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Branches and Divisions of Pharmacology 1

PART - I

GENERAL PRINCIPLES

IntroductionPharmacology (pharmakon,”drug” in ModernGreek; and -logia, ”study of”) is the branch ofmedicine and biology concerned with the studyof drug action.

Where a drug can be broadly defined as anyman-made, natural, or endogenous (within thecell) molecule which exerts a biochemicaland/or physiological effect on the cell, tissue,organ, or organism.

The two main areas of pharmacology arePharmacodynamics and Pharmacokinetics. Theformer studies the effects of the drugs onbiological systems, and the latter deals with theeffects of biological systems on the drugs. Inbroad terms, pharmacodynamics discusses theactions of drugs with biological receptorsand pharmacokinetics discusses the absorption,distribution, metabolism, and excretion of drugsfrom the biological systems.

Pharmacokinetics Vs. Pharmacodynamics

⇓ ⇓ What the body does What the drug does to the drug to the body

Dioscorides’ De Materia Medica is oftensaid to be the oldest and most valuable work inthe history of pharmacology. The originsof clinical pharmacology date back to the middleages in Avicenna’s The Canon of Medicine, Peterof Spain’s Commentary on Isaac, and John ofSt Amand’s Commentary on the Antedotary ofNicholas. Clinical pharmacology owes much ofits foundation to the work of William

1Branches andDivisions of Pharmacology

Withering. Pharmacology as a scientificdiscipline did not further advance until the mid-19th century amid the great biomedicalresurgence of that period. Before the second halfof the nineteenth century, the remarkable potencyand specificity of the actions of drugs such asmorphine, quinine and digitalis were explainedvaguely and with reference to extraordinarychemical powers and affinities to certain organsor tissues. The first pharmacology departmentwas set up by Rudolf Buchheim in 1847, inrecognition of the need to understand howtherapeutic drugs and poisons produced theireffects.

Early pharmacologists focused on naturalsubstances, mainly plant extracts. Pharmacologydeveloped in the 19th century as a biomedicalscience that applied the principles of scientificexperimentation to therapeutic contexts.

DrugThe word drug comes from a French word‘Drogue’ meaning a dry herb. It can be definedas:

Natural or synthetic substance which (whentaken into a living body) affects its functioningor structure, and is used in the diag-nosis, mitigation, treatment, or prevention of adisease or relief of discomfort in man or animals.According to WHO “Substance or material thatis used or intended to be used to modify orexplore physiological processes or pathologicalstates, for the benefit of the recipient.”

C H A P T E R

Pharmacology: A Comprehensive Approach4

Drug Sources1. Plant sources: Obtained from plant parts or

products. Seeds, stems, roots, leaves, resins,and other parts yield these drugs. Examplesinclude digoxin from digitalis and morphinefrom opium.

2. Animal sources: Glandular products fromanimals are used, such as insulin andthyroid.

3. From micro-organisms (fungi, bacteria):Penicillin was discovered by AlexanderFleming in 1928 as a product of Penicilliumnotatum (a mold growing in his lab).

4. Mineral sources: Some drugs are preparedfrom minerals, for example, lithium carbonate(an antipsychotic), MgSO4 (MagnesiumSulphate) (a laxative). .

5. Synthetic sources: Laboratories duplicatenatural processes, and may modify theproducts. Frequently this can eliminate sideeffects and increase the potency of the drug.Examples include sulfonamides, andaspirin.

6. Recombinant proteins: Proteins that aresynthesized by expression of cloned genesin recombinant cells, such as interferon’s(INF ‘s), antibodies.

7. Hybridoma technique: E.g., monoclonalantibodies (MAB).

Drug Nomenclature

Chemical name: Represents the exactdescription of the drug’s chemical composition.

Generic name (non-proprietary) : Simpler thanthe chemical name and derived from thechemical name itself. Easier to remember.

Example 1: The chemical name 2-methyl-5-nitroimidazole-1-ethanol is metronidazole. Theword methylnitro is condensed to metro and ni-dazole is due to its imidazole ring.

Example 2: Metoclopramide is the condensedform of the word methoxychloroprocainamide:where Me is retained and th is written as t; chlorois written as clo: and procainamide is written aspramide.

Brand or trade name (proprietary): It isdeveloped by the company requesting approvalfor the drug and identifies it as the exclusiveproperty of that company.

Example 1: Metrogyl® is the trade name forMetronidazole.

Example 2: Reglan® is the trade name forMetoclopramide.

Example 3: Amoxil® is the trade name forAmoxycillin.

Example 4: Celebrex® is the trade name forCelecoxib.

The Nature of DrugsA. 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 allowselectivity of action and small enough toallow adequate movement i.e., permeabilitywithin the various compartments in the body(Fig. 1-1).

B. Chemistry and reactivity: Drugs may besmall, simple molecules (amino acids, simpleamines, organic acids, alcohols, esters, ions,etc.), carbohydrates, lipids, or even proteins.Binding of drugs to their receptors thespecific molecules in a biologic system thatmediate drug effects, is usually bynoncovalent bonds (hydrogen bonds, van derWalls attractions, and ionic bonds), and lesscommonly by covalent bonds. Weaker,noncovalent bonds require a better fit of thedrug to the receptor binding site and, usually,a reversible type of action. Very strongbonding, e.g., covalent bonds, usuallyinvolves less selectivity and an irreversibleinteraction.

C. Shape: The overall shape of a drug moleculeis important for the fit of the drug to itsreceptor. Between a quarter and a half of alldrugs in use exist as stereoisomers. In mostcases the stereoisomers are chiralEnantiomers. Enantiomers are mirroredimage twin molecules that result from thepresence of an asymmetric carbon, or in afew cases, other asymmetric atoms in their


Fig 1-2: The two hands represent the enantiomer of Drug H. The shape of the Levo enantiomerallows it to bind tightly to the drug-binding site in the receptor.

Note: that this binding is reversible.

