4.2.2 Pharmacokinetics

Effect of Mode of Administration on Kinetics

The different modes of administration can have a significant impact on the pharmacokinetics of a drug, including its absorption, distribution, metabolism, and elimination. The following is a brief overview of how each mode of administration can influence pharmacokinetics:

Mode of administration:	Effect on pharmacokinetics:
Oral	Oral administration is the most common mode of drug administration, but drugs can be subject to a range of factors that can influence their pharmacokinetics. For example, oral administration may result in a slower and less complete absorption due to the presence of gastric or intestinal barriers, and may also result in significant first-pass metabolism in the liver.
Parenteral	Parenteral administration, including intravenous (IV), intramuscular (IM), subcutaneous (SC), and intradermal injections, bypasses the gut and results in rapid and complete absorption of the drug. However, the distribution of the drug can be influenced by its lipid solubility, protein binding, and the permeability of target tissues.
Topical	Topical administration involves the application of drugs to the skin or mucous membranes, and the extent of absorption can vary depending on the site of application, the type of drug, and the patient’s individual factors.
Inhalation	Inhalational administration involves the inhalation of drugs in the form of aerosols, gases, or vapours, and is a fast and effective way of administering drugs, particularly those used to treat respiratory conditions.
Rectal	Rectal administration involves the insertion of drugs into the rectum, and the extent of absorption can depend on the type of drug, the dose, and the individual patient factors.
Transdermal	Transdermal administration involves the absorption of drugs through the skin using patches and is a slow and sustained mode of administration that is often used for drugs with a low therapeutic index or for drugs that need to be administered over an extended period of time.
Sublingual	Sublingual administration involves the placement of drugs under the tongue, and the drugs are rapidly absorbed into the bloodstream due to the rich blood supply in this area.

In conclusion, the choice of mode of administration will depend on various factors, including the pharmacokinetics and pharmacodynamics of the drug, the condition being treated, and the patient’s individual circumstances, and each mode of administration has its own unique impact on pharmacokinetics (Rang, 2007).

Protein Binding – Consequences in Health and Disease

Protein binding refers to the interaction between a drug molecule and plasma proteins, such as albumin and globulins, in the bloodstream. This interaction can have significant consequences for both health and disease.

Consequences for drug pharmacokinetics: Protein binding can influence the pharmacokinetics of drugs in a number of ways. For example, drugs that are highly protein bound are more likely to remain in the bloodstream for a longer period of time, which can result in a prolonged half-life and a slower elimination rate. On the other hand, drugs that are only weakly bound to proteins may be rapidly eliminated from the bloodstream, resulting in a short half-life and low bioavailability.

Consequences for drug efficacy: Protein binding can also affect the efficacy of drugs, as it can alter their pharmacodynamics by either enhancing or reducing their activity. For example, drugs that are highly protein-bound may have a reduced ability to bind to their target receptors, while drugs that are only weakly bound may have an increased affinity for their target receptors.

Consequences for drug-drug interactions: Protein binding can also influence the risk of drug-drug interactions. For example, drugs that are highly protein-bound may displace other drugs from their binding sites, leading to a change in their pharmacokinetics and pharmacodynamics. Conversely, drugs that are only weakly bound to proteins may be displaced by other drugs, resulting in a change in their pharmacokinetics and pharmacodynamics.

Consequences for disease: Protein binding can also have important consequences for disease, particularly in patients with renal or hepatic impairment. For example, drugs that are highly protein-bound may accumulate in the bloodstream in patients with impaired renal function, leading to an increased risk of toxicity. On the other hand, drugs that are only weakly bound to proteins may be rapidly eliminated from the bloodstream in patients with impaired hepatic function, leading to reduced efficacy.

In conclusion, protein binding is a complex and important aspect of pharmacology that can have significant consequences for both health and disease. Understanding the role of protein binding in drug pharmacokinetics, efficacy, and drug-drug interactions is crucial for optimizing the therapeutic use of drugs and improving patient outcomes (Rowland, 2011).

Clinical Pharmacokinetics

Clinical pharmacokinetics is the branch of pharmacology that focuses on the application of pharmacokinetic principles to the safe and effective use of drugs in human beings. The goal of clinical pharmacokinetics is to optimize the therapeutic use of drugs by considering the individual patient’s unique characteristics and the pharmacokinetic parameters that influence drug disposition and efficacy (Davis, 2010).

