Basic Pharmacology Review Course

Contents

Pharmacokinetics

Pharmacokinetics is defined as the study of the time course of drugs and their metabolites through the body (i.e., what the body does to a drug).

Pharmacodynamics

Pharmacodynamics is defined as the study of the time course and intensity of the pharmacological effects of drugs (i.e., describes what the drug does to the body).

Pharmacokinetics vs Pharmacodynamics

First, we will review Pharmacokinetic principles and then we will dive into Pharmacodynamic principles!

Pharmacokinetics

Pharmacokinetics is defined as the study of the time course of drugs and their metabolites through the body (i.e., what the body does to a drug).

 

Routes of Administration 

The most common routes of administration for medications are:

Enteral: Oral, Sublingual, Buccal

Parenteral: Intravenous, Intramuscular, Subcutaneous

Other routes: Nasal/inhalation, intrathecal, intraventricular, Topical, Transdermal, Rectal.

Four pharmacokinetic properties determine the onset, intensity, and duration of action of drugs:

  1. Absorption: In order for a drug/medication to enter the plasma (bloodstream) it must be absorbed from the site of administration (e.g., skin, muscle, gut, oral mucosa, etc.)
  2. Distribution: Drugs/medications may distribute into the interstitial and intracellular fluids depending on the its chemical properties (i.e., drugs that are more lipophilic but not TOO lipophilic are likely to distribute rapidly throughout the body as these drugs can readily cross lipid bilayers and distribute widely into fat and other body tissues).
  3. Metabolism: Drugs/medications may be transformed by enzymes in the liver or other tissues to prepare for excretion. Usually this means making the drugs more water soluble (i.e. hydrophilic). Some drugs do not undergo metabolism (e.g., lithium)
  4. Excretion: Drugs/medications and their metabolites are eliminated from the body in urine, bile, or feces. The term “Elimination” refers to both metabolism and excretion of drug.

 

Absorption

Most, but not all, enterally administered drugs are absorbed by the gastrointestinal tract by one or more of the following mechanisms:

  1. Passive diffusion
  2. Facilitated diffusion
  3. Active transport
  4. Endocytosis

Factors influencing drug absorption include:

  • pH of absorption site
  • Blood flow to the absorption site
  • Total surface area available for absorption
  • Length of time the drug is in contact at the absorption surface
  • Relative expression of membrane proteins such as P-glycoprotein which act to transport drugs across membranes.

In the diagram below, one can appreciate how absorption of drugs changes depending upon the pH of the environment and whether the drug is a weak acid or a weak base. Drugs that are weak acids are absorbed more readily when in an acidic environment (such as the stomach). This is because the acid remains in the unionized form and can cross lipid membranes more readily. Drugs that are weak bases are absorbed more readily when in a basic environment. This is because weak bases will become protonated and ionized in acidic environments and this means less ability to cross lipid membranes. See the diagrams below. 

Distribution

Distribution is the process by which a drug leaves the intravascular space (blood) and enters the extracellular compartment (tissues). The drug will distribute throughout the body depending on its properties until an equilibrium occurs between the blood and tissues. For intravenously administered drugs, the rapid decrease in plasma concentration immediately after administration (see plasma concentration vs time curves) represents the distribution phase. Distribution depends on cardiac output/blood flow, capillary permeability, the tissue volume, the degree of plasma/tissue protein binding, and the lipophilic nature of the drug.

Volume of Distribution, Vd

Volume of distribution is defined as the fluid volume required to contain all the drug in the body at the same concentration measured in the plasma. Realize that the Vd is not a real physical volume. The Vd is an artificial or “apparent” parameter used in pharmacology. Note that the greater the volume of distribution of drug, the less drug present in plasma which means less drug available for metabolism and excretion…this increases the drugs apparent half-life (t1/2).

Vd = Amount of drug in the body / Plasma concentration at time zero

Bioavailability

Bioavailability refers to the rate and extent to which an administered drug reaches the systemic circulation. For example, if 100mg of drug A is given orally and only 70mg of drug A reaches the systemic circulation then the BA = 0.7 or 70%. To determine the BA of orally administered drug we plot the plasma concentration vs time of both oral and IV drugs and determine the area under the curve (AUC) of both routes (see AUC section below). The ratio of the AUC of both routes is the calculated BA. Drugs given intravenously have a BA = 1 or 100%.

Bioavailability = AUCoral/AUCIV x 100

Bioavailability is influenced by first pass metabolism (Liver and Gut metabolizes the drug before it reaches the systemic circulation), the solubility of the drug, the chemical instability of the drug, and how the drug is formulated (salt form, enteric coatings, extended release binders, etc).

Concentration vs Time Curves

In pharmacology, the plasma drug concentration can be measured over time starting at time 0. For intravenously administered drugs, there is a rapid decline in concentration at the beginning which reflects the rapid distribution of drug from the intravascular space (blood) to the extravascular space (tissues) and is termed the distribution phase. The linear decline seen later represents the elimination phase as the drug is being eliminated (metabolized and excreted) from the body.

 

Steady State

Steady State occurs when the rate of drug elimination equals the rate of drug administration. Roughly 4-5 half lives are necessary to achieve steady-state. The sole determinant of the rate that a drug achieves steady state is the half life of the drug. When infusion is stopped, the plasma concentration of the drug declines (washes out) to zero with the same time course observed in approaching the steady state. Note how drugs administered orally are represented by many “peaks” on the drug concentration-time curves and accumulate over time. The “peaks” and “troughs” fluctuate around the steady state line that would be obtained if the drug was given IV.  

Elimination Half-Life

Elimination Half-Life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. After 1 elimination half-life, the plasma concentration is halved and only 50% of drug remains in the body. After 2 half-lives, 25% of the drug remains in the body. After 3 half-lives only 12.5% of the drug remains in the body. And after 4 half-lives 6.25% of drug remains. The half-life of a drug depends on the clearance of the drug and its volume if distribution (see below for more on clearance and volume of distribution). Half-life is independent of the amount of drug in the body.

Area Under the Curve (AUC)

The area under the plasma drug concentration-time curve (AUC) is the integral of the plasma drug concentration-time curve and reflects the actual body exposure to drug after administration of a given dose of the drug. Units of AUC are expressed in mg*h/L. This area under the curve is dependent on the rate of elimination of the drug from the body and the dose administered (i.e., the higher the dose administered and the slower the rate of elimination, the greater the AUC).  The AUC is inversely proportional to the clearance of the drug (i.e., the higher the clearance, the less time the drug spends in the systemic circulation and the faster the decline in the plasma drug concentration). Therefore, the smaller the total body exposure to the drug and the smaller the AUC.

Note that the AUC represents only the drug measured in the plasma and therefore is the fraction of the total dose administered that reaches the systemic circulation, also known as the bioavailability of the drug.

Metabolism, Excretion, and Clearance

Drug Clearance: Clearance estimates the amount if drug cleared from the body per unit of time. Remember that once a drug enters the body, the process of elimination almost immediately begins. Drugs are metabolized in the liver, gut, kidneys, lungs, etc. to more soluble compounds which can then be excreted in feces, urine, sweat, breast milk, tears, lungs, saliva, skin, hair, etc. Total drug clearance is a composite estimate reflecting all mechanisms of drug elimination:

CL = 0.693 x Vd/t1/2

NOTE: The kidneys cannot efficiently eliminate lipophilic drugs due reabsorption in the distal convoluted tubule. Therefore, drugs must be metabolized and transformed into more soluble substances in the liver. This occurs via two sets of reactions termed phase I and phase II reactions.

 

 

Phase I Reactions convert drugs into more polar molecules by polar functional groups such as -OH and -NH2. These reactions usually involve reduction, oxidation, or hydrolysis. Phase I reactions may or may not utilize the Cytochrome P450 enzymes (CYP3A4/5, CYP2D6, CYP2C8/9, CYP1A2, CYP2C19, CYP2A6, CYP2B6, CYP2E1). It is important to note that drugs may be substrates, inducers, or inhibitors of these CYP enzymes and have a clinically significant interaction with other drugs. There is also considerable genetic variability in the CYP450 system in terms of expression and efficiency of enzymes. For example, some individuals have low CYP2D6 activity and therefore obtain little to no benefit from the analgesic codeine because they lack CYP2D6 that activates the drug. Phase I reactions not involving CYP450 enzymes include amine oxidation, alcohol dehydrogenation, esterases, and hydrolysis.

Phase II Reactions consists of conjugation reactions. Glucuronic acid, sulfuric acid, acetic acid, or an amino acid may be conjugated to drugs to achieve a more hydrophilic state. Usually, but not always, Phase II reactions result in inactive drug metabolites. Note that some drugs undergo both sets of reactions (Phase I and II) in sequence while other drugs only undergo phase I or only undergo phase II or don’t undergo either.

 

Renal Elimination

Elimination of drugs via the kidneys into urine involves the processes of glomerular filtration, active tubular secretion, and passive tubular reabsorption. These concepts are not reviewed here and can be reviewed in any pharmacology textbook. 

Nonlinear vs Linear Elimination

Zero-Order Elimination Kinetics (nonlinear kinetics): Elimination of a constant quantity per time unit of the drug quantity present in the organism.

First-Order Elimination Kinetics (linear kinetics): Elimination of a constant fraction per time unit of the drug quantity present in the organism. The elimination is proportional to the drug concentration.

NOTE: The term “Linear kinetics” refers to the linear shaped curve in the logarithmic plasma concentration vs time plot after an IV bolus of administered drug. This is confusing for many people because zero order kinetics is represented by a linear curve on the plasma concentration-time plot whereas first order kinetics is represented by an exponential decay on the plasma concentration-time plot. For a more in-depth discussion, refer to any pharmacology textbook.