Fig 1-1: Molecular weights of several endogenous molecules and drugs. Lithium is used to treatpeople with psychiatric disorders, fentanyl is an opioid analgesic and trastuzumab is an antibody

used to treat women with breast cancer.

structures. Here drug action is based on therotation of drug molecule, (Fig. 1-2) forexample : Levo cetrizine and cetrizine actionsfor allergic reactions. Chiral enantiomersoften differ in their ability to bind to and alterthe function of receptors. They also can differin their rates of elimination and in theirtoxicity. Most chiral drugs are still providedas racemic mixtures (mixtures of isomers)because it is expensive to separate thestereoisomers. In the past, little was knownabout the relative activity of stereoisomers.However, the Food and Drug Administration

(FDA) now requires information about thestructure and activity of each isomer presentin a racemic mixture of a new medication.

Branches of PharmacologyFollowing are the important branches ofPharmacology:

1. Pharmacokinetics2. Pharmacodynamics3. Pharmacotherapeutics4. Chemotherapy5. Toxicology


6. Clinical pharmacology7. Pharmacy8. Pharmacognosy9. Pharmacoeconomics

10. Pharmacogenetics11. Pharmacogenomics12. Pharmacoepidemiology13. Comparative Pharmacology14. Posology15. Animal Pharmacology16. Behavioural pharmacology17. Environmental pharmacology18. Neuropharmacology19. Psychopharmacology

1. Pharmacokinetics: The word Pharmaco-kinetics is derived from two words,pharmacon meaning “drug” and kineticsmeaning “putting in motion”. It can bedefined as:“The branch of pharmacology that dealswith the absorption, distribution,metabolism and excretion of drugs andtheir relationship with the onset, duration

and intensity of the drug effect”. What thebody does to the drug is pharmacokinetics.

2. Pharmacodynamics: Pharmacodynamics isthe branch of pharmacology that deals withthe mechanism of action of drug and therelation between the drug concentration andits effect, study of physical and chemicaleffects of drugs on body, parasites andmicroorganisms. What the drug does to thebody is pharmacodynamics. For example,adrenaline acts on adrenal receptors,stimulates adenyl cyclase system producingeffects such as cardiac stimulation andhyperglycemia was studied inpharmacodynamics.

3. Pharmacotherapeutics: The branch ofpharmacology that deals with the art andscience of treatment of disease. It is theapplication of pharmacological informationtogether with the knowledge of disease, forthe prevention and cure of the disease.

4. Chemotherapy: Chemotherapy refers to thetreatment of diseases by chemicals that killthe cells, especially those of microorganismsand neoplastic cells. It is classified into twodivisions:

Fig 1-3: A variety of topics involved with pharmacology, including neuropharmacology, renalpharmacology, human metabolism, intracellular metabolism, and intracellular regulation.


(a) Antibiotics: Includes the choiceof drugs most potent against theorganism or least toxic. Examplesinclude Erythromycin given for grampositive organisms and Aminogly-cosides for gram negative organisms.

(b) AntineoplasticsExamples include:Methotrexate, which is anticancer drug.It inhibits the dihydrofolate reductaseand interferes with the DNA synthesisand repair.Vinca alkaloids, which bind tubulin ofmicrotubules and arrest mitosis inmetaphase.

5. Toxicology: Toxicology is the branch ofpharmacology which includes the study ofadverse effects of drugs on the body. It dealswith the symptoms, mechanisms, treatmentand detection of poisoning caused bydifferent chemical substances.The main criterion is the dose. Essentialmedicines are poisons in high doses andsome poisons are essential medicines in lowdoses.

6. Clinical pharmacology: Clinicalpharmacology is the scientific studyof drugs in man. It includes pharmacokineticand pharmacodynamic investigations inhealthy or diseased individuals. It alsoincludes the comparison withplacebos, drugs in the market andsurveillance programmes.

The main objectives are:1. Maximize the effect of drug2. Minimize the adverse effects3. Promote safety of prescription

Aims include:1. Generate optimum data for use of drug.2. Promote usage of evidence based

medicine.7. Pharmacy: Pharmacy is the branch of

pharmacology and is the art and science ofcompounding by dispensing drugs,preparing suitable dosage form foradministration to man and animals. Thehealth profession blends health science withchemical science and effective use of drugs.

8. Pharmacognosy: Pharmacognosy is theidentification of drugs by just seeing orsmelling them. It is a crude method no longerused. Basically it deals with the drugs incrude or unprepared form and study ofproperties of drugs from natural sources oridentification of new drugs obtained fromnatural sources.

9. Pharmacoeconomics: Pharmacoeconomicsdeals with the cost of drugs. In thisdiscipline the cost of one drug is comparedwith another for same use. Thecheap drugs are preferred.

10. Pharmacogenetics: Branch ofpharmacology dealing with the geneticvariations that cause difference in drugresponse among individuals or population.Example includes succinyl choline whichis a skeletal muscle relaxant used in generalanaesthesia. It is metabolized bypseudocholine esterase and has shortduration of action. The presence of enzymeis determined by the gene and lack of this isrecessively inherited. This may lead torespiratory paralysis, apnea and death.

11. Pharmacogenomics: Pharmacogenomics isthe broader application of genomictechnologies to new drug discovery andfurther characterization of older drugs.Recombinant DNA technology involves theartificial joining of DNA of one species toanother. E. coli is mostly used. In this waywe can get huge amounts of drug inpurified form which is less antigenic.Examples include GH (Growth Hormone),inter interferon and vaccines.

12. Pharmacoepidemiology: Pharmacoepi-demiology deals with the effects of drugs ona large population. The effects may be goodor harmful. It is conducted in three ways:(a) Observational cohort studies(b) Case control studies(c) Phase trials(a) Observational cohort studies: Patients

receiving drugs are collected andfollowed up to determine theoutcomes. It is prospective (forwardlooking) research, however, is timeconsuming and lengthy.


Fig 1-4: Phases of clinical drug development

(b) Case control studies: These areretrospective studies. They reverse thedirection of scientific logic fromforward looking to backward looking.

(c) Phase trials: These include differentphases: (Fig. 1-4 ).

13. Comparative pharmacology: Branch ofpharmacology dealing with thecomparison of one drug to anotherbelonging to the same or another group.

14. Posology: Posology deals with the dosageof drugs. Example includes paracetamolgiven as one tablet of 500 mg thrice a dayfor an adult.

