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Hi, my name is Carmen Kosicek and I am a psychiatric mental health nurse practitioner. Today I will be speaking about the clinical pharmacology of psychotropic medications. While we are all very familiar with the medications that we prescribe every day, it’s important to have a refresher on how they work, in order to fill in any gaps in knowledge we may have.
First, we will review the basic concepts of pharmacology. We’ll then discuss how these processes impact treatment decisions and patient management.
Let’s refresh our minds with some introductory information about the core concepts of clinical pharmacology, which include pharmacokinetics, the way medications travel throughout the body, and pharmacodynamics, the way that drug mechanisms can change the body.
Pharmacokinetics consists of four main processes–absorption, distribution, metabolism, and excretion. The rate of absorption of a particular medication is affected by several factors, including route of administration, dose, and formulation. Absorption may occur in the tissues of skin, gastrointestinal tract, and respiratory system.
Once absorbed, medications are distributed throughout the body. Lipid solubility is an important factor that determines key aspects of distribution, including the speed at which the medication is absorbed, as well as how it crosses membranes to reach tissues. Because of this, lipid-soluble drugs are distributed more completely than those that are lipid-insoluble. Impaired absorption can reduce the bioavailability of a drug.
Some medications form drug-protein complexes. These are too large to cross capillary membranes due to plasma proteins in the bloodstream. Barriers to distribution include anatomical roadblocks like the placenta in pregnant women and, most relevant to psychiatry, the blood-brain-barrier.
Medications in pill form are first broken down in the GI (gastrointestinal) tract. This is called “first-pass metabolism.” However, an oral spray will be directly absorbed through the mucous membranes, while an injection will go directly into the bloodstream. Avoiding first-pass metabolism can be advantageous, as many medications are converted into an inactive form before they are absorbed.
It is important to take these considerations into account when deciding on a medication for your patients. Route of administration may also determine how quickly your patient will feel the effects of a medication.
Metabolism largely occurs in the liver through the hepatic microsomal enzyme system, also known as the cytochrome P450 or CYP-450 pathway. We will discuss this in greater length later, as this pathway is a key player in mediating drug-drug interactions.
Once medications are broken down, they are excreted from the body primarily through the kidneys. Excretion rate determines concentration of the drug in the bloodstream and therefore the duration of the effect.
Let’s take a look at a hypothetical example of a pharmacokinetics curve after administration of a single dose of medication we’ll call Drug X. Its duration of action lasts from two to eight hours, with plasma concentration levels increasing from 6 mcg/mL to peak at 10 mcg/mL and then decreasing back to 6 mcg/mL. This window of time is referred to as the therapeutic range. If levels of Drug X are out of range, plasma concentrations could be less effective or, at the other extreme, be toxic. I should note that this example refers to a single drug, whereas many people take more than one medication, which can complicate these curves.
Another simple dosing example shows how a drug is distributed quickly and uniformly with a constant rate of infusion. Plasma concentration smoothly increase until it reaches a plateau. This is called the steady state of a drug, where the rate of drug input is equivalent to the rate of its elimination
A medication’s duration of action is described by its half-life, which is the time it takes for peak plasma concentrations to decrease by half. This also affects rate of excretion. For example, the longer the half-life, the longer the drug effect, and the longer it takes to be excreted. While drug half-lives indicate the likely time-course at which the drug will reach steady state, some drugs have active metabolites that are broken down more slowly.
Consider this information when you prescribe so that you can monitor safety and efficacy of medications appropriately. You can review for a drug’s half-life in its package insert prescribing Information, which will be discussed later.
Now let’s turn our attention to pharmacodynamics. Medications either take effect by acting on an ion channel, through an intracellular G-protein coupled receptor (GPCR), through an inner membrane enzyme, or by affecting intranuclear receptors. These effects may lead to alterations in gene transcription and protein synthesis. Drugs that work on ion channels can produce effects within milliseconds, whereas the other types produce much slower response.
Psychotropic medications take effect by exerting actions on receptors within different neurotransmitter systems. For example, SSRIs work by altering function of serotonin receptors. They are a number of different ways a drug can affect receptors in the brain.