Half-life (t½):

Half-life (t½) is a fundamental concept in pharmacokinetics that refers to the time it takes for the concentration of a drug in the body to decrease by half. Half-life is a measure of the rate of elimination of a drug from the body and is an important factor in determining the duration of action and the frequency of dosing required to maintain a therapeutic concentration of the drug.

Half-life is calculated from the equation: t½ = 0.693 / k

Where k is the elimination rate constant for the drug. The elimination rate constant represents the rate at which the drug is eliminated from the body, and is proportional to the amount of the drug in the body and the elimination rate.

Half-life is important in determining the duration of action of a drug, as it reflects the amount of time it takes for the drug to decrease to half its original concentration. If the half-life of a drug is short, then it will have a short duration of action and may need to be dosed more frequently to maintain a therapeutic concentration. Conversely, if the half-life of a drug is long, then it will have a longer duration of action and may only need to be dosed once or twice a day.

Half-life is also an important factor in drug interactions, as it affects the rate at which drugs are eliminated from the body and can influence the pharmacokinetics of other drugs that are taken simultaneously. The half-life is a key pharmacokinetic parameter that reflects the rate of elimination of a drug from the body and has important implications for the safe and effective use of drugs (Rowland, 2011).

Tmax/Cmax:

Tmax (time to maximum concentration) and Cmax (maximum concentration) are two important parameters in pharmacokinetics that describe the absorption and distribution of a drug in the body.

Tmax refers to the time at which the maximum concentration of a drug (Cmax) is achieved in the bloodstream after administration. Tmax depends on the rate and extent of drug absorption and is a crucial factor in determining the onset and duration of a drug’s action. A rapid Tmax is generally associated with a rapid onset of action, while a slower Tmax may indicate slower drug absorption and a longer time to reach maximum concentration.

Cmax, on the other hand, represents the maximum concentration of a drug in the bloodstream achieved after administration. Cmax is an important parameter for determining the potency of a drug and is often used to compare the efficacy of different drug formulations or to evaluate the effect of changes in the dosing regimen.

Tmax and Cmax are two important pharmacokinetic parameters that provide valuable information on the absorption and distribution of drugs in the body. They have important implications for optimizing dosing regimens and predicting the onset and duration of a drug’s action (Rang, 2007).

Volume of distribution (Vd):

The volume of distribution (Vd) is a pharmacokinetic parameter that describes the distribution of a drug within the body. It represents the apparent volume of fluid into which a drug is dispersed after administration and is usually expressed as litres (L) or litres per kilogram (L/kg) of body weight.

Vd is a crucial parameter in determining the pharmacokinetics of a drug and can be used to predict its concentration in various tissues and organs of the body. It is an important factor in determining the dosing regimen of a drug and the total amount of drug required to achieve therapeutic concentrations.

Vd can be influenced by various factors, including the chemical and physical properties of the drug, the presence of other drugs or proteins that can affect drug distribution, and the patient’s age, weight, and medical condition. For example, highly lipophilic drugs tend to distribute into fatty tissues and have a higher Vd compared to hydrophilic drugs, which tend to remain in the plasma and have a lower Vd.

The volume of distribution is a key pharmacokinetic parameter that provides important information on the distribution of drugs within the body. It is an essential factor in determining the dosing regimen and the efficacy of a drug and is used to predict the concentration of a drug in various tissues and organs (Rowland, 2011).

Area Under the Curve (AUC):

The area under the curve (AUC) is a pharmacokinetic parameter that provides a measure of the total exposure to a drug over a certain period of time. It is calculated by integrating the concentration-time profile of a drug from the time of administration to the end of the dosing interval and is expressed as the total amount of drug in the body over time, usually in milligrams per litre (mg/L) x hours.

The AUC is a crucial parameter in determining the pharmacokinetics of a drug and can be used to predict its efficacy, safety, and overall pharmacological effect. The AUC is also an important factor in determining the dosing regimen of a drug and in monitoring drug exposure during therapy.

There are several factors that can affect the AUC, including the dose, route of administration, rate of drug absorption, drug metabolism, and elimination. For example, a higher dose of a drug will result in a higher AUC, while a more rapid elimination of a drug will result in a lower AUC.

AUC is a valuable pharmacokinetic parameter that provides information on the total exposure to a drug over a certain period of time. It is an essential factor in determining the efficacy, safety, and overall pharmacological effect of a drug, as well as in determining the dosing regimen and monitoring drug exposure during therapy.

Relevance to prescribing:

Half-life (t1/2), the volume of distribution (Vd), and the area under the curve (AUC) are important pharmacokinetic parameters that have relevance to prescribing medications.