15. Animal pharmacology: Animalpharmacology deals with the differentproperties of drugs in animals. A vastvariety of animals are utilized includingrabbits, mice guinea pigs, etc. Drugs aregiven to the animals and all parameters(their behaviour, activities, vital signs,

physiological and anatomical changes etc.)are recorded. Any change is noted down. Ifany change was found to be useful inanimals, then the drug is tested on humans.

16. Behavioural pharmacology: Behaviouralpharmacology, also referred to aspsychopharmacology, is an interdis-ciplinary field which studies aboutbehavioural effects of psychoactive drugs.It incorporates approaches and techniquesfrom neuropharmacology, animalbehaviour and behavioural neuroscience,and is interested in the behavioural andneurobiological mechanisms of action ofpsychoactive drugs. Another goal ofbehavioural pharmacology is to developanimal behavioural models to screenchemical compounds with therapeuticpotentials. People in this field (calledbehavioural pharmacologists) typically usesmall animals (e.g., rodents) to study


psychotherapeutic drugs such asantipsychotics, antidepressants andanxiolytics, and drugs of abuse such asnicotine, cocaine, methamphetamine, etc.

17. Environmental pharmacology: Environ-mental pharmacology is a new dis-cipline. Focus is being given to unders-tand gene-environment interaction, drug-environment interaction and toxin-environment interaction. There is a closecollaboration between environmentalscience and medicine in addressing theseissues, as healthcare itself can be a causeof environmental damage or remediation.Human health and ecology is intimatelyrelated. Demand for more pharmaceuticalproducts may place the public at riskthrough the destruction of species. Theentry of chemicals and drugs intothe aquatic ecosystem is a more seriousconcern today. In addition, the productionof some illegal drugs pollutes drinkingwater supply by releasing carcinogens.

18. Neuropharmacology: Effects of medicationon central and peripheral nervous systemfunctioning.

19. Psychopharmacology: Effects of medicationon the psycho; observing changedbehaviours of the body and mind, and howmolecular events manifest in a measurablebehavioural form.

HypersensitivityHypersensitivity (or allergy) is an exaggeratedresponse of the immune system to antigenchallenge, harmful to the organism itself.Although the basic phenomenology of mosttypes of hypersensitivity reactions wasestablished at the end of the 19th century and inthe early years of the 20th century (Koch’sphenomenon, Richet and Portier’s anaphylaxis,Arthus’s phenomenon and serum sickness), itwas only in 1963 that Patrick Gell and RobinCoombs produced a comprehensiveclassification of hypersensitivity reactionsaccording to their underlying immune effectormechanism.

The Gell and Coombs classificationdistinguishes four types of reactions based onantibody (I-III) or cell-mediated (IV) effectormechanisms. Since the original classification, ourunderstanding of the molecular and cellularimmune reactions has considerably developedand several number of attempts have been madeto revise or re-interpet the Gell and Coombsscheme but, to this time, the Gell and Coombsclassification remains the most valid and usefulframe work for understanding hypersensitivity.

There is a significant difference between Type Ihypersensitivity and the other types ofhypersensitivity caused by antibodies (Type IIand III), namely the fact that Type I reactionsoccur only in a proportion of the subjects exposedto the agent in question (atopic individuals).Type II and III reactions, instead, occur in allindividuals. For example, haemolytictransfusion reactions (HTR) occur whenever ablood transfusion between ABO incompatibleindividuals is carried out, the haemolytic diseaseof the newborn occurs whenever a Rh- motherproduce an antibody response to Rh+, foetalRBC and serum sickness occurs wheneverrepeated and substantial doses of foreign serumis injected in patients for therapeutic purposes,as it occurred in the early days of serotherapy(Injections of a serum obtained especially froman immune animal). The common feature of TypeI, II and III is that in all cases the antibodyreactions induce cell or tissue damage (hence itappears justified that Gell and Coombs defineall these reactions Hypersensitivity) but in themajority of Type II and III reactions there is noindividual susceptibility or exaggeratedresponse and, in the case of the HTR due to ABOincompatibility, there is not even a firstsensitisation phase.

Type I Hypersensitivity

Antigens causing Type I hypersensitivityreactions (or immediate-type hyper-sensitivity)are defined as allergens and induce theformation of antibodies of the IgE isotype incertain individuals. IgE-based antibodyresponses are common physiologically inparasitic infections but atopic


individuals produce IgE responses against anumber of non-parasitic antigens that induceeither no antibody response or antibodyresponse of a different isotype, typically IgG, innormal individuals. Atopic individuals thus aresusceptible to either generalised anaphylaxislocal tissue reactions that involve a similarpathogenetic mechanism, namely asthma, hayfever, eczema or food allergies.

The tissue response caused by type Ihypersensitivity reactions is now wellunderstood and is determined by the binding ofIgE antibodies to a high affinity receptor whichbinds the Fc portion of IgEs with subnanomolaraffinity and located on the membrane of mastcells and basophils. As a result, a significantfraction of the IgE produced following initialcontact with antigen, becomes ‘fixed’ on thesurface of these cells and, in case of a secondcontact with antigen, the antigen-antibodyreactions occurs not only in solution but also orpredominantly on the mast cell and basophilmembrane .

The IgE-antigen reaction occurring on thesurface of basophils and mast cells leads toreceptor cross-linking and degranulation, i.e.,release of vasoactive amines (histamine andserotonin) and other agents (heparin, eosinophiland neutrophil chemotactic factors, platelet-activating factor, a variety of cytokines andprostaglandins and leukotrienes) from thecytoplasmic granules, which collectively causecontraction of smooth muscle cells, vasodilation,increased vascular permeability and plateletaggregation and degranulation. These reactionscan affect a single tissue or organ (as in asthma,hay fever or eczema) or multiple ones (as ingeneralised anaphylaxis) depending on local orgeneral re-exposure to the allergen.

Type II Hypersensitivity

Unlike Type I reactions, Type II hypersensitivityis caused by direct antibody-mediated celldamage or lysis. The actual mechanismsunderlying cell destruction are multiple (Type IIhypersensitivity - antibody-dependent cytotoxicity):

(i) Complement-dependent red blood celllysis, for example, as a result of

haemolytic transfusion reactions (HTR)caused by ABO incompatibility and inother forms of haemolytic anaemias.