Antagonists block the activity of a receptor, therefore decreasing its activity, and agonists bind to the receptor, mimicking its natural effect and increasing activity. Each drug binds or blocks receptors with a different affinity, or tightness. Partial agonists bind to the receptor and increase its activity but not to a full extent; therefore, the effects may not be as strong as the full agonists. The same is true for partial antagonists.
Partial agonists can either behave as agonists or antagonists, and this is dependent upon the endogenous levels of the respective neurotransmitter. For example, if the endogenous serotonin levels are high, a partial agonist could function as an antagonist to reduce serotonin in that area of the brain. On the other hand, if the endogenous levels of a neurotransmitter are low, a partial agonist may function as an agonist to raise these levels.
Antagonists can also be competitive, non-competitive, or non-receptor mediated in nature. However, some drugs take effect by interacting with enzymes or transport proteins. A competitive antagonist will literally “compete” with the neurotransmitter that normally would bind to a receptor in the absence of a drug. This means that the dose of a competitive antagonist would need to be very high to block the effects of the neurotransmitter. Antagonists can also slow the rate of absorption of another drug, which can lead to drug-drug or drug-food interactions.
For these reasons, it is very important to do a full history on a patient before prescribing to avoid potential interactions and to check in with patients to see if they recently changes any other medications as well. You can review the mechanism of action section of a drug’s Prescribing Information to see how it works.
Let’s now move on to discuss how psychotropic medications are metabolized.
As you know, there are several different classes of antidepressant medications. SSRIs, SNRIs, and tricyclics block the reuptake of monoamines through transporter inhibition, while MOAIs block monoamine oxidase, a mitochondrial enzyme, which normally metabolizes monoamines.
SSRIs, SNRIs, and tricyclics are metabolized by different isozymes of the CYP-450 pathway, such as 2D6 and 3A4. Their interactions with other drugs are determined by the specific enzyme substrate they bind to. Therefore, these medications can increase or decrease the breakdown of other medications that also affect this pathway.
MAOIs include an array of diverse drugs that are broken down in different ways, with some affected by CYP-450. MAOIs inhibit break down of tyramine, an amino acid found in many foods, including cheese; this is often referred to as “the cheese effect.”
While some mood stabilizers act through the CYP-450 pathway, others are broken down by metabolites. Therefore, their interactions with other drugs, ranging from contraceptives to antivirals and even chemotherapeutics, vary widely.
The potential drug-drug interactions discussed certainly do not represent an exhaustive list. Rather, they are examples to show the importance of fully understanding both the mechanism of action of medications you prescribe, as well as their specific drug-drug interactions.
It’s essential to communicate to your patients these potential interactions and emphasize that they notify you when they start or stop a medication for another condition. Even herbal supplements should be noted, as many can interfere with psychotropic medications.
There is clearly a lot involved in the pharmacology of psychotropic medications. As we discussed earlier, I find it helpful to review the Prescribing Information, or PI, of each medication I prescribe.
I start by taking a glance at the highlights section on the first page to get a quick snapshot of the medication. Section 7 is important to review to learn more about specific drug-drug interactions, as we just mentioned.
I then review the mechanism of action, which is usually labeled as Section 12. This section also has information on pharmacokinetics and pharmacodynamics.
Other parts of the PI contain dosage and administration information. You can also see the common side effects experienced by patients in the clinical trials. I find the PI to be a great reference tool worth referring back to.
To summarize our discussion today, a greater understanding of pharmacokinetics and pharmacodynamics is vital to making informed treatment decisions.
Identifying factors specific to individuals that can affect the rate of medication absorption, distribution, metabolism, and excretion is key to achieving optimal outcomes. Therefore, it’s imperative that we as providers thoroughly review patient medication lists, including herbs and supplements, and medical history, to determine if certain conditions such as those that affect the liver or kidney may impede pharmacokinetics.
Finally, different classes of psychotropic medications are broken down differently in the body. And, as many patients take more than one psychotropic medication or medications for other conditions, it’s essential to review each drug’s metabolic pathway to avoid side effects and drug-drug interactions.
Remember to check the PI for essential information about the medications you prescribe so you can be properly prepared to monitor safety and efficacy and help set your patients up for success.
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This resource is intended for educational purposes only and is intended for US healthcare professionals. Healthcare professionals should use independent medical judgment. All decisions regarding patient care must be handled by a healthcare professional and be made based on the unique needs of each patient.
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