Half-life (t1/2) is the time it takes for a drug to decrease by half of its initial concentration in the body. The half-life of a drug determines its duration of action and is used to determine the dosing interval and frequency of administration. Drugs with a shorter half-life require more frequent dosing, while drugs with a longer half-life may require less frequent dosing. For instance, a drug with a half-life of 6 hours may be given every 12 hours, while a drug with a half-life of 24 hours may only be required once daily.

Volume of distribution (Vd) is the theoretical volume in which a drug would be evenly distributed if it were present in a homogeneous solution. Vd is used to determine the amount of drug that is distributed in the body and its distribution into various tissues. Understanding the Vd of a drug is important as it can impact the efficacy and safety of the drug, especially in patients with altered Vd, such as in cases of liver or kidney disease.

Area under the curve (AUC) is the measure of the total exposure of a drug in the body over a specific period of time. AUC provides information on the total amount of drug in the body and is used to determine the efficacy, safety, and overall pharmacological effect of a drug, as well as the dosing regimen and monitoring drug exposure during therapy.

In conclusion, half-life, the volume of distribution, and area under the curve are critical pharmacokinetic parameters that have relevance to prescribing medications. Understanding the concepts and applications of these parameters is essential for postgraduate education in the field of pharmacology and therapeutics and for making informed decisions when prescribing drugs (Gibaldi, 1982).

Principle of Kinetic Modelling – Linear Versus Zero-Order Kinetics:

Kinetic modelling is a mathematical representation of the pharmacokinetics of a drug in the body. The principle of kinetic modelling involves the development of mathematical equations to describe the rate and extent of drug absorption, distribution, metabolism, and elimination. There are two main types of kinetic models in pharmacokinetics, linear and zero-order kinetics:

Linear kinetics refers to a situation where the rate of drug elimination is proportional to the concentration of the drug in the body. This means that as the concentration of the drug increases, the rate of elimination also increases. Linear kinetics are commonly observed in the elimination of drugs with low molecular weight, high lipid solubility, and low protein binding. For example, linear kinetics are observed in the elimination of ethanol and barbiturates.

First-order kinetics describes the rate of drug elimination in the body as being proportional to the concentration of the drug. This means that as the concentration of the drug increases, the rate of elimination also increases. First-order kinetics is a type of linear kinetics.

Zero-order kinetics, on the other hand, refers to a situation where the rate of drug elimination is constant, regardless of the concentration of the drug in the body. This means that the rate of elimination is not proportional to the concentration of the drug. Zero-order kinetics are commonly observed in the elimination of drugs with high molecular weight, low lipid solubility, and high protein binding. For example, zero-order kinetics are observed in the elimination of aspirin and phenytoin.

In conclusion, linear and zero-order kinetics are two important principles in the field of pharmacokinetics that describe the rate and extent of drug elimination in the body. Understanding the concepts of linear and zero-order kinetics is essential for postgraduate education in the field of pharmacology and therapeutics and for making informed decisions when prescribing drugs.

Practical implications:

The practical implications of first-order, linear, and zero-order kinetics are important for understanding how drugs are eliminated from the body and how their pharmacokinetics can be predicted and optimized.

Linear kinetics: Drugs that follow linear kinetics have a rate of elimination that is proportional to their concentration, regardless of the type of relationship between the concentration and the rate of elimination. This means that the pharmacokinetics of these drugs can be predicted and optimized using simple mathematical models, as with first-order kinetics.

First-order kinetics: Drugs that follow first-order kinetics are eliminated from the body at a rate that is proportional to their concentration. This means that as the concentration of the drug increases, the rate of elimination also increases. This type of kinetics is commonly observed for drugs with a high therapeutic index (i.e., drugs that have a wide margin between therapeutic and toxic doses) and for drugs that are metabolized by the liver. The practical implications of first-order kinetics are that the pharmacokinetics of drugs following this type of kinetics can be predicted using simple mathematical models and that the dose can be adjusted to achieve the desired concentration and effect.

Zero-order kinetics: Drugs that follow zero-order kinetics are eliminated from the body at a constant rate, regardless of their concentration. This type of kinetics is commonly observed for drugs that are eliminated by renal excretion, rather than metabolism. The practical implications of zero-order kinetics are that the rate of elimination is not affected by changes in the dose or concentration of the drug, which makes it difficult to predict the pharmacokinetics of these drugs and adjust the dose to achieve the desired effect.

In conclusion, the practical implications of first-order, linear, and zero-order kinetics are important for understanding how drugs are eliminated from the body and how their pharmacokinetics can be predicted and optimized. Understanding the type of kinetics that a drug follows is essential for making informed decisions about dosing and therapeutic management.

CYP450 system – Major Isoforms; Substrates, Inducers and Inhibitors

The cytochrome P450 (CYP450) system is a group of enzymes that are responsible for the metabolism of many drugs and other xenobiotics (substances foreign to the body) in the liver. The CYP450 system is a key component of the body’s defence against potentially toxic compounds, as it helps to convert these compounds into less toxic metabolites that can be more easily eliminated from the body (Raucy, 2011).

There are multiple isoforms (or subtypes) of the CYP450 enzymes, each of which has a specific pattern of substrate specificity (i.e., the types of compounds it can metabolize) and reactivity. Some of the major CYP450 isoforms include CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5.

Substrates of the CYP450 system include many commonly used drugs, such as anti-inflammatory agents, antidepressants, and pain medications. The metabolism of these drugs by the CYP450 system can affect their efficacy and toxicity, as well as the risk of drug-drug interactions.

Inducers of the CYP450 system are compounds or drugs that increase the activity of one or more CYP450 isoforms, leading to increased metabolism of other drugs that are substrates of that isoform. This can result in reduced drug efficacy and an increased risk of toxicity.

Inhibitors of the CYP450 system are compounds or drugs that decrease the activity of one or more CYP450 isoforms, leading to decreased metabolism of the substrates of that isoform. This can result in increased drug concentrations and an increased risk of toxicity.

Examples:	Summary:
Inducers	Rifampicin, a powerful inducer of CYP3A4 and CYP2C9, is used to treat tuberculosis. Carbamazepine, an anticonvulsant and mood stabilizer, is a CYP450 inducer. Carbamazepine (Tegretol), an anticonvulsant and mood stabilizer, is a CYP450 inducer. Phenobarbital, a barbiturate used for epilepsy and sleep disorders, is a CYP450 inducer.
Inhibitors	Cimetidine, an H2 receptor antagonist used in the treatment of acid reflux, is a potent CYP450 inhibitor. Fluconazole, an antifungal agent, is a CYP450 inhibitor that may increase plasma levels of other medications metabolized by this pathway. Fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI), is a potent CYP2D6 inhibitor. Paroxetine (Paxil), an SSRI, is a CYP2D6 inhibitor.
Foods	Grapefruit juice, for example, is a well-known CYP3A4 inhibitor, which can increase the plasma concentrations of drugs metabolized by this pathway, leading to potential toxicity.
Tobacco	Smoking can induce CYP1A2 and CYP2B6, leading to a faster metabolism and reduced efficacy of drugs metabolized by these pathways.
Alcohol	Chronic alcohol consumption can induce CYP2E1 and CYP3A4, leading to increased drug metabolism.

It’s important to note that the specific CYP450 isoform that is induced or inhibited by a particular medication can depend on several factors including dose, administration route, and patient-specific characteristics. Additionally, many psychiatric medications can have complex and multifaceted pharmacokinetic profiles, so it’s important to consider both CYP450 metabolism and other factors when evaluating their efficacy and safety.

In conclusion, the CYP450 system is an important component of the body’s defence against potentially toxic compounds and plays a critical role in the metabolism of many drugs. Understanding the major CYP450 isoforms and their substrates, inducers, and inhibitors is essential for predicting and avoiding drug-drug interactions and optimizing drug therapy (Whirl-Carrillo, 2012).

References:

(1) Davis, A. P. (2010). Clinical pharmacology. Edinburgh: Churchill Livingstone.

(2) Gibaldi, M., & Perrier, D. (1982). Pharmacokinetics. New York: Marcel Dekker, Inc.

(3) Rang, H. P., Dale, M. M., Ritter, J. M., & Moore, P. K. (2007). Rang and Dale’s pharmacology (6th ed.). Edinburgh: Churchill Livingstone.

(4) Raucy JL. Cytochrome P450 Enzymes. In: Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill; 2011:97-114.

(5) Rowland, M., & Tozer, T. N. (2011). Clinical pharmacokinetics and pharmacodynamics: concepts and applications (4th ed.). Philadelphia, PA: Lippincott Williams & Wilkins.

(6) Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, Altman RB, Klein TE. Pharmacogenomics Knowledge for Personalized Medicine. Clinical Pharmacology and Therapeutics. 2012 Apr;91(4):844-8.