(ii) Antibody-dependent red blood celldegradation occurs, for example, as theresult of binding of antibodies to the redcell membrane which fail to activatecomplement but promote macrophageuptake and RBC degradation. Thisoccurs for example, in the haemolyticdisease of the newborn (HDN) causedby Rh incompatibility.

(iii) Antibody-dependent cell-mediatedcytotoxicity (ADCC), which occurs whencytotoxic antibodies become fixed on thesurface of cytotoxic T cells andsubsequent antigen binding induceperforin-dependent cell lysis of the cellbearing the antigen.

Type III Hypersensitivity

Type III hypersensitivity reactions are causedby antibody-antigen complexes. Whensignificant quantities of such immune complexesare formed, they can deposit in tissues and leadto a tissue reaction which is initiated bycomplement activation and leads to mast celldegranulation, leukocyte, predominantlyneutrophil, chemotaxis and an inflammatoryreactions caused by the activation of these cells.

There are systemic forms of type IIIhypersensitivity reactions, such as serumsickness, a disease which is now of pure historicinterest but was a common occurrence inpatients receiving repeated injections of anti-diphtheric horse serum and in which immunecomplex deposition occurred in a variety oftissues and organs leading to fever, generalisedvasculitis with edema and erythema, arthritisand glomerulonephritis.

There are also local forms of immunecomplex diseases, such as the Arthusphenomenon . In both systemic and local formsof Type III hypersensitivity reactions, theemergence as well as the resolution of the tissue


lesions and clinical symptoms follow strictly theformation of the immune complexes, the causeof tissue damage (see Fig 1-5). The principalmechanism responsible for tissue damage as aresult of deposition of immune complexes ismediated by complement components, mainlythe C3a and C5a anaphylotoxins, that attractphagocytes and mast cells and, followingbinding to complement receptors on the surfaceof such cells, lead to degranulation causing alocal inflammatory reaction (vasodilation,increased vascular permeability, etc.)

Type IV Hypersensitivity

The prototypical Type IV (or delayed-typehypersensitivity, DTH) tissue reaction is Koch’sphenomenon. Type IV hypersensitivityreactions are caused by activated TH1 cells thatare activated by intracellular pathogens,including bacteria, fungi and protozoa, as wellcertain chemicals (hair dyes, nickel salts)leading to clonal expansion and differentiationof antigen-specific cells into TH1 clones. Thiscorresponds to the sensitisation phase of DTH.

Fig 1-5: Types of hypersensitivity reactions


Upon re-encounter with antigen, in the so-called effector phase, the antigen-specific TH1clones undergo further clonal expansion andsecretion of a variety of effector molecules. Theseinclude both cytokines (such as IFN-gamma,TNF-beta, IL-2 and IL-3) and chemokines suchas IL-8, Monocyte chemotactic and activatingfactor (MCAF) and a migration inhibiting factor(MIF) that collectively lead to macrophageactivation and to the development of a local tissuereaction.

Thus DTH is ultimately mediated by themacrophages recruited and activated by theproducts of antigen-specific TH1 clones. UnlikeType I, II and III reactions that can be transferredby serum (i.e., serum antibodies), passive transferof type IV requires the transfer of antigen-specificTH1 clones that orchestrate the macrophageresponse.

Drug Response and FactorsAffecting Drug ResponseVariations in the response to the same dose of adrug between different patients and even in thesame patient on different occasions have beenobserved. The range of variability is more markedwith drugs disposed by metabolism than withdrugs excreted unchanged in urine. The dose ofdrug is generally expressed in the range, whichgives therapeutic effect in majority of patients.The dose range usually based on the averagerequirements of an adult and is not strictlyapplicable under all circumstances.

Important FactorsModifying Drug Action are:

Body Weight/Size

Age

Sex

Environmental factors

Route of drug administration

Time of drug administration

Emotional factors

Genetic factors

Pathological states or presence of disease

Metabolic disturbances

Cumulative effect of drugs

Other drug therapy

Additive effect or summation

Synergism

Potentiation

Tachyphylaxis/desensitization

Tolerance

Antagonism

Body weight/size: Obese (overweight) patientsmay require more medication than thin patientsbecause of the drug has more tissue to which itcan go. The dosage of many drugs is calculatedon a weight basis. For example, a person mightbe prescribed a drug that has a dosage of 5milligrams of drug per pound of patient bodyweight i.e., 5 mg × 5 pounds = 25 mg.

Age: As a rule, the very young and the elderlyrequire less than the normal adult dose of mostmedications. Part of this requirement for lessmedication is due to the altered metabolism ofthe drug. Since body enzyme systems greatlyinfluence drug metabolism, considering thedifferences in these enzyme systems based uponage is important especially CYP Enzyme. In theinfant, some enzyme systems are not yet fullydeveloped. On the other hand, the enzymesystems of the elderly may not function as wellas in the past. Although several formulas areavailable for calculating a child’s dose ofmedication, the two most accepted methods arethose based upon the patient’s weight (that is,milligrams per kilogram of body weight) or bodysurface area (that is, milligrams per square meterof surface area). Many examples of age-relateddifferences in the response of individuals to aparticular drug have been documented. In manycases these differences can be related to modifieddistribution, metabolism or excretion of the drug.There is evidence that in neonates and theelderly, the extent and rate of these processesare less than those in older children and youngadults.


Anatomical changes: Age-related changes in thekidneys, liver, and other organs will influencethe way many medications work. Nutritionalstatus, multiple chronic diseases, and functionaland cognitive deficits are other age-relatedfactors that may have an impact on drug therapy.In general, because of a loss of muscle mass,elderly persons are physically smaller thanyounger adults. In addition, the percentage ofbody fat increases, and body water decreases.Cardiac output (the amount of blood that theheart pumps in one minute) decreases in mostelderly persons as well. Kidney functiongradually declines, and the effectiveness of theimmune system decreases. These changes requirea decrease in the dose of some medications tooptimize their benefits and avoid toxicity andadverse reactions.