 

Pharmacodynamics

Pharmacodynamics is defined as the study of the time course and intensity of the pharmacological effects of drugs (i.e., describes what the drug does to the body).

The most useful information for developing dosing regimens for newly developed drugs relates the concentration of drug in biological fluids such as blood or cerebrospinal fluid with the pharmacological effects. This is where dose-response curves become important. Note that there is considerable variability (based on genetics, gender, race, body composition, medical comorbidities, etc.) in dose-response curves between populations and even between individuals

 

Dose Response Curves

Dose response curves are useful for determining risk-benefit of various drugs. Note that in the figure below, the shape of the curve is sigmoid. However, not all dose-response curves are sigmoid. Additionally, note that as the drug concentration increases above a certain level, there is little to no additional gain in effect. We call this the Emax. Emax often relates to saturation of receptor targets. Drugs rarely have a single pharmacological effect or interact with only a single receptor population or molecular target and therefore multiple curves can exist for any given drug. The EC50 represents the concentration of drug that produces a response equal to 50% of the maximum effect (Emax). The potency of drugs can be compared using the EC50. The smaller the EC50, the more potent the drug.

The Therapeutic Window

The Dose–response curves for a drug that produces a therapeutic effect and mild and severe toxicity are shown below. The greater the separation between the curves for therapeutic and toxic effects, the more safely the drug can be administered in increasing doses and the larger the “therapeutic window.”

Potency

In pharmacology, potency is a measure of drug activity in terms of the amount of drug required to produce a given effect. High potency drugs require low concentrations to produce a given effect, whereas low potency drugs require higher concentrations to produce the same effect.

Binding Affinity

This is a measure of the electrostatic (van der Waals) forces between a neurotransmitter or medication and its receptor.  Affinity is how well a drug can bind to a receptor.

Efficacy

In pharmacology, efficacy refers to the ability of a drug to cause a given effect once bound to a receptor. It refers to the relationship between receptor occupancy and the ability to initiate a response.

Potency vs Efficacy

Potency has more to do with affinity of a drug for it’s receptor whereas efficacy has more to do with the drugs ability to produce a maximum response. Some drugs can be equally potent based on EC50 values but have different Efficacies (represented by Emax). 

Common Terms

Psychotropic medication: An ion or compound used primarily to treat the signs and symptoms of mental diseases, defects, or disorders.  By historical convention, anticholinergic medications used to treat acute extra-pyramidal symptoms induced by neuroleptic medications have been included under this definition.  Some medications, e.g. antiepileptics, may vary as to whether they fit this definition, depending on the intent of use.  For example, Valproic acid (Depakene or Depakote) used to treat a partial motor seizure would not be classed as a psychotropic medication, while the same medication used to treat bipolar mood disorder would be classed as a psychotropic medication.

Agonist: An ion or molecule, which when bound to a receptor, produces an effect on signal transduction similar in direction and degree to the naturally occurring neurotransmitter.

Antagonist: An ion or compound, which when bound to a receptor does not activate the receptor.  That is, signal transduction is antagonized.  An example of this is the opiate antagonist, naltrexone or antipsychotics such as haloperidol (dopamine antagonist)

Partial agonist: An ion or compound, which when bound to a receptor produces a change in signal transduction which is in the same direction as the natural neurotransmitter, but weaker.  An example of this is the second-generation antipsychotic, aripiprazole (dopamine partial agonist).

Inverse agonist: An ion or compound, which when bound to a receptor acts on signal transduction in a manner opposite to that of the naturally occurring neurotransmitter.  An example of this is the benzodiazepine inverse agonist flumazenil.

Allosteric modulation: This form of receptor modulation occurs when a medication acts by binding to a secondary site on a receptor protein.  An example of this is benzodiazepine binding.  Benzodiazepines bind to a secondary site on the alpha subunit of the gamma-amino butyric acid (GABA) receptor.  Benzodiazepine binding alone does nothing, however, if GABA is simultaneously bound to the receptor, the frequency of opening of the chloride channel controlled by the GABA receptor is increased, amplifying the effect of the GABA, e.g. greater sedation.  Binding of the antipsychotic, clozapine, to the glycine site on the NMDA receptor also fits this model and accounts for clozapine’s capacity to increase glutamate signal transduction.

Reuptake inhibitor: A number of neurotransmitters have their signal terminated by being actively transported back into the presynaptic neuron by a reuptake transport molecule located in the cell membrane on the proximal side of the synaptic cleft.  A reuptake inhibitor acts by binding to and decreasing the activity of the reuptake transporter.  For example, SSRI antidepressants act by inhibiting the reuptake transporter for serotonin, while SNRI and tricyclic antidepressants inhibit the reuptake of both serotonin and norepinephrine. 

Overview of Drug Development 

References

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