Introduction to Basic Pharmacology

Fundamental Definitions and Terminologies in Pharmacology

Pharmacology is defined as the scientific study of substances that interact with living systems through chemical processes. This field encompasses the study of the biochemical and physiological aspects governing drug effects. This detailed study includes processes such as absorption, distribution, metabolism, elimination, and toxicity, as well as the specific mechanisms of drug action. Alternatively, pharmacology can be described as the study of the effects of chemical substances on the function of living systems.

A drug is characterized as a substance that induces a change in biological functions through its chemical actions. Professionally, a drug is defined as a chemical substance of known structure, distinctly separate from nutrients or essential dietary ingredients. When administered to a living organism, a drug must produce a biological effect. A pro-drug refers to a chemical that remains inactive until it is converted into an active drug or form by biological processes occurring inside the body.

A medicine is defined as a chemical preparation that usually, though not necessarily, contains one or more drugs. It is administered with the specific intention of producing a therapeutic effect. Unlike pure drugs, medicines typically contain other substances known as excipients, stabilizers, and solvents to make the preparation more convenient for use.

Clinical Terminology and Dosing Parameters

A dose is the specific amount of a drug to be administered at a single point in time. Dosage refers to the size or frequency with which a medicine or drug is administered; for example, "a dosage of $450\,\text{milligrams}$ a day." A course is defined as a period of continual treatment with a drug, which may involve variable dosages and may conclude by tapering the dose.

A loading dose is an initial high dose of a drug administered at the start of a treatment course to rapidly achieve therapeutic levels before transitioning to a lower maintenance dose. A maintenance dose is the rate of drug administration where the amount given is equal to the rate of drug elimination from the body.

Quantitative Measures of Drug Efficacy, Safety, and Potency

Several quantitative terms are used to define the safety and efficacy profiles of drugs:

• Therapeutic dose: The specific amount of a drug required to treat a disease.
• Effective Dose ($ED_{50}$): The drug dose that produces the desired therapeutic effect in $50\,\%$ of the population.
• Toxic Dose ($TD_{50}$): The dose that produces a toxic effect in $50\,\%$ of the population.
• Lethal Dose ($LD_{50}$): The dose that produces a lethal effect in $50\,\%$ of the population.

The Therapeutic Index ($TI$) serves as a measure of a drug's safety. It is defined as the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response. The formula is expressed as:

$TI = \frac{\text{Toxic dose}}{\text{Effective dose}} = \frac{TD}{ED}$

A higher $TI$ indicates a wider margin of safety between effective and toxic doses. Conversely, a narrow $TI$ indicates a higher risk of toxicity and requires closer monitoring. Examples of drugs with a narrow $TI$ include Gigoxin, Gentamycin, and Wafarin.

Drug Concentration and Time-Action Curves

Half-life ($T_{1/2}$) refers to the time required for the body to eliminate $50\,\%$ of a drug. Understanding half-life is critical for planning the frequency of dosing. For example, if Drug A has a half-life of $2\,\text{hours}$ and the initial plasma level after a single dose is $1200\,\text{mg/L}$, the plasma level calculation over time is as follows:

• Initial: $1200\,\text{mg/L}$
• After $2\,\text{hours}$ ($1$ half-life): $600\,\text{mg/L}$
• After $4\,\text{hours}$ ($2$ half-lives): $300\,\text{mg/L}$
• After $6\,\text{hours}$ ($3$ half-lives): $150\,\text{mg/L}$
• After $8\,\text{hours}$ ($4$ half-lives): $75\,\text{mg/L}$

Shelf life is the storage time period under specified conditions within which the drug product remains compliant with its established specifications.

Key terms regarding drug plasma concentration curves include:

• Onset time: The time required for a drug to elicit a therapeutic response.
• Duration of action: The total time during which the drug concentration is sufficient to elicit a therapeutic response.
• Minimum Effective Concentration (MEC): The minimum plasma concentration required to produce a biological effect.
• Minimum Toxic Concentration (MTC): The minimum concentration above which toxic effects may be experienced.
• Therapeutic Range: The concentration range between the MEC and MTC.
• $C_{\max}$: The peak plasma concentration reached.
• $T_{\max}$: The time at which $C_{\max}$ is achieved.
• AUC: Area Under the Curve, representing the total drug exposure over time.
• Termination of action: The point in time when the drug effect ceases.

Therapeutic Effects and Adverse Reactions

The therapeutic effect is the desired clinical result of administering a medication. In contrast, several negative or unintended outcomes can occur:

• Drug allergy: An immunologically mediated reaction characterized by specificity, the involvement of antibodies or lymphocytes, and recurrence upon new contact with the drug.
• Side effect: Any unintended effect of a drug occurring at normal therapeutic doses that is related to its pharmacological properties.
• Adverse Drug Reaction (ADR): A noxious and unintended response to a drug occurring at doses used for prophylaxis, diagnosis, or therapy of disease, or the modification of physiologic function.