Physiologic changes: Physiologic changes thatnormally occur with aging may affect the waydrugs work within the body. However, in a givenage group there is no consistent trend for alldrugs. In some cases the increased plasmaconcentration of the drug would be regarded asan advantage as it prolongs the response, but itis certainly not true for drugs such asstreptomycin, warfarin and the hypoglycemicagents. Two points which emerge from theresults of many studies with neonates and theelderly are that interindividual variations inplasma half-lives, metabolite and drug excretionand protein binding are significantly larger thanthose in young adults and that in the case of theelderly, chronological age does not necessarilyreflect biological age. In combination thesefactors emphasise the importance of individualdrug monitoring of plasma levels and hence ofknowing the pharmacokinetic constants of thedrug in the individual patient. In clinicalpractice, the dose of a drug is most commonlycalculated on the basis of body weight or surfacearea. This is generally perfectly acceptable forolder children and adults, but is not always areliable formula for neonates and the very old.Simple changes in such parameters as urine pHcan override calculations based upon body size.

Sex: Physiological differences between the sexesmay influence the dose or the requirement fordrugs. Since females have proportionately more

fat tissue than males, drugs, which have a highaffinity (likeness) for fat, may require larger dosesin females. Moreover, estrogen and testosterone,two sex hormones, can affect the patient’s rateof metabolism which can, in turn, influence therate at which a drug is absorbed, metabolized,or excreted from the body. The requirement foriron is much higher in the female than in themale, because of the loss of blood in eachmenstural cycle. In women consideration mustbe given to mensturation, pregnancy andlactation. Drugs given during pregnancy mayaffect the fetus. Marked physiological changesoccur during pregnancy that can alter the drugdisposition. For example, G.I.T motility isdecreased that results in delayed absorption ofdrug, plasma protein concentration andconsequently binding of drug to proteins isincreased during pregnancy, enzyme inductionis observed and renal blood flow increases thatcause rapid elimination of drug. The overalleffect on drug disposition is complex anddifficult to predict; drugs should be carefullygiven during pregnancy. A number of drugs likeclonidine, methyldopa, and α-blockers interferewith sexual function in males but not in females.Gynecomastia produced by drugs like Digitalis,Cimetidine, Ketoconazole, Metoclopramide,Spironolactone and Chlorpromazine occur inmales not in females.

Environmental factors: Drug metabolism is slowat high altitude due to oxygen deficiency.Cigarette smokers and industrial workersexposed to some pesticides metabolize drugsrapidly due to enzyme induction. Metabolism islow in hot and humid climate. Purgatives actbetter in summer while diuretics act better inwinters. Oxidation of drugs is low at higheraltitudes.

Route drug of Administration: Some drugs areincompletely absorbed after oral intake, whengiven intravenously; their dose has to be reduced.Examples include morphine and magnesiumsulphate. Magnesium sulphate when givenorally is osmotic purgative, but its 20% solution


is injected intravenously to control theconvulsions in eclampsia of pregnancy.Aminoglycosides like streptomycin when givenintravenously cause neuromuscular blockage,which is not observed after intramuscularinjection.

Time of drug Administration: Hypnotics(producing sleep) act better when administeredat night and smaller doses are required. There isdelayed drug absorption when drug is givenorally after meals, which slows down the effectsof drug. Drugs are usually given after meals toprevent gastric irritation. Under certaincircumstances drugs must be given before meals.

To prevent mixing of drug with food:Anthelmintics.

To get immediate effect: Drugs used forprevention of motion sickness.

To prevent formation of insoluble complexes:Tetracyclines.

To prevent specific side effects, for example,to prevent hypoglycemia, insulin andsulfonylureas are given before meals.

Emotional factors: Personality of physician andpatient may influence the effects of drug.Sometimes inert dosage forms can relieve thesymptoms this is called “PLACEBO”. Placeboresembles the actual medicine in physicalcharacteristics; it works by psychological ratherthan pharmacological effects and often producesresponse equivalent to the actual drug. Placebois used to compare the therapeutic effects ofvarious drugs during therapeutic trials of thedrugs. Personality of patient also affects the drugresponse, nervous and anxious patients requiremore general anesthetics than normal personsdo. Word placebo means “I SHALL PLEASE”.Placebo resembles the actual medicine inphysical characteristics. Placebo can be givenorally as well as parenterally. It does not producedrug – drug interactions. Substances used asplacebo are lactose, distilled water and dextrose.

Genetic factors: Genetic abnormalities influencethe dose of a drug and response to drugs. It affects

the drug response in individuals at 2 levels. Atthe level of receptors and at the level of drugsmetabolizing enzyme. Thus, interfering with thefunctions such as rate of plasma drug clearance.Pharmacogenetics is the study of therelationship between genetic factors and drugresponse. Idiosyncrasy is the abnormal drugreaction due to genetic disorder. It is theunpredictable response seen on first dose of drugon hereditary basis. This may be due toAcetylation, Oxidation, Succinylcholine apneaand Glucose 6-phosphate dehydrogenasedeficiency.

All individuals do not respond in similarway to same drug. Idiosyncrasy is used todescribe abnormal drug response onadministration of first dose.

Genetic polymorphism: The existence in apopulation of two or more phenotypes with respectto the effect of a drug. E.g., Acetylation enzymesdeficiency-Acetyl transferase (non-microsomal)affects isoniazid, sulphonamides, etc.

Slow acetylator phenotype may showperipheral neuropathy.

Rapid acetylator phenotype may showhepatitis.

Pseudocholinesterase deficiency: Succinylcholine is a skeletal muscle relaxant.Succinylcholine apnea may occur due toparalysis of respiratory muscles.

Malignant hyperthermia: Occurs by succinylcholine due to inherited inabilityto chelatecalcium by sarcoplasmic reticulum resulting inCa+2 release, muscle spasm and rise intemperature.

Oxidation polymorphism: In case ofDebrisoquine.

Extensive metabolizers (EM) - need larger dose.

Poor metabolizers (PM) – need smaller dose.

Deficiency of Glucose-6 phosphatedehydrogenase (G-6-PD): G-6-PD Deficiency inRBCs leads to haemolytic anaemia uponexposure to some oxidizing agents like


Antimalarial drug, primaquine

Long acting sulphonamides

Fava beans (favism)

Pathological states/ Presence of disease:Diseases cause individual variation in drugresponse.

In liver diseases, prolonged duration of actionoccurs because of increased half life. Plasmaprotein binding for warfarin, tolbutamide isdecreased leading to adverse effects, If hepaticblood flow is reduced; clearance of morphine,propranolol may be affected. Impaired livermicrosomal enzymes may lead to toxic levels ofdiazepam, rifampicin and theophylline.

In renal disease GFR, tubular function andplasma albumin may be affected leading toabnormal effects of digoxin, lithium, gentamycinand penicillin. In Malnutrition plasma proteinbinding of drugs is reduced along with theamount of microsomal enzymes, leading toincreased portion of free, unbound druge.g., warfarin

Metabolic disturbances: Changes in water andelectrolyte balance, body temperature and acidbase balance may modify the effects of drug. Forexample, aspirin reduces body temperature onlyin presence of fever and have no effect on bodytemperature when it is normal. Iron is wellabsorbed in states of iron deficiency.Vasoconstrictor effect of norepinephrine isreduced in presence of metabolic acidosis.

Cumulative effect of drugs: Cumulative effectof drugs is1. Due to many frequent doses.2. Due to prolonged continued administration.

By cumulative effect is meant the unexpected,intense action of a drug after it has been givenfor some time, as differing from an immediateintense action of a drug which would show anidiosyncrasy.1. The too frequent administration of a drug

which is slow of excretion will cause it to

accumulate and sooner or later produce apoisonous effect. Therefore, “the duration ofthe action of a drug”, it is very important toremember how long it ordinarily takes a givendrug to be excreted. For instance, if a drugthat is excreted in eight hours wasadministered every two hours, at the end ofeight hours five doses will have been taken,only the first of which has been completelyexcreted, leaving three doses acting and onebeginning to act in the system.

2. Cumulative action from too long continuedadministration of a drug means thedevelopment of symptoms which show anover-action of the drug. This is of frequentoccurrence and is sometimes accidental, butis often caused deliberately by pushing adrug to its full physiologic effect. In cases inwhich this action occurs unexpectedly andis undesired, the drug should be immediatelystopped, and not again given in doses thatcould cause such an effect. Some drugs givenotice of such an impending action bypremonitory symptoms; such is true ofdigitalis.

In some diseases such cumulativephysiologic action of certain drugs is desired.The drug is then stopped temporarily, and thenagain pushed to the point of tolerance, the bestway to combat such over-action, and whichdrugs will produce an over-action withoutdanger to the patient, can be learned only by thestudy of the pharmacology of the drugs.

Other drug therapy: Drugs may modify theresponse to each other by pharmacokinetic orpharmacodynamics interaction between them.Drug interaction does not necessarily mean thattheir concurrent use is contraindicated; manydrugs can be used beneficially with dosingschedule adjustment.

Additive effect or Summation: When totalpharmacological effect produced by concomitantuse of two or more drugs is equal to the sum oftheir individual effects, it is called “Additiveeffect”.

1 + 1 = 2


Example: Combination of ephedrine andtheophylline in the treatment of asthma. Theindividual side effects of an additive pair maybe different, and may not add up. Thecombination is better tolerated than higher doseof one component.

Aspirin + paracetamol as analgesic/antipyretic

Nitrous oxide + ether as general anaesthetic

Antihypertensive drugs

Cardiac stimulants

Synergism: When total pharmacological effectproduced by concomitant use of two or moredrugs is higher than the sum of their individualeffects, it is called “Synergism”.

1 + 1 = > 2.

Example: Codeine + Aspirin > Analgesia

Sulphonamide + Trimethoprim >Antibacterial effect

Potentiation: Enhancement of effect of one agentby another; so that the combined effect is morethan the sum of their individual effects is called“Potentiation.” In case of potentiation one agenthas no effect when give alone but increases theeffects of other co-administered drug.

0 + 1 2

Example: Acetylcholine + physostigmine.Physostigmine inhibits the action of esteraseprolonging the effect of acetylcholine.

Levodopa (Parkinsonism) + carbidopa/benserazide. Levo/dopa is decarboxylatedperipherally, carbidopa inhibits thedecarboxylase.

Sulphonamide (effective against somemicroorganisms) when combined withtrimethoprim is effective against a wider rangeof microorganisms.

Levodopa + Carbidopa = Parkinsonism.

Ampicillin + Clavulanic acid = Antibacterial effect.

The action is more than the normaltherapeutic effect.

Tachyphylaxis and Desensitization: Repeatedadministration of a drug at short intervals of timeleads to decrease in pharmacological response.Desensitization and tachyphylaxis aresynonymous terms used to describe thisphenomenon which often develops in course offew minutes. This occurs with indirectly actingdrugs like amphetamine, ephedrine, MDMA(3,4-methylenedioxy-N-methylamphetamine).On repeated administration, depletion ofendogenous receptors occurs. It is also knownas acute tolerance. Example includes ephedrine,which acts by releasing noradrenaline fromadrenergic stores. After repeated administration,these stores are exhausted and pharmacologicalaction is not restored even on increasing thedose.

Characteristics: Tachyphylaxis is characterizedby the rate sensitivity: The response of the systemdepends on the rate with which a stimulus ispresented. To be specific, a high-intensityprolonged stimulus or often-repeated stimulusmay bring about a diminished response alsoknown as desensitization. (Fig. 1-6)

Molecular interaction: In biological sciences,molecular interactions are the physical basis ofthe operation system. The control of theoperation, in general, involves interaction of astimulus molecule with a receptor/enzymesubsystem by, typically, binding to themacromolecule A and causing an activation oran inhibition of the subsystem by forming an

Fig 1-6: Tachyphylaxis


activated form of the macromolecule B. Thefollowing schematic represents the activity:

pA B

where p is the activation rate coefficient. It iscustomary that p is called a rate constant, but,since p stands for measure of the intensity of thestimulus causing the activation, p may bevariable (non-constant).

The above scheme is only the necessarycondition for the rate sensitivity phenomenon,and other pathways of deactivation of B may beconsidered, with the subsequent return to theinactive form of the receptor/enzyme A.

Examples:

Calcitonin: Calcitonin demonstrates tachyphy-laxis in 2–3 days when being used to treathypercalcemia of malignancy. This reaction isanticipated and calcitonin is given along withbisphosphonates, which have their maximumeffect in 2–3 days.

