J., Kemper, E., Campbell, B. J., & VanDenBerg, C. (2007).
Selegiline transdermal system: An examination of the potential for CYP450-dependent pharmacokinetic interactions with 3 psychotropic medications. Journal of Clinical Pharmacology, 47, 146–158. doi: 10.1177/0091270006296151
Gupta, A., Hammarlund-Udenaes, M., Chatelain, P., Massingham, R., & Jonsson, E. N.
(2006). Stereoselective pharmacokinetics of cetirizine in the guinea pig: Role of protein binding. Biopharmaceutics & Drug Disposition, 27, 291–297. DOI: 10.1002/bdd.509