PRINCIPLES OF PHARMACOLOGY j | 3rd Edition | = HL Sharma io, mans Formerly, Professor, Dept of Pharmacology SMS Medical College, Jaipur; Prof and Head, Dept of Pharmacology Jaipur Dental College, Jaipur Rajasthan, India KK Sharma, wo, avs National Scientific CME Coordinator National Academy of Medical Sciences New Delhi, India Formerly, Prof and Head Dept of Pharmacology University College of Medical Sciences Dilshad Garden, Delhi; Prof and Head, Dept of Pharmacology School of Medical Sciences & Research; Dean, School of Allied Health Sciences Sharda University, Greater Noida UP, india Paras Medical Publisher Hyderabad » New DelhiPublished by Divyesh Arvind Kothari ‘for Paras Medical Publisher 5:1-475, First Foor, Putibowi ‘Hyderabad-500095, india 2012, Reprint 2013, 2nd Reprint 2013, 3rd Reprint 2015, 3 Ealtion 2017. _ Revised Reprint 201 RINCIPLES OF PHARMACOLOGY All rights reserved, No part of this plication may be reproduced o transmitted in any form or by any means, electronic or mechanical, including photocopy, ‘evording or any information storage and retieval system without the prior Permission in writing from the publisher Disclamer: Mein isan ever-changing sciace, As new research and clinical expe- ‘iene broaden our knowledge, changes inthe diggnoss and treatment occu The tulbors andthe publisher ofthis work have checked with sources believed to be ‘eile in their efforts to provide information that is complete and generally in ‘coord with the standards accepted at the time of palction. Drug dasage sche wes are constantly beng revised; new indications, contraindication, drug interac. _ fons and adverse cg ects ae resopnced wh thepasage of time, The reader shoul rele tthe aproprae relay bodyathoried webs, guidlines and ther suitable sources of fran, deemed eleva and applicable. This ee ‘ommendation is particularly important in connection with new | Theropeutic agent or 0 irrequnty wed drag. When moe died formation abut ony dr sre ‘ied it may be obtained fom te manufac ofprtdr dr. Honevet, in view of psy of aman enor or canes ia medi since, he author pb lise or any eter pean winks ben olen prepaiton of hs work axes 10 responsibilty for any eos oF onions or resus obained fom se of inf Into given in the boo. Every eft hasbeen made opt reference to tbls and figs. The authors have made chery effort to ace the copyright holders fer bor- rowed ‘ieial. If they have inddvertetly oveslooked any, they will ‘be pleased to. rake te nese acungemes at ft opera. Ti book is Deing pb lish wit te ndesanig hat emit provide hath) egal, This book isos in india ony and amt be expo itiut be perniion of the pubis iawn. Any spt and leg! mates by seed under Hyderabad tition onl. Printed in Hydro, daAckoch Kevclan Proaracstoy FF 70% 25 14 Our Families For their support, endurance and encouragementuae ean ON Pharmacology as a medical discipline has its routes in therapeutics. It equips a doctor with the knowledge and skills to prescribe and evaluate medication therapy not only forthe alleviation of the disease and maintenance of health but also to serve the best interest ofthe patient. With the advancements ofthe molecular biology and better understanding of the pathophysiological basis of disease processes, the pace and magnitude of introduction of new drugs has increased that has not been witnessed earlier. Today a treating physician should not only understand what is new ina new drug but also how an old drug can be utilized in a better way in the light ofthe new information, and the ones which cannot perform better may get superseded, All who are involved in prescribing (medical doctors) and administration, evaluation and monitoring of drug responses (health professionals - nurses and pharmacists) must remember that in the era of internet, the expectation of patients are high and the community at large demand from them an up-to-date evidence-based knowledge about medicines with which they deal for their safe and effective use in the practice and how they are discovered and developed. A performance in this manner would not only earn them a respectable position which they deserve in the society but also protect them from increasing criticism and also civil or even criminal law suits. As a result the doctor-drug-patient interaction has become more intimate as the survival of each one of them depends on this intimacy. In view of this background in mind, the rd edition ofthe book is humbly presented to all students of medicine, and professional colleagues who are no different than the former as far as the quest forthe knowledge of pharmacology is concemed. This edition retains al elements of principles laid in earlier editions. Updated and prudently precise information has been included in a reader-friendly and simple language so that it can be assimilated by even the beginner in the field. It will not only help them to grasp the basic concepts of drug selection and its use as per patient's need but also would provide them an ability to successfully sal through their academic courses as well as face competition during university licensing and PG entrance examination of the National Board of Examinations (NBE-India), Throughout the book, drug-related information has been organized inthe same format of sections on mejor topies and chapters on drugs classes. However, changes on comprehensive y WVe been undertaken in view ofthe availability of significant and addtional information on the existing and newly discovered drugs, receptors, transporters and mechanism of action that put the physiology, pathophysiology and pharmacology of the relevant organ systems in a new clinical perspective. Chapters that have substantial new information are: + Drug discovery and clinical evaluation; concept of pharmacovigilance and essential medicines with special emphasis on Indian scenario. Major revision of chapters on sympathomimetics; local anaesthetics; drug therapy of gout, hypertension, angina thrombotic disorders (novel oral anticoagulants and their antagonists), heart failure, dyslipidaemia; CNS disorders, especially depression, psychosis and epilepsy; hormonal disorders - adrenocortical steroids and anti-diabetics; bronchial asthma; obesity and immune disorders.1 Substantial changes in antimicrobial chemotherapy in view ofthe introduction of new drugs ornew information on old drugs in the areas of new antibiotics, tuberculosis, malatia and vital diseases, «Description of important new drugs approved until 2016. «A vital chapter on micronutrients deficiency disorders has been added providing a thorough information on the importance of micronutrients and the diseases caused due to its deficiency. Comprehensive updating and modification of well organized, tables, figures and introduction of boxes in view of the availability of new information and introduction of new drugs. Notes are added wherever an existing drug(s) was withdrawn or taken off from the market and revised warnings on th existing or newly introduced drug(s) have been issued 1 Pharmacovigilance is going to be @ major responsibilty ofthe future drug prescribers - as ADR data of Indian population are already meager and how long we are going to rely on the drug safety data of other countries, especially US and western nations. Therefore new drugs, especially the biotechnologically derived products, which have been released by US-FDA under Risk Evaluation and Mitigation Strategy (REMS) program, such as anti-dyslipidaemic drugs, lomitapide and mipomersen and anti-obesity drug-combination - phentermine plus topiramate (Qsymia) have been prominently mentioned so that these drugs as and when available are prescribed with caution with 2 mindset of pharmacovigilance approach, ie, ADR data has to be compulsorily collected, collated analyzed and reported for the large good of the mankind. These points have been aptly stressed in the chapter of drug development, pharmacovigilance and at places where availability of new drug has been mentioned. Future medical doctors need tobe sensitized towards their responsibility to actively participate in ADR reporting not only of new drugs but also of old drugs, as its high time we create out ‘own National Database of ADRs and formulate risk management strategies for the better good of Indian people. ‘The widespread adoption ofthe first two editions of this book by the graduate, postgraduate medical students and professionals, alike isthe testimony that this further transformed edition would also fulfill an important learning need of the medical pharmacology curriculum; we believe that this edition will serve this need even more successfully. We whole heartedly acknowledge the constructive and critical feedback provided by a large number of medical students - both graduates and postgraduates who through e-calls and e-mails not only discussed and sent ther critiques but also offered suggestions to improve the presentation ofthe text ofthe book, We firmly believe that sucha support would also be available in future as well. We would like to express our gratitude to our colleagues in the Departments of Pharmacology at University College of Medical Sciences and other medical colleges located in Delhi; School of Medical Sciences and Research, Sharda University, Greater Noida and Mahatma Gandhi Medical College, Jaipur, who reviewed the manuscripts, corrected errors and improved the text in multitude ways. They have been friends and colleagues for many years and represent everything that a pharmacologist and professor should be. Also our sincere thanks to Dr (Mrs) Pushpa Jain, Dr Nitin Kothari and Dr. Manikandan who also have gone through the book keenly for a reality check and informed our errors with suggestions for correction.Al possess an encyclopedic knowledge of pharmacology, extraordinary people skills and wisdom- an unbeatable combination, Finally, we wish to record our deep appreciation and warmest thanks to Mr Divyesh Arvind Kothari, Paras Medial Publisher, Hyderabad, for his faith in us and continued support, encouragement and an exemplary job of coordination, Further amore, we extend our thanks to Mrs K Sada Lakshmi of Paras Medical Publisher and Mrs Laxmi Sabbarwal and Ms Vinita for their meticulous and whole hearted support in preparation of