Hormone replacement: Hormonereplacement when used in menopausal womenin the form of estrogen and progesteroneimplants is cited as having potential to lead totachyphylaxis, but that citation is based on asingle study done in 1990 and no follow-upresearch is available to support thisinterpretation.

Psychedelics: Psychedelics such as LSD-25 and psilocybin containing mushroomsdemonstrate very rapid tachyphylaxis. In otherwords, one may be unable to ‘trip’ two days in arow. Some people are able to ‘trip’ by taking upto three times the dosage, yet some users maynot be able to negate tachyphylaxis at all until aperiod of days has gone by.

Centrally-acting analgesics: In a patient fullywithdrawn from centrally-acting analgesics,viz., opioids, going back to an intermittentschedule or maintenance dosing protocol, afraction of the old tolerance level will rapidlydevelop, usually starting two days after opioidtherapy is resumed and, in general, levelling offafter day 7. Whether this is caused directly byopioid receptors modified in the past or effecting

a change in some metabolic set-point is unclear.Increasing the dose will usually restore efficacy;relatively rapid opioid rotation may also be ofuse if the increase in tolerance continues.

Beta-2 adrenergic receptor gene: Gene encodingthe beta-2 adrenergic receptor (ADRB2) issituated on chromosome 5q31. Individuals whoare homozygous for the Gly16 form of the beta-2adrenergic receptor gene have attenuatedresponses and more rapid tachyphylaxis toadrenergic bronchodilator medications than dothose with the wild type, homozygous Arg16form of the gene.

Nicotine: Nicotine may also showtachyphylaxis over the course of a day, althoughthe mechanism of this action is unclear.

Other examples: Nitroglycerine demonstratestachyphylaxis, requiring drug-free intervalswhen administered transdermally.

Repeated doses of ephedrine may displaytachyphylaxis, since it is an indirectlyacting sympathomimetic amine, which willdeplete noradrenaline from the nerve terminal.Thus, repeated doses result in less noradrenalinereleased than the initial dose.

Hydralazine displays tachyphylaxis if givenas a monotherapy for antihypertensivetreatment. It is administered with a beta-blockerwith or without a diuretic.

Metoclopramide is another example.

Dobutamine, a direct-acting betaagonist used in congestive heart failure, alsodemonstrates tachyphylaxis.

Desmopressin used in the treatment of type 1 von Willebrand disease is, in general,given every 12–24 hours in limited numbers dueto its tachyphylactic properties.

Mechanisms that give rise to thisphenomenon are :1. Change in receptors (Rapid desensitization)2. Loss of receptors (down-regulation)3. Exhaustion of mediators4. Increased metabolic degradation5. Physiological adaptation


Change in receptors (Rapid desensitization): Aslow conformational change in the receptor,resulting in tight binding of the agonist moleculewithout the opening of the ionic channel (e.g.,ligand-gated ion channels such as nicotinicreceptors at the neuromuscular junction) →rapid and reversible.

Phosphorylation of intracellular region of thereceptor protein, leading to:

Desensitization of ion channel, orinterference with the receptor’s (e.g., GPCR)ability to activate second messenger cascade,though it can still bind the agonist molecule →slow and reversible.

Loss of receptors (down-regulation): Prolongedexposure to agonists often results in a gradualdecrease in the actual number of receptorsexpressed on the cell surface. The vanishingreceptors are taken into the cell by endocytosisof patches of the membrane; a process that alsodepends on phosphorylation. It occurs moreslowly than rapid desensitization and is lessreadily reversible. This is because down-regulation involves a net degradation of receptorspresent in the cell, requiring new receptorbiosynthesis for recovery, in contrast to rapiddesensitization which involves reversiblephosphorylation of existing receptors. ManyG protein–coupled receptors and many hormonereceptors are down-regulated by undergoingligand-induced endocytosis and delivery tolysosomes. Down-regulation generally occursonly after prolonged or repeated exposure of cellsto agonist (over hours to days).

Example: Chronic administration of salbutamol(β2 agonist) can cause internalization ofreceptors → less receptors available forstimulation → decreased bronchodilation.

Exhaustion of mediators: Depletion of a signalingmolecule or an essential intermediate substancerequired for biological response.

Example 1: prolonged stimulation of G-proteincoupled receptors can lead to depletion ofintracellular secondary messengers.

Example 2: Indirectly acting sympathomimetics(e.g. amphetamine) act by releasing tissue storesof adrenaline and noradrenaline and otheramines from the nerve terminal → tachyphylaxisoccurs because the amine stores becomedepleted.

Increased metabolic degradation: Increase in therate of metabolism and/or elimination of drug.Lowers plasma drug concentrations.

Example: barbiturates and ethanol induce theexpression of metabolic enzymes (cytochromeP450s) that degrade the drug → low plasma drugconcentration.

Physiological adaptation: A drug’s decreasingeffects may occur because it is nullified by ahomeostatic response. These homeostaticmechanisms are very common and if they occurslowly the result will be a very graduallydeveloping tolerance.

Example 1: The blood pressure-lowering effectof thiazide diuretics is limited because of agradual activation of the renin-angiotensinsystem.

Example 2: It is a common experience that manyside effects of drugs such as nausea andsleepiness tend to subside even thoughadministration is continued.

Tolerance: Resistance to normal therapeutic doseof drug, producing lesser response to normaltherapeutic dose is known as tolerance. This isacquired character. Examples include morphine,person is initially responsive, if continued,changes occur at cellular and pharmacokineticlevel, reducing the action. Thus one has toincrease the dose of drug to overcome. Alcoholicsdo not respond to hypnotics and analgesics,dose of which has to be increased many folds. Infact they may even tolerate toxic levels.


• Tissue tolerance: Tissue tolerance refers to thechanges that occur on the tissue or cell thatis affected by the drug.Example is barbiturates.