Indications are the reasons for administering a medication or performing a treatment. Contra-indications are factors (such as allergies) that prevent the use of a specific medication or treatment.

Drug Interactions and Chronic Usage Phenomena

Drug interactions can lead to varied effects:

• Drug synergy: Occurs when drugs interact to enhance or magnify one or more effects or side-effects.
• Synergetic effects: When the drug's effect is increased.
• Antagonistic effects: When the drug's effect is decreased.

Prolonged or repeated drug use can lead to the following states:

• Tolerance: A gradual decrease in responsiveness to a drug, typically taking days or weeks to develop, resulting in a decreased pharmacological effect upon repeated administration.
• Drug dependence: A state where drug-taking becomes compulsive, taking precedence over other needs, involving both physical and psychological aspects. It is considered a reversible pharmacological phenomenon.
• Addiction: A distinct, chronic, relapsing human condition and illness that is characterized by compulsive use and is separate from acute illness cured by abstinence.
• Habituation (Adaptation): A process occurring during repeated drug administration where the cessation of the drug causes an aversive effect (negative reinforcement), leading the subject to attempt to escape through self-administration.

Branches of Pharmacology: Pharmacokinetics and Pharmacodynamics

Pharmacology is split into two primary branches:

1. Pharmacodynamics: Defined as the actions of the drug on the body. It refers to the relationship between drug concentration at the site of action and the resulting intensity and time course of therapeutic and adverse effects.
2. Pharmacokinetics: Defined as the actions of the body on the drug.

Pharmacokinetics (PK) is summarized by the acronym ADME:

• Absorption (A): The process of a drug entering the blood from the site of administration.
• Distribution (D): The movement of the drug to its site of action.
• Metabolism (M): The chemical alteration of the drug, primarily by the liver.
• Elimination (E): The removal of the drug from the body via excretion.

Key Pharmacokinetic Parameters include:

• Bioavailability ($F$): The fraction of an administered drug that reaches systemic circulation. For example, if $100\,\text{mg}$ is administered orally and $80\,\text{mg}$ is absorbed, $F = 0.8$ (or $80\,\%$). Intravenous (IV) administration has $F = 1$ (or $100\,\%$).
• Volume of Distribution ($V_d$): Describing distribution.
• Extraction Ratio ($ER$): Describing metabolism.
• Clearance ($CL$): Describing elimination.
• First-pass metabolism: The intestinal and hepatic degradation of a drug taken by mouth. This process removes some of the active substance from the blood after absorption but before it enters general circulation.

Protein Targets for Drug Binding

Drugs typically act by binding to four main kinds of regulatory proteins serving as primary targets:

1. Receptors
2. Enzymes
3. Carrier molecules (transporters)
4. Ion channels

A drug receptor is a specialized target macromolecule located on the cell surface or intracellularly. Receptors function as sensing elements in the chemical communication system that coordinates cellular functions. For a receptor to be effective, it must be selective in choosing ligands to avoid constant, promiscuous activation, and it must change its function upon binding to alter the biological system.

Drug-Receptor Interactions and Models

The "Lock and Key Model" explains signal-receptor interaction. Ligands, such as hormones or neurotransmitters (the "key"), affect target cells by binding to specific receptors (the "lock") usually located in the cell membrane. This binding "unlocks" the cellular response.

• Agonist: A chemical messenger or drug that binds to a receptor and triggers the cell's response, mimicking a normal messenger's action. An example is pilocarpine, a muscarinic receptor agonist.
• Antagonist: A molecule that competes for a receptor with normal chemical messengers but does not trigger the cell's response, thereby blocking signal transduction. An example is atropine, a muscarinic receptor antagonist that prevents the binding of acetylcholine (ACh).

Sources of Drugs

Drugs are derived from several diverse sources:

• Synthetic chemicals: Developed through chemical reactions in laboratories.
• Plants: Sources of quinine, digitalis, atropine, ephedrine, strychnine, and vinca alkaloids. Morphine is purified from opium.
• Fungal sources: Primarily used for antibiotics such as penicillin and streptomycin, as well as anti-infective, anticancer, and immunosuppressant drugs.
• Animal sources: Includes insulin and nutrients/vitamins derived from fish fats.
• Marine organisms: Products derived from sea life.
• Genetic engineering: Modern products of biotechnology.
• Semi-synthetic drugs: Natural products that are chemically modified, such as Beta-Lactam antibiotics (e.g., cephalosporins).

Evaluation Questions

• What is Pharmacology?
• What is a drug?
• What is a pro-drug?
• What is Pharmacokinetics?
• What is drug bioavailability?
• What is half-life of drugs?
• What is pharmacodynamics?
• What is therapeutic index?
• What do you understand by the terms tolerance, habituation, dependence and addiction?

References

• Katzung, Bertram G, Masters, Susan B, & Trevor, Anthony J. (2006). Basic & clinical pharmacology (10th Ed) Sciences.
• Rag and Dale’s( 2007) Pharmacology 6th Editions Churchill vingstone