manuscript whenever we needed it most ‘We will ever remain indebted to our teachers who made us what we are today and authors of those books, reviews and research papers who we consulted throughout our professional life; few have already been mentioned in the bibliography at the end of the book. These are the giants whose shoulder made us to look what otherwise we would have not seen and had an in- depth understanding ofthe subject of pharmacology and the wisdom to propagate and disseminate it further. Suggestions, comments and constructive critiques are always welcome. They may be sent tous through mail or in care to the publisher. HL Sharma 20% water and volatile oil andlor < 50% hydrocarbons, waxes, or polyols as the vehicle This dosage form is generally for external application tothe skin or mucous membranes Gels The active drug is dissolved in a liquid and then dispersed in some gelling agent (soft gelatin, et.) These are usually transparent preparations, e.g., contraceptive gels. However, the ferm is also used for colloidal aqueous suspensions of hydrated inorganic substances, eg. aluminium hydroxide gel. Paste Itis like an ointment but it does not have a greasy base. Instead, they are prepared with some adhesive material (like starch) or @ foaming agent (like carboxymethyl cellulose), eg., zine oxide paste, toothpastes, etc. THEDRUGS 13 DOSAGE FORMS OF Plaster It contains a drug mixed in a resinous base spread over a muslin cloth. Some plasters are coated with water repellent film also. The preparation remains hard at oom temperature but becomes sticky at body temperature. These are meant for protective action and also for antiseptic action, e.g, zinc oxide plaster, belladona plaster and Band-Aid SPECIAL AND NOVEL DOSAGE FORMS Inhalants Liquid preparations containing a drug tobe inhaled as vapour, €.g, tinct, benzoin inhalation and Karvol inhalant. The contents may be poured into a jug of boiling water and inhaled. Solid inhalants ike Fintal (God. cromoglycate) are inhaled with the use of turbo spin inhaler. Aerosols These are devices in which therapeutically active ingredients) dissolved in a liquid is put inside a cylindrical container (nebulizer) and is then filled with a propellant gas (air or oxygen) under pressure ‘A push at the valve releases the drug through a nicrofined orifice in the form of liquid mist which is inhaled. If one push releases @ measured dose of the drug, then these are called as “metered aerosols”, e.g., salbutamol metered aerosol, terbutaline metered aerosol A spinhaler is an aerosol device in which therapeutically active ingredient(s) are packaged in the form of a powder, that are released upon activation ofan appropriate valve system inthe form of microfined powder mist, eg. tiotropium metered spinhaler Suppositories (rectal), Pessaries (vaginal) and Bougies (urethral) These contain the drug mixed with glycerine or gelatin or hard soap or coca butter, These remain soli at room temperature but become slippery and melt at body temperature. Suppositories are bullet shaped, pessaries are conical, while bougies are pencil shaped. For example: Dulcolax suppositories14 GENERAL PRINCIPLES OF PHARMACOLOGY and Candizole-T (miconazole+ tinidazole) vaginal pessaries, Transdermal Adhesive Patch ~/ In these adhesive patches, the drug is incorporated into a polymer (usually polyisobutylene) which in turn is bonded to an adhesive plaster. The drug is delivered at the skin surface by diffusion, for Percutaneous absorption into circulation. These Preparations are designed to provide steady and “smooth plsina concentration ofthe drug fora period ranging from 1~3 days from the site oftheir application (usually chest, abdomen, upper arm or mastoid region), Examples are transdermal patches of nitroglycerin (Nitroderm-TTS), nicotine (Nicotinell-TTS) and estradiol (Estraderm-TTS), pecnuna DRUG TARGETING: SPECIAL DRUG DELIVERY SYSTEMS For better patient compliance and to improve the drug delivery, at the site where itis required, special drug delivery systems have recently been developed which have an added advantage of prolonged duration of drug action. Some ofthese systems are: Ocuserts These are thin elliptical microunits that contain the drug in a reservoir from which the drug is slowly released through a membrane by diffusion ata steady rate. For example: Pilocarpine ocusert used in slaucoma, which is placed under the lower eyelid to deliver pilocarpine for a period of 7 days, thus avoiding the need for instilling eye drops repeatedly every day, Progestaserts This isan intrauterine contraceptive device which is inserted into uterus where it delivers progesterone constantly at a specified rate for a period of one year. Drug Encapsulated in Liposomes for Intrave- nous Infusion Liposomes are minute vesicles produced by sonication of an aqueous suspension of certain Phospholipids. They can be filled with non-lipid soluble drugs, which are retained until the liposome is disrupted. Amphotericin (an antifungal drug used to treat systemic mycoses) is available in a liposomal formulation for intravenous infusion; the Preparation is less nephrotoxic and better tolerated than the conventional forms, albeit considerably ‘more expensive, Prodrugs Thisis an inactive form of drug which gets metabolised in the body to an active drug. These are used to overcome the pharmacokinetic disadvantage of the useful drug. For example: Dopamine is very useful in treating parkinsonism, but-it does not cross blood- brain barrier. Levodopa, is prodrug, can cross BBB, which is then converted to dopamine in the CNS Prodrug may also be used to provide longer duration of drug action, e.g, esters of penicillins get slowly hydrolysed in the body to provide stow and sustained release of penicillins (eg. Procaine Penicillin-G and Benzathine Penicilin-G). Computerised Miniature Pumps These are programmed to release drugs at a definite rate, either continuously as in the case of insulin or intermittently in pulses as in the case of GnRH (gonadottophin-releasing hormone). These pumps may also be provided with glucose sensor devices which trigger the desired dose of insulin as per body’s demand, Both invasive aswell as non-invasive miniature pumps are now available Monoclonal Antibodies (MAbs) as Drug Carriers Antibodies produced after immunisation are usually “polyclonal antibodies” because natural antigens have multiple epitopes (antigenic determinants) each of which generates separate clones of activated B- lymphocytes. On the contrary, those antibodies which are produced by a. single clone and are ditected against a single antigenic determinant (epitope), are called “monoclonal antibodies” (MAbs) Large agains “hybri hybric (fom mous: hybric capaci nyelo mmyelo in hyp enzyt subse a tum surfer lymph immut alycol in HA the hy hybrid and ca (MAbs use (FiLarge scale production of monoclonal antibodies against any specific. antigen is now done by using “hybridoma technology”. HyPridomas are somatic cell hybrids, obtained by fusing a specific B-lymphocyte (forming antibody against a specific antigen) with @ mouse myeloma (tumour) cell, The resultant hybridoma, therefore, retains the antibody-forming capacity of the B-lymphocyte with an ability of the myeloma tumour cel to proliferate endlessly. ‘To generate these antibodies, the mouse ‘myeloma cells are first grown in a culture deficient in hypoxanthine phosphoribosy! transferase (HPRT) enzyme so ast inactivate antigen and to prevent the subsequent formation of immunoglobulins (because ‘a tumour cell itself has a specific antigen on its surface). These myeloma cells are then fused with B- lymphocytes, obtained from the spleen of mouse immunised withthe desired antigen, in polyethylene alycol. The fused cells (hybridomas) ae then placed in HAT medium and cloned, In HAT medium, only the hybridomas can survive and replicate, Such hnybridomas can be maintained endlessy in thisculture and can continue to produce monoclonal antibodies (MAbs) which can be eluted and purified for clinical use (Fig. 3.1) Mouse injected with antigen having | ——> } B+ epitopes ‘a’ and 'b’ to a a | Expansion and elution of a( Bay ~ better permeability than the drug alone. After the complex crosses the membrane, the carrier dissociates from the drug, The carrier then either returns to the original side of the membrane for reuse or is essentially produced on one side and eliminated at the other side, The carrier-mediated transports are of two types: Facilitated Diffusion ‘The characteristic features of this process are: a) Carrier can move a drug substrate along its con- centration gradient only (down-hill diffusion, Fig, 51) Bloodstream [os Ob aw Facilitated Diffusion Carrier-mediated transport from higher c to lower concentration LC Ly op 0 D a \ ‘Active Transport Energy-dependent carrier-mediated transport from lower c to higher concentration |_ S++ poo i) D+) c | D FILTRATION® Processes of Biotransportation. D = drug; E = energy; C = carrierGENERAL PRINCIPLES OF PHARMACOLOGY SECTION 1 b) As in passive diffusion, no extracellular energy is requited for translocation of drugs and c) Its capacity limited process, ie, the rate of diffusion depends upon the binding ability ofthe dug to its carrier ands limited by the availability of carrier, The plot describing the absorption rate- concentration relationships forthe passive diffu- sion is linear over the entire concentration range while thet of facilitated diffusion shows linear re- lationship at concentrations only at lower range. As the concentration increases, the rate of ascent of the curve decreases and eventually the absorp- tion rate becomes constant regardless of the dose, which reflects the saturation of the cartier pro- cess (Fig. 5.2) 4) Two drugs or the substrates having similar physico-chemical characteristics can compete for the same transfer mechanism and thus interfere with each other’s absorption. Drugs that permeate by facilitated diffusion are: amino acids in brain; antimetabolite-anticancer drugs; antiviral drugs; adenosine-like drugs; certain vitamins, .g., riboflavin, thiamine and B,,. Active Transport (up-hill transport) Imagine @ situation where a delegation of some politcal leaders from abroad has got down at the airport and they are to