• Cross-tolerance: It refers to a pharma-cological phenomenon, in which a patientbeing treated with a drug exhibits aphysiological resistance to that medicationas a result of tolerance to a pharmacologicallysimilar drug. In other words, there is adecrease in response to one drug due toexposure to another similar acting drug. It isobserved in treatment with antivirals,antibiotics and especially with opiateanalgesics and many other medicationsincluding benzodiazepines.Cross-tolerance is particularly frequentamongst users of illicit drugs. For example,users with a high tolerance to thestimulant amphetamine may also exhibit ahigh tolerance to the structurallysimilar methamphetamine or other amphe-tamine-like stimulants. The phenomenon isalso observed in cigarette smokers, in whomthere is a demonstrably lessened sensitivityto the effects of caffeine. Cross-tolerance isalso frequent in response to use ofhallucinogens (e.g., LSD). General toleranceto the effects of tryptamines suchas psilocybin, may be dramatic in responseto repeated use, and this often translates intoa tolerance to effects of other drugs suchas mescaline. This is also true ofbenzodiazepines such as alprazolam andclonazepam, even opiates as well.

Pseudo Tolerance: It is confined to oraladministration of drug. Example is feudal kingstaking of small amounts of arsenic poison bymouth.

Mechanism of tolerance development

Pharmacokinetic tolerance: Pharmaco-kinetictolerance - Also known as dispositionaltolerance occurs because of a decreased quantityof the substance reaching the site it affects. Thismay be caused by an increase in induction of

“Reduced responses to repeated admini-stration of the same dose or increase in the doseare required to produce the same magnitude ofresponse is called tolerance”.

Types of Tolerance

True Tolerance: It is seen on both oral andparenteral administration of drug, and is dividedinto: Natural and Acquired.

Natural Tolerance: This is seen in various animalspecies and also among the human races. Itincludes.• Species tolerance: Certain animal species can

tolerate certain drugs in quantities that arelethal to man.Example: Rabbits can tolerate large quantitiesof belladona than humans due to presenceof an enzyme atropine esterase that detoxifiesit.

• Racial tolerance: Ephedrine solution whenincorporated in to conjunctival sac inCaucasians it may produce pupil dilatationbut not in Negros.

Acquired Tolerance: This type of tolerance unlikethe racial and species tolerance develops onlyon repeated administration of drug. Many drugslike opiates, barbiturates, nitrites, and CNSdepressants frequently develop tolerance. Anuninterrupted presence of drug in the bodyfavours the development of tolerance. Howeversignificant tolerance does not develop toatropine, digitalis, sodium nitroprusside andNSAIDs.

Fig 1-7: Tolerance


the enzymes required for degradation of the druge.g., CYP450 enzymes.

Pharmacodynamic tolerance: Also known asreduced responsiveness, the response to thesubstance is decreased by cellular mechanisms.This may be caused by a down regulation ofreceptor numbers.

Antagonism: When two drugs, administeredsimultaneously, oppose the action of each otheron the same physiological system, thephenomenon is called antagonism. It can be offollowing types.

Chemical antagonism: It involves reduction ofthe biological activity of a drug by a chemicalreaction with another agent e.g., between acidsand alkalis: BAL (British anti lewisite) andarsenic. Antacids, used for dyspepsia involveadministration of sodium bicarbonate to reactwith hydrochloric acid. In cases of heavy metalpoisoning chelating agents are used likedimercaprol.

In iron poisoning deferoxamine is givenwhich binds sulfhydryl groups forminginsoluble complexes which can be easilydetoxified.

Pharmacological antagonism: Pharmacologicalantagonism is of two types:

Competitive or reversible antagonism: In thistype of antagonism the agonist and antagonistcompete with each other for the same receptors.The extent of antagonism will depend on therelative number of receptors occupied by the twocompounds. Other features are:

(a) Antagonist has chemical resemblance withagonist.

(b) Antagonism can be overcome by increasingthe concentration of the agonist at receptorsite. It means the maximal response toagonist is not impaired.

(c) Antagonist shifts the dose response curveto right.

(d) Emax of agonist is obtained with highconcentration of agonist.

(e) Duration of action is short. It depends ondrug clearance.

Example is of acetylcholine and atropineantagonism on muscarinic receptors. In presenceof antagonist, log dose response curve of agonistshifts to right, indicating a higher concentrationof agonist is required for same response.Maximum height of the curve can be attained byovercoming the action of antagonist. This leadsto a parallel shift of log dose response curvetowards right.

Non competitive antagonism: Here an antagonistinactivates the receptor(R) in such a way so thatthe effective complex with agonist cannot beformed irrespective of the concentration of theagonist. This can happen by various ways:

The antagonist might combine at the samesite in such a way that even higher concentrationof the agonist cannot displace it.

The antagonist might combine at a differentsite of R in such a way that agonist is unable toinitiate characteristic biological response.

The antagonist might itself induce a certainchange in R so that the reactivity of the receptorsite where agonist should interact is abolished.

Other features of this antagonism are:1. Antagonist has no chemical resemblance

with agonist.2. Maximum response is suppressed.

3. Although antagonist shifts the dose responsecurve to right, the slope of the curve isreduced.

4. The extent of antagonism depends on thecharacteristics of antagonist itself andagonist has no influence upon the degree ofantagonism or its reversibility.

5. Emax of agonist is decreased even with highconcentration of agonist.

6. Duration of action is long which dependsupon new receptor synthesis.

7. Example is of phenoxybenzamine andadrenaline at alpha adrenergic receptors.


Physiological antagonism: In this interaction oftwo drugs, both are agonists, so they act atdifferent receptor sites. They antagonize theaction of each other because they produceopposite actions. Classical example ofphysiological antagonism is adrenaline andhistamine. Former causes bronchodilatationwhile later bronchoconstriction. So adrenalineis a life saving drug in anaphylaxis.Acetylcholine slows the heart, and epinephrineaccelerates it. Acetylcholine stimulates intestinalmovement, and epinephrine inhibits it.Acetylcholine constricts the pupil, andepinephrine dilates it; and so on.

Pharmacokinetic antagonism: The situation inwhich the drug which may be termed the

“antagonist” effectively reduces theconcentration of the active drug (the “agonist”)at its site of action. This may be due to an increasein metabolism or renal excretion of the “agonist”drug or to decreased absorption of the drug fromthe gastro-intestinal tract.

Example is warfarin and phenobarbital

Clinical significance of drug antagonism:1. It helps to correct adverse effects of a drug

e.g., ephedrine and phenobarbitone.2. It is useful to treat drug poisoning e.g.,

morphine with naloxone.3. It guides to avoid drug combinations with

reduced drug efficacy such as penicillin andtetracycline combination.

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