Sarfraz Ahmed · Suvash Chandra Ojha · Muhammad Najam-ul-Haq · Muhammad Younus · Muhammad Zaffar Hashmi   Editors

Biochemistry of Drug Resistance

Biochemistry of Drug Resistance

Sarfraz Ahmed · Suvash Chandra Ojha ·Muhammad Najam-ul-Haq ·Muhammad Younus ·Muhammad Zaffar HashmiEditors

Biochemistry of DrugResistance

EditorsSarfraz AhmedDepartment of Basic SciencesUniversity of Veterinary and AnimalSciencesNarowal, Pakistan

Muhammad Najam-ul-HaqDepartment of ChemistryBahauddin Zakariya UniversityMultan, Pakistan

Muhammad Zaffar HashmiDepartment of ChemistryCOMSATS University IslamabadIslamabad, Pakistan

Suvash Chandra OjhaDepartment of Infectious DiseasesThe Affiliated Hospital of SouthwestMedical UniversityLuzhou, China

Muhammad YounusDepartment of PathobiologyUniversity of Veterinary and AnimalSciencesNarowal, Pakistan

ISBN 978-3-030-76319-0 ISBN 978-3-030-76320-6 (eBook)https://doi.org/10.1007/978-3-030-76320-6

© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer NatureSwitzerland AG 2021This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whetherthe whole or part of the material is concerned, specifically the rights of translation, reprinting, reuseof illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, andtransmission or information storage and retrieval, electronic adaptation, computer software, or by similaror dissimilar methodology now known or hereafter developed.The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoes not imply, even in the absence of a specific statement, that such names are exempt from the relevantprotective laws and regulations and therefore free for general use.The publisher, the authors and the editors are safe to assume that the advice and information in this bookare believed to be true and accurate at the date of publication. Neither the publisher nor the authors orthe editors give a warranty, expressed or implied, with respect to the material contained herein or for anyerrors or omissions that may have been made. The publisher remains neutral with regard to jurisdictionalclaims in published maps and institutional affiliations.

This Springer imprint is published by the registered company Springer Nature Switzerland AGThe registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Foreword

Drug resistance is used in the sense of resistance that bacteria, hosts, or living cellsmay have developed or have evolved, resulting in a decrease in the efficacy of adrug to treat a disease or disorder. Drug resistance is currently rising to dangerouslyhigh levels worldwide and jeopardizing our ability to cure even common infectiousdiseases. With the use of herbs, modern medicine started to end up with chemicallybased drugs. Such drugs may be used as DNA, RNA, protein, and lipid-based ther-apies. Drug resistance can, with high health risks, lead to socially and economicallyadverse effects. The general opinion is that pandemic drug use in humans and farmanimals has shown to a significant driver of global drug resistance. A high degree ofresistance to previous medicines contributes to creating novel treatments that maycope with these infectious and other diseases.

Depending on the type of drug and the cell type, there are myriad ways in whichall populations of cells develop drug resistance. However, drug resistance literaturewas scarcely accessible or very dispersed through many disciplines without mean-ingful interpretation. Fighting the growing resistance to drugs is a race against time.Therefore, understanding the different molecular mechanisms underlying antibioticresistance and therapeutic other medicines will help create new drugs to addressincreasing drug resistance.

Thismonograph is an extensive collection of state-of-the-art research anddevelop-ment information on the subject by leading experts worldwide. Its comprehensive listof chapters covers almost every issue, including drug resistance to bacterial diseases,viral diseases, parasitic diseases, fungal diseases, ENT infectