INTRODUCTORY PHARMACOLOGY

Introduction

Pharmacology simply means study of drugs and how they interact with the body system. The word pharmacology is coined from two greek words: ‘pharmacon’ meaning drug and ‘logy’ meaning study. A pharmacologist should know the use of drugs, mode and site of action e.g. Antacid is a drug which neutralises the effect of an acid in the stomach by increasing the pH of the stomach which is usually 1 or less than 1.

 

What are Drugs?

Drugs are chemicals that act on living systems at the chemical (molecular) level.

Sources of Drug  

Natural (plant-based) drugs: cannabis, opium, and coca products are examples of natural drugs that can be consumed in their natural form to produce a psychoactive effect. The psychoactive ingredients of plant-based drugs may be extracted and concentrated to intensify the effects or to facilitate ingestion, but the psychoactive ingredients are not chemically altered. Natural drugs are generally chewed, eaten, drunk, or smoked. Examples of plant-based drugs are cocaine and morphine, the active principles in coca leaf and opium poppy, respectively. Heroin is sometimes also considered plant-based, although it is produced by minor chemical modifications of morphine, and should therefore be more accurately classified a ‘semi-synthetic’ drug. The group of synthetic drugs comprises, for example, the stimulants amphetamine and methamphetamine, ecstasy, the depressant drugs methaqualone, various benzodiazepines (commonly known under such trade names as valium and librium), and synthetic painkillers related to fentanyl, to name but a few.

Semi-synthetic drugs: Semi-synthetic drugs are substances that are found in nature, can be ingested in their natural state for narcotic effects, but can also be chemically processed to produce a different (more potent) synthetic drug. Heroin is the best example of a drug that is classified as semi-synthetic.

Synthetic drugs: Synthetic drugs are those substances that are produced entirely from chemical reactions in a laboratory. Their chemical structure can be identical to naturally occurring drugs, such as cocaine and opium, but they are often designed to enhance effects from naturally occurring drugs, or to prevent side effects that are unwanted. Many purely synthetic compounds with no alternative natural source are classified by the chemical structure of the parent synthetic compound. Drugs that share a common core structure belong to a particular group. But members within a particular group may produce different effects. Pharmacological activity within a group may vary widely.

The Nature of Drugs 

Size: The great majority of drugs lie in the range from molecular weight 100 to 1,000. Drugs in this range are large enough to allow selectivity of action and small enough to allow adequate movement within the various compartments in the body.

Chemistry and reactivity: Drugs may be small, simple molecules (amino acids, simple amines, organic acids, alcohols, esters, ions, etc.), carbohydrates, lipids, or even proteins. Binding of drugs to their receptors, the specific molecules in a biologic system that mediate drug effects, is usually by noncovalent bonds (hydrogen bonds, van de Waals attractions, and ionic bonds), and less commonly by covalent bonds. Weaker, noncovalent bonds require a better fit of the drug to the receptor binding site and, usually, a reversible type of action. Very strong bonding, eg, covalent bonds, usually involves less selectivity and an irreversible interaction.

Shape: The overall shape of a drug molecule is important for the fit of the drug to its receptor. Between a quarter and a half of all drugs in use exist as stereoisomers. In most cases the stereoisomers are chiral enantiomers. Enantiomers are mirrored image twin molecules that result from the presence of an asymmetric carbon, or in a few cases, other asymmetric atoms in their structures. Chiral enantiomers often differ in their ability to bind to and alter the function of receptors. They also can differ in their rates of elimination and in their toxicity.

Two major methods of dispensing drugs

Drugs are mainly available by prescription or as over the counter (OTC) medication and the same methods two major methods are used for dispensing the drugs. There are advantages and disadvantages to both methods of dispensing. The methods are explained thus;

1. Over-The-Counter (OTC): They do not need prescription and can be purchased at the chemical shops; examples are pain relievers, blood tonics, vitamin preparations, ORS, antacids, Antimalarials etc.
2. Prescription: They need a prescription and must be controlled from abuse and dependence; e.g. antibiotics, anti-hypertensives, sedatives, diabetic drugs etc.

Pharmacodynamics

This simply deals with the effect of the administered drug on the body. This can be further explained with the following:

• Concentration-Response: A fundamental principle of pharmacology is that a relationship exists between the concentration of a drug at its site of action and its beneficial or toxic action. The reliance of pharmacodynamic effects upon drug concentration provides the key link between pharmacokinetics and pharmacodynamics for it is the action of the body upon a drug that determines its concentration at its site of action.

Figure 1: The therapeutic and toxic effects of drugs are determined by their concentration in the vicinity of drug receptors. At high concentrations, effects plateau and further increases in drug concentration do not produce greater effects.

• Properties of Drug Receptors: Most receptors are proteins (eg, enzymes, hormone and neurotransmitter receptors); in addition, some DNA and RNA molecules serve as drug binding targets. A successful receptor must distinguish between different ligands. That is, it must bind selectively to certain ligands. In many cases, drugs bind to a site on a protein that normally binds to an endogenous small molecule or protein.

• Types of Drug-Receptor Interactions: When a drug activates a receptor that it binds to, the drug is an agonist. Most agonists mimic the effects of small molecules or proteins that serve as endogenous regulators of the receptor to which the drug binds. Pharmacologic antagonists have the opposite effect. That is, they prevent the effect of endogenous agonists on the function of the receptor. Most of the time, a pharmacologic antagonist binds to the same site as an agonist and competes with the agonist for binding to a critical site on the receptor. Pharmacologic antagonists have two important properties; in the absence of an agonist, they do not elicit a biologic response and the effects of a competitive pharmacologic antagonist can be overcome by adding more agonist.

• Graphical Representation of Concentration-Effect Relationships: The relationship between drug concentration and receptor binding, and drug concentration and pharmacodynamic effect can best be understood through the use of graphical representations such as shown in Figure 1. In the “Drug-Receptor Interactions” session later in Prologue, you will learn to construct concentration-response graphs and use these graphs to make inferences about the pharmacodynamic effects of drugs.

Drug	Clinical Use	Drug Receptor	Type of Molecule
Albutolol	Asthma	Neurotransmitter receptor	Protein on cell surfaces
Penicillin	Infection	Bacterial enzyme	Secreted bacterial protein
Digoxin	Congestive heart failure	Na,K-ATPase	Protein transporter on cell surfaces
Lidocaine	Local anesthesia	Voltage-gated sodium channels	Protein ion channel on cell surfaces
Cyclophosphamide	Cancer	DNA	Nucleic acid

 Table 1: Examples of different types of endogenous molecules that serve as  receptors, or targets, of drugs.

Pharmacokinetics

Pharmacokinetics concerns the effects of the body on the administered drug. It can be pictured as the processes of absorption, distribution, and elimination. Elimination includes both metabolism and excretion. All of these processes involve movement of drug molecules through various body compartments and across the barriers separating those compartments. Drugs are absorbed from their sites of administration into the blood, distributed via the blood to the tissues and then eliminated. The concentration of drugs at their sites of interaction with receptors is determined by these pharmacokinetic properties. Concentration-dependent interaction with receptors produces therapeutic and toxic effects.

Figure 2: Drugs are absorbed from their sites of administration into the blood, distributed via the blood to the tissues and then eliminated. The concentrations of drugs at their sites of interaction with receptors is determined by these pharmacokinetic properties. Concentration-dependent interaction with receptors produces therapeutic and toxic effects.

Absorption of Drugs

Drugs usually enter the body at sites remote from the target tissue and are carried by the circulation to the intended site of action. Before a drug can enter the bloodstream, it must be absorbed from its site of administration. The rate and efficiency of absorption differs depending on the route of administration. Common routes of administration of drugs and some of their features include:

1.      Oral (swallowed): Maximum convenience but may be slower and less complete than parenteral (non-oral) routes. Dissolution of solid formulations (eg, tablets) must occur first. The drug must survive exposure to stomach acid. This route of administration is subject to the first pass effect (metabolism of a significant amount of drug in the gut wall and the liver, before it reaches the systemic circulation).

2.      Sublingual (under the tongue): Permits direct absorption into the systemic venous circulation thus avoiding the first pass effect. May be fast or slow depending on the physical formulation of the product. Nitroglycerin is administered by this route in the treatment of angina.

3.      Rectal (suppository): Same advantage as sublingual route; larger amounts are feasible. Useful for patients who cannot take oral medications (eg, because of nausea and vomiting).

4.      Intramuscular: Absorption is sometimes faster and more complete than after oral administration. Large

volumes (eg, 5 - 10 mL) may be given. It requires an injection process. Generally more painful than subcutaneous injection. Vaccines are usually administered by this route.

5.      Subcutaneous: Slower absorption than intramuscular. Large volumes are not feasible. It requires an injection process. Insulin is administered by this route.

6.      Inhalation: For respiratory diseases, this route deposits drug close to the target organ; when used for systemic administration (e.g., nicotine in cigarettes, inhaled general anesthetics) it provides rapid absorption because of the large surface area available in the lungs.

7.      Topical: Application to the skin or mucous membrane of the nose, throat, airway, or vagina for a local effect. It is important to note that topical drug administration can result in significant absorption of drug into the systemic circulation. Drugs used to treat asthma are usually administered this way.

8.      Transdermal application to the skin for systemic effect: Transdermal preparations generally are patches that stick to the skin and are worn for a number of hours or even days. To be effective by the transdermal route, drugs need to be quite lipophilic. Nicotine is available as a transdermal patch for those who are trying to stop cigarette smoking.

9.      Intravenous: Instantaneous and complete absorption (by definition, 100%); potentially more dangerous because the systemic circulation is transiently exposed to high drug concentrations.

Distribution of Drugs

The distribution of drugs from the site of absorption, through the bloodstream and to the target tissue depends upon:

1. The blood flow to the tissue is important in the rate of uptake of a drug. Tissues that receive a high degree of blood flow (eg, brain, kidney) have a fast rate of uptake whereas tissues with a low degree of blood flow (eg, adipose tissue) accumulate drug more slowly.

2. Solubility of the drug in the tissue. Some tissues, eg, brain, have a high lipid content and dissolve a higher concentration of lipophilic agents.

3. Binding of the drug to macromolecules in the blood or tissue limits their distribution.

4. The ability to cross special barriers. Many drugs are poorly distributed to the brain and the testis because these tissues contain specialized capillaries (the smallest type of blood vessel). The endothelial cells that line these capillaries form a blood-brain barrier and a blood-testis barrier by preventing the movement of hydrophilic molecules out of the blood and into the tissue, and by actively pumping lipophilic molecules out of the endothelial cell and into the blood. Of special concern is the ability of drugs to distribute to breast milk in lactating women, and the ability of drugs to cross the placenta (the specialized tissue connecting a pregnant woman and her fetus) and affect the developing fetus. A number of drugs are known to be teratogens (drugs that cause abnormal fetal development) and should be avoided in pregnancy. Women taking drugs that are considered unsafe for infants and that achieve appreciably high concentrations in breast milk should not breast-feed their infants. Information about the safety of drugs in pregnancy and breast-feeding is available in many textbooks, guidebooks and electronic drug databases.

Elimination of Drug

The rate of elimination (disappearance of active drug molecules from the bloodstream or body) is almost always related to termination of pharmacodynamic effect. Therefore, knowledge of plasma concentrations of a drug is important in describing the intensity and duration of a drug’s effect. There are two major routes of elimination:

1. Excretion: The most common route for drug excretion is through the kidney and out of the body in the urine. To be excreted by the kidney, drugs need to be reasonably hydrophilic so that they will remain in the fluid that becomes the urine. Patients with impaired kidney function usually have a reduced ability to eliminate hydrophilic drugs. To avoid excessively high drug concentrations in these patients, you will need to reduce their dosages or give dosages less frequently. A few drugs enter the bile duct and are excreted in the feces.

2. Metabolism: The action of many drugs, especially lipophilic compounds, is terminated by enzymatic conversion, or metabolism, to biologically inactive derivatives. In most cases, the enzymatic conversion forms a more hydrophilic compound that can be more readily excreted in the urine. Most of the enzymes that catalyze drug-metabolizing reactions are located in the gastrointestinal tract and the liver. Some drugs inhibit drug-metabolizing enzymes and thus cause drug-drug interactionswhen co-administered with drugs that depend upon metabolism for elimination.

Hydrophilic drugs (A) are usually eliminated by renal excretion. They remain in the fluid that becomes urine because they cannot easily cross the membranes of cells that line the tubules in the kidney. Lipophilic drugs can cross the membranes of cells that line the tubules in the kidney. They slip back into the blood and recirculate. They usual require metabolism, a process that makes them more hydrophilic and usually also destroys their pharmacologic activity, for elimination.

 

Drug Nomenclature/ Naming of Drugs

This is the system that puts drugs into classification and the three name classifications of drugs are the Chemical/Molecular/Scientific name, the Generic or Non-Proprietary name, and the Brand or Trade or Proprietary name.

Chemical Name: It depicts the chemical/molecular structure of the drug. It states the structure in terms of atoms and molecules accompanied by a diagram of the chemical structure. They are long and can be clumsy and are useful to a few technically trained personnel. For example acetyl-p-amino-phenol is for Paracetamol and the image above gives the structure of Vitamin C.

Non-Proprietary/Generic/Approved Name: This is the abbreviated and approved name of the drug. It is the official medical name assigned by the producer in collaboration with the Food and Drugs Board and Nomenclature Committee. The generic name may be used by any interested party and it removes the confusion of giving several names to the same drug regardless of who manufactures them once they have the same chemical structure. A generic drug name is not capitalized; for example, aluminum hydroxide.

Proprietary/Trade/Brand Name: These are names given to the drug by the manufacturing and marketing company. They are copyrighted terms selected by a manufacturer to designate a particular product Copyright laws prevent any other person from using the name, and other laws prevent pharmacists from substituting chemically identical products for the trade name article. In most cases one drug could have so many trade/brand names e.g Acetaminophen has about 30 trade names. Some are Paracetamol, Tylenol, Paramol, Panadol, Capol etc. 

Pharmacology Terms

Absorption Rate Constant: The rate at which a medication is absorbed from dosage site to measurement location. This is applicable to all drugs except intravenous medications.
Accumulation: The amount of a medication found within a bodily fluid at a specific point when a steady state has been attained.
Accuracy: The amount of error found in the results of a scientific equation.
Addiction: A situation where use of a drug has changed the behaviour and methods of the user, creating a need for it in order to continuing using or to obtain more of it.
Affinity: The extent to which one substance tends to want to bind with another.
Allergic Response: A situation in which the body forms antibodies against a specific drug, causing a physical reaction that may or may not be severe.
Analgesic: A medication that alleviates pain without the patient losing consciousness.
Anaesthetic: A medication that causes loss of sensation. This is sometimes used to alleviate pain or for loss of consciousness for surgical procedures.
Antagonism: The combined result of two drugs being less than the sum of the two drugs put together. In essence, the whole is less than the sum of its parts.
Area Under the Curve: The area on a graph that falls under the curve when plotting time after administration of a drug against the plasma concentration of a drug. It is used to estimate how long it takes for a drug to be removed from the body.
AUC: The abbreviation of Area under the Curve, or, the area of a graph that falls under the curve when plotting administration of a drug against the plasma concentration of a drug.
Availability: Also referred to as bioavailability, this is the amount of a drug dosage that is absorbed into circulation after administration of a specific dosage.
Bo: On a graph, the slope that occurs when concentration is plotted against the drug half life (or C is plotted against t).
Bioassay or Biological Assay: Establishing the strength of a chemical, physical, or biological agent, by way of a biological marker.
Bioavailability: Also referred to as availability, this is the amount of a drug that is absorbed into circulation after administration of a specific dosage.
Biopharmaceutics: The study of how the pharmaceutical expression of certain drugs can impact their pharmacodynamic and pharmacokinetic behavior.
Biotransformation: The chemical change of a drug that happens due to the effects the body has on it.
Biotranslocation: The transfer and movement of drugs in and throughout biological organisms.
Blind Experiment: A type of experiment in which the participants are unaware of the drug doses or treatments involved, so as not to affect the outcome.
Ceiling: The maximum result of a drug within a bodily tissue, regardless of the volume of the drug administered.
Chemotherapy: The treatment of cancerous or parasitic illnesses, where the drug affects only the neoplastic cells or invading organisms.
Clearance: The amount of the bodily fluid from which a drug is eliminated or excreted.
Clinical Therapeutic Index: An assessment of a drug having more safety at an acceptable level of potency or more potency at an acceptable level of safety within the recommended drug dosage.
Compartment(s): The area within the body that a drug tends to dwell in after it has been absorbed.
Compliance: The level of cooperation of a patient when following a prescribed treatment regimen.
CT Index: The measure of the effects of a drug as calculated by plotting drug concentration against time.
Dependence: A physical need to maintain administration of a specific drug in order to avoid withdrawal symptoms.
Disintegration Time: The time it takes for a drug tablet to dissolve into pieces of a set size or smaller.
Dissolution Time: The time it takes for a certain amount of a drug to be reduced to a solution from a solid form.
Distribution: The volume within a person in which the administrated drug appears to have been dispersed; also known as volume of distribution.
Dosage Form: The physical structure and appearance in which the drug to be administered is in for use.
Dose: The amount or form of a drug that is given to a user.
Dose-Effect Curve: On a graph, this is the result of plotting the dose of a drug against its effect on the bodily system.
Dose-Duration Curve: On a graph, this is the result of plotting the dose of a drug against its duration of time in the body.
Drug: A substance used in the prevention and treatment of illness or disease.
Drug Abuse: The misuse of a drug resulting in potentially destructive consequences.
Drug Dependence: Also referred to addiction, this is a situation where use of a drug has changed the behaviour and methods of the user, creating a need for it in order to continuing using or to obtain more of it.
Dummy: A form of treatment that is meant to have no effect on the user, yet imitates the contrasting drug in every way. This is also known as a placebo.
Effective: A situation where an administered drug is successful in attaining its purpose.
Efficacy: The ability of a medication to produce a change in its intended cell receptor.
Elimination Rate Constant: On a graph, this is the result of plotting the logarithms of concentration against time.
Equipotent: Being equally effective or equally able to produce the drug effect of certain strength.
Equivalence: When drugs provide identical results when administered in the same amount, or those that contain equal dosages of the same type of drug, yet are named differently.
First Order Kinetics: The relationship of the speed of a chemical reaction in proportion to the concentrations of the reactants
First Pass Effect: The absorption of a drug through the liver or intestines when taken in through the gastrointestinal tract but before reaching systemic circulation.
Food and Drug Administration: A federal organization responsible for ensuring compliance with the Food, Drug and Cosmetic Act.
Generic Drugs: Drugs that have exactly the same ingredients and effectiveness as another, named drug or formulary.
Habituation: A psychological feeling of need for a certain drug due to its effects on the body.
Half-Life: The time it takes for a drug concentration within the body to be reduced by one half of its original amount.
Hypersensitivity: The necessary condition for a person to show an allergic response to a drug.
Hypnotic: A medication that produces an effect that causes a change in consciousness or is similar to a state of sleep.
Idiosyncratic Response: An abnormal response from a drug that is specific to the person having the response.
Infusion Kinetics: The plasma concentration of a drug over a long period of time as it is proportional to the rate of the drug administration and inversely proportional to the rate of excretion and the area through which the drug is distributed.
Intrinsic Activity: The quality of a drug that ascertains what the biological result will be. This is also referred to as intrinsic efficacy.
Latent Period or Latency: The period of time between administration of a drug and the time at which an effect is achieved.
Loading dose: The first dose of a series that is larger than subsequent doses.
Maintenance Dose: The doses in a series that follow the initial loading dose.
Median Effective Dose: The dose of a drug calculated to produce a result in 50 percent of the users of whom the drug was administered.
Multiple Dose Regimens: A treatment schedule for a drug in which it is given at certain intervals.
Narcotic: A drug that is able to create an analgesic effect, which may sometimes induce an altered state of consciousness.
Negative Control Drug or Negative Control Procedure: A procedure incorporated into an experiment that it should not affect the experimental system in the same way as the independent variable.
Pharmacodynamics: The study of how drugs produce their effects on the body.
Pharmacogenetics: The study of the inheritance of certain interactions from drugs on the human body.
Pharmacokinetics: The study of absorption, distribution, and biotransformation of drugs on the body.
Pharmacology: The study of the features and characteristics of drugs and medications.
Placebo: A form of treatment that is meant to have no effect on the user, yet imitates the contrasting drug in every way. This is also known as a dummy.
Positive Control Drug: A drug used in an experiment that has the expectation that its results will be similar to those of the independent variable.
Potency: The strength of a drug in terms of the concentration or amount administered.
Potentiation: A situation where the result of one drug is increased by the use of another drug that has no effect.
Priming Dose: The first dose of a series that is larger than subsequent doses
Prodrug: A substance with little action that becomes more active after being in the body.
Precision: The accuracy with which certain values of input can be understood by measured values of output.
Receptors: The part of a cell that responds to an administered drug.
Reference Standard: A drug with specific aspects that is used as the foundation of comparison with other substances that have similar aspects
Reliability: The degree to which the drug and organism relationship is reproducible if it is studied again under similar conditions.
Risk: The probability that damage will result from exposure to a specific agent.
Selectivity: The ability of a drug to affect one type of cell over others.
Sensitivity: The ability of a specific group to respond to a drug in a certain way compared to other organisms.
Side Effects: Undesirable effects from drug treatment that are not intended as part of the therapeutic effect.
Standard Drug: Establishing the strength of a chemical, physical, or biological agent, by way of a biological marker.
Specificity: The ability of a drug to show only one type of result.
Standardized Safety Margin: The amount of a drug that is effective in almost all of the population that must be surpassed in order to produce a fatal effect on a minimum amount of a population
Supersensitivity: An excessive amount of sensitivity to a drug.
Synergy: The use of two drugs together provides a greater effect than the sum of the original drugs.
Tachphylaxis: The building of tolerance to a drug after repeated administrations.
Therapeutic Index: A number that measures the relative safety of a drug.
Therapeutics: The discipline and actions of returning patients to a healthy state.
Threshold Dose: A dose of a drug that is just enough to produce its desired effect.
Time Concentration Curve: On a graph, the time concentration curve is the relationship between the dose of a drug and its latency period.
Tolerance: The reduced effectiveness of a drug after repeated administrations.
Toxic Effects: An effect of a drug that is harmful or lethal to the user.
Toxicology: The study of the effects of poisonous substances on the body.
Volume of Distribution: Also known as distribution, this is the volume within a person in which the administered drug appears to have been dispersed.
Zero Order Kinetics: A condition in which the speed of an enzymatic reaction is independent of the strength of the substrate.