be received and welcomed to visit the capital as per protocol; but there are massive demonstrations against them at the airport. That meats, the concentration of the demonstrators against them, inside the boundary, is high as compared to the number of foreign delegates waiting outside for their entry. Their safe entry will nt be possible unless a police force is called and adequate security arrangements are made. Analogously, we can define the active transport of drugs as a energy-dependent, carrier-mediated transport taking place against the electro-chemical gradient (i.e, electrical as well as concentration gradient). The energy needed forthe active transport is generated by the membrane ATPase. Further, if these demonstrations are ‘widespread, eg, inside the city also then obviously their entry would be delayed, Similarly, the process of active transport can he blacked by inhibiting cell ‘metabolism or by reducing the ATP levels by giving agents like sodium cyanide, sodium fluoride or 24- dinitrophenol. Moving the story a step further, as the entry ofthe Head ofthe delegation is taking place under police cover, other members of the delegation would also be seeking their entry under the same security cover. Ina similar manner, the drugs or substrate, having similar physico-chemical characteristics can also compete for the same carrier-mediated active transport process. A step further, if the number of delegates is large, while the police force is meagre to control the massive demonstrations, their entry cannot take place in a linear fashion, As an analogous consequence, active transport, like facilitated diffusion, is also a capacity limited process where this up-hll ransport depends upon the availability of the carrier. That means, as the concentration of the drug increases, the rate of the ascent of the absorption rte-concentration curve decreases and eventually the absorption rate becomes constant regardless of the dose, which reflets the saturation of the carrier process (Fig. 5.2) Rate of absorption Drug concentration Curve B: Facilitated Diffusion or Active Transport, The following drugs are among those which are actively transported: 5-Fluorouracil by intestine; nitrogen mustard by lymphocytes; digitalis slycosides by liver; sympathomimetic amines by neural tissue and choline by cholinergic neuron.Depending upon the driving force, the active transport can be subdivided into primary or secondary active transport (Fig. 5.3) In primary active transport, the bio- transportation of drugs is directly coupled with ATP hydrolysis for deriving the energy (i.e., enetgy- dependent) and is usually carried by ABC (ATP Binding Cassette) group of biotransporters (e.g., P- glycoprotein). ABC transporters work like “evacuators” and mediate the unidirectional efflux of many drugs like antibioties, anticancer drugs, HIV protease inhibitors, digoxin and anticonvulsants. In secondary active transport, one ion or the solute (X) supplies the driving force fr the transport of other ion/sotute (Y). Depending on the direction offlux ofX and Y, the transporters can be called either a symporter or an antiporter. A symporter (or cotransporter) transports X and Y in the same direction (eg., Na‘/K'/2CI symporter, Ch.16). An antiporter (ot exchanger or counter-transporter), on the contrary, transports X and Y in the opposite directions (e.g,, Na‘ and H* exchanger, Ch. 16). These transport mechanisms are not directly linked to ATP Higher concentration < HOW DRUGS AREBIOTRANSPORTED } 25 hydrolysis (as discussed above). The transportation here is driven by a difference in electrochemical ‘gradient established by the active transport (or even by facilitated diffusion) of X andY. Membrane Transporters ‘Membrane transporters are usually the proteins that control the therapeutic response or toxicity of a drug through their ability to influx or efflux the drug from a cell. These are located in intestine, kidney, lung, [5 liver and BBB, ete, and control absorption, tissue \> » distribution and elimination of a drug. There are two superfamilies of drug transporters. ATP Binding Cassette (ABC) Superfamily of Transporters ‘These are involved in primary active transport and are coupled to ATP hydrolysis and energy generation out ofthe hydrolysis. There are 7 subclasses ofthis group (ABC-A to ABC-G) which are encoded by 49 genes. The most important example is P-glycoprotein {also called ABCB, or MDR-1). The multi-drug resistance (MDR) gene isa member of the functionally Lower concentration (outside) Drug. + Drug (inside) Tod +—« Energy (ATP) Primary Active Transport @4 on/solute @Q—F >@ |—(® Ion/solute Q<« O< Symporter ® ton/solute @ ton/solute ‘Secondary Active Transport ae Classification of Membrane Transport Mechanisms. T = ATP Binding Cassette (ABC) Group of Transporters (e.g., P-glycoprotein)26 I GENERAL PRINCIPLES OF PHARMACOLOGY diverse ABC transmembrane superfamily of transport proteins and the multiple drug resistance occurs from a single mutation of MDR/ gene. Hence the name MDRI for the P-glycoprotein. MDRI inducers or inhibitors can lead to serious drug-drug interactions (Ch.22,Ch. 62) Solute- Linked Carrier (SLC) Group of Transporters ‘The SLC superfamily of transporters are involved in facilitated diffusion or secondary active transport, 43 SLC families, encoded by different genes, are known till date, Prominent SLC transporters are various neurotransmitter transporters (Ch. 10) like for serotonin, norepinephrine and dopamine. SLC transporters that are non-neuronal include glucose transporters (GLUT, Ch.47), cholesterol transporters (Ch. 23), and a variety of renal symporters and antiporters (Ch. 16) etc, PINOCYTOSIS/PHAGOCYTOSIS (ENDOCYTOSIS) ‘The mechanism of transport by endocytosis involves the celluar uptake of exogenous molecules or complexes, inside plasma membrane-derived vesicles. Ths process canbe divided into two major categories: Pinocytosis (or fluid uptake) Pino (Greek) meaning “I drink”, eylos meaning a “hollow vessel” denoting acell, and osisa process”, Pinocytosis, therefore, is a process where a cell drinks or engulfs a fluid or a drug in solution, The stages of pinocytosis include (Fig. 5.1} (a) Macromolecular solutes are first trapped in the microscopic cavities formed on the membrane sur- face (invaginations). (b) The membrane then fuses around and completely encloses the fluid (contain- ing the solutes) to form a vesicle and (c) Later, the vesicle is pinched off, passing some fluid and the solute across the membrane into the interior of the cell. This mechanism is of some importance for drugs, mosily polypeptides, e.g., insulin which crosses the blood-brain barrier by this process. Many antitumour drugs, entrapped into liposomes, are biotransported by this method. Receptor mediated absorption of LDL in liver also takes place through pinocytosis. Pinocytotic activity is rather marked at the alveoli ofthe langs and atthe walls of blood vessles but this process does not represent the transfer mechanism for large quantities of materials, since the numberof vesicles that would have to be formed is beyond the capacity. Phagocytosis (uptake of particles) In some cases, the particulate matter can also be transferred by local invagination of the cell membrane. Such a process is termed as phagocytosis (phago meaning “to eat”). The process is rare but certainly poisoning by botulinum toxin and allergic reactions occurring after ingestion of offending proteins (antigens) are well-known examples for this type of absorptive process. Both these processes require an expenditure of cellular energy, but the translocation of the drug does not require its combination with any carrier as is seen in active transport or facilitated diffusion FILTRATION ‘You must have seen some passengers traveling in a train without a ticket. They usually get down atthe railway station and move around till they fin some broken places in wire fencing to sneak into the city premises. But to be successful in this venture they should be lean and thin (smaller in size) and should not be carrying any luggage (unbound or free). Lastly, the driving force for such movement will depend on the number of such persons waiting in a queue (the pressure gradient) Similarly, the free or unbound drugs (or metabolite) of smaller molecular size can pass through the pores or spaces between the cells by the process of filtration. It is purely a physical process where the rate of filtration is proportional to apressure gradient. This is an important mecha- nism for drugs of small molecular size (e.g. urea, alcohol, glucose) which are filtered through glome- rus.CHAPTER Peace) Although the transport processes described in Chapter 5 can adequately account for the passage of drugs across any biological membrane, they can hardly explain their movement over any great distance How then is the movement of drugs over greater distances accomplished? The circulatory system, then, serves as a common pathway for carrying drugs from the inner side of the biological barrier to any tissue or organ, Hence, unless the drug is purposely injected directly into the blood stream (where absorption is completely bypassed), getting to its site of action involves two separate processes. The first ofthese is absorption, i, the movement of drug into the blood stream from it site of administration The second process then is distribution, i.e., movernent of drug molecules from the blood into the tissues (10 be discussed later). We shall here discuss only some important sites from where the drug enters into the systemic circulation. The factors affecting absorption shall be discussed along with bioavailability of drugs (see following text), ABSORPTION VIA GASTROINTESTINAL TRACT Some aspects about the absorption of drugs through GiT have already been discussed catlier (refer Ch. 4 and Ch, 5), and shall be discussed again in factors affecting absorption and bioavailability. Briefly speaking, the absorption of drugs from GIT is mainly by passive diffusion through the lipid sheath, Few drugs, however, are small enough to diffuse through the pores in the cell membrane; while uptake of sugar and other nutrients is by active transport. The gut is more permeable to nonionised lipid-soluble form of drugs and less permeable to the ionised form. The ability ofa drug to be absorbed via GIT and to reach the systemic circulation is compromised as a result of drug loss due to: (i) its efflux by the P-glycoprotein localised in the enterocytes, (ii) its metabolism in these cells an liver, (ii) by vomiting o (iv) by disease that may affect drug absorption, The whole process of absorption through GIT is summatised below. From mouth: Saliva pH is slightly acidic, but the pH of stimulated saliva (as with sublingual drugs) reaches 7.4 (alkaline), Hence, lipid-soluble (non-ionised) basic orneutral drugs can be absorbed form tis site. After the sublingual absorption, the drug directly goes into systemic circulation, bypassing first-pass metabolism (ce,, metabolism of drug taking place in liverfintes- tine/lungs before it reaches systemic circulation). For example: isosorbide dinitrate given sublingually for angina From stomach: pH aciic, Hence, lipid-soluble (un- ionised) acidic or neutral drugs are absorbed from this site, After absorption they pass through hepatic portal system before going to systemic circulation hence chances of first-pass metabolism are increased From intestine: pH alkaline. Hence, lipid-soluble (unionised) basic or neutral drugs are absorbed from here, eg., morphine, Because of the larger surface area, itis the major site of absorption for most of the drugs. However, the drugs have to pass through hepatic portal system before going to systemic circulation: hence, there are chances of first-pass affect. From liver, some drugs may be secreted into intestine through bile and are reabsorbed back (enterohepatic circulation, see following text) From large intestine or colon: pH alkaline. Hence, unionised (lipid soluble) basic or neutral drugs are absorbed from this site, From external baemorthoidal vein, the major amount of the drug goes directly to systemic circulation, hence minimal first-pass effect. The rate of absorption from fastest to lowest is: sublingual -> rectal oralSECTION 1. GENERAL PRINCIPLES OF PHARMACOLOGY ABSORPTION VIA PARENTERAL SITES Drugs when injected intravenously are completely absorbed and rapidly distributed, as they reach the bloodstream directly without crossing any membrane. Absorption following intramuscular and subeutane- ous injections usually occurs by passive diffusion fromthe injection site to the plasma or lymph, Filtra- tion through channels in the endothelial capillary membrane is also very efficient (Ch. 5) Absorption of drugs from intramuscular injection is usually more rapid than from subcutaneous sites, because of the higher vascularity of the muscle compared to the subcutaneous tissue but the difference is not large. ‘The extent of absorption from highest to lowest is: intravenous + intramuscular > subcutaneous However, te absorption from S.C. and IM. route is reduced inpatients with circulatory fulure (eg, shock) in whom the tissue perfusion gets decreased. ABSORPTION VIA LUNGS Lipid-soluble drugs when given ina vapourised form (general anaesthetics), or as aqueous solution spray (salbutamol) or as spray of suspended microfined patticles (disodium cromoglycate) are absorbed by simple diffusion from the pulmonary epithelium and mucous membrane of trachea and lungs. Absorption is rapid because of the large surface area and high vascularity, First-pass metabolism is avoided. ABSORPTION VIA TOPICAL SITES Absorption of most drugs through the intact skin is of course poor as the keratinised epidermis behaves like a barrier to permeability, However, the underlying dermis is quite permeable to many lipid-soluble drugs and therefore significant absorption can occur ifthe skin is abraded, As discussed above, a transdermal application of some drugs (nitroglycerin, scopolamine and clonidine) and application of some drugs on mucous membranes (@.., oxytocin and vasopressin as nasal spray) enhances the systemic absorption mainly because of'the thin and highly vascular absorbing surface. Ophthalmic drugs-in the form of eye drops or ointment are absorbed through the cornea, METHODS FOR DELAYING ABSORPTION Using an Appropriate Dosage Form ‘The “slow release” dosage forms, like retard tablets (¢g., potassium chloride retard tabs. and diclofenac sodium sustained release tabs.) spansules (e.., iron formulations, like Fefol® and isosorbide dinitrate spansule), depot injections (eg, testosterone depot inj, and fluphenazine depot inj.) and subcutaneous implants (eg, testosterone pellets) are some ways to obtain a slow but sustained absorption of drugs (refer Ch. 3). Changing the Physical Characteristics of the Drug Physical characteristics of some drugs may also be changed to retard their rate of absorption, eg, insulin zine suspension. Depending upon the pH of the reaction, insulin can form a fine amorphous zine suspension (semilente) which is relatively rapidly absorbed or a cloudy zine suspension (ultralente) ‘which isslowly absorbed. Each can be used separately depending upon the effect desired or can also be mixed together (Iente) to produce an immediate but sustained effect. Similarly, procaine penicillin-G is such asaltof pencilin which i only slightly water souble. When injected as an aqueous suspension itis slowly absorbed and exerts a prolonged action ‘Adding a Vasoconstrictor Drug or Applying a Tourniquet The addition of a vasoconstricting drug, like noradrenaline or adrenaline to a solution ofa local anaesthetic, e.g., xylocaine, reduces the absorption of the local anaesthetic into the general circulation, This usefully prolongs the local anaesthetic effect and reduces the chances of systemic toxicity Application ofa tourniquet to arrest the blood flow, followed by the LV. injection of local anaesthetic below the tourniquet (eg, in whole limb) delays the systemic absorption but prolongs the local anaesthotic effect. Decrease peripheral blood flow in conditions of “shock” significantly reduces the rate of absorption of injected drugsMETHODS TO FACILITATE ABSORPTION The rate limiting factors in absorption from the injection site are: (a) diffusion through the tissue and (b) removal by local blood flow. The importance of the former is shown by the powerful effect of hyaluronidase, an enzyme which breaks down the intercellular matrix. Adding hyaluronidase to the injection fluid increases the rate of diffusion through the interstitial spaces and greatly speeds up the drug absorption. Similarly the absorption from the site of injection may be increased by increasing the local blood flow by applying hot fomentation or doing massage CE ee ss In case you hire a set of persons (i.e, men of same age, height, weight and strength) from different nationalities to complete a desired tsk in stipulated time, you will notice that the rate at which these persons appear at the desired site of work and the extent to which they perform their job differ from persons of one nationality to another. In other words, their availability at the desired site and their work output is not identical. The same holds true with the drugs also Different brands ofthe same generic drug can be chemically equivalent (je., they may satisfy all the chemical and physical standards as laid down in the pharmacopoeia), yet may not be biologically. or therapeutically equivalent (ie., may not yield similar concentration of drug in bloodstream at the same time and may not provide the same therapeutic effect) if given by any route other than intravenous BIOAVAILABILITY is defined as per US Food and Drugs Administration as “the rate at which and the extent fo which the active concentration of the drug is available at the desired site of action (ot practically speaking in the bloodstream)”. Probably the term bioavailability came into existence through an unusual incidence of phenytoin toxicity in epileptic patients which occurred in the year 1968 in Australia and due to the differences in the bioavailability observed with different digoxin formulations in the year 1971. Tn Australia, in the year 1968, there was a sudden outbreak of phenytoin toxicity in epileptic patients, The pharmaceutical frm which was marke- Sev ee PHARMACOKINETICS | 29 ting “Dilantin Sodium Capsules” was using calcium sulphate as inert excipient. Since stocks of calcium sulphate got exhausted, they substituted it with lactose thinking that this minor change in inert excipient should be immaterial. But with this “reformulated product” the plasma concentration of phenytoin reached around 30 pgiml leading to phenytoin toxicity. The reason was that lactose gets 3: more easily wetted This resulted in faster dissolution with implied quicker absorption and consequently higher plasma concentration, leading to toxicity. BIOAVAILABILITY is an absolute term which requires measurement of both the true rate and total amount (extent) of drug that reaches the general circulation from an administered dosage form, EQUIVALENCE isa relative term which means a comparison of two different brand products of the same drug with a set of established standards. Equivalence could be of several types: BIOEQUIVALENCE Iftwo or more similar dosage forms ofthe same drug reach the blood circulation at the same relative rate and to the same relative extent, these are called bioequivalent preparations (brands) of the generic drug. In other words, the two similar dosage forms of cone drug entity can be called bioequivalent if their ‘plasma level profiles] are comparable and ‘uperimposable or fall within specific (and regulated) limits, For example, two brand preparations of phenytoin like Dilantin (Parke Davis) and Eptoin (Boots) may or may not be bioequivalent. Differences in bioavailability are primarily seen with oral dosage forms because bioavailability of any drug after].V, administration is 100 percent and is sometimes assumed to be close with LM. of $.C. route aiso. The latter may not always be true because some drugs, like phenytoin, digoxin, diazepam and chlordiazepoxide partly get precipitated atthe site of injection and hence their bioavailability gets reduced, if given by S.C ‘or LM. route. Differences of tess than 25% in bioavailability among several formulations of one drug_will usually have no significant effect on clinical outcome, hence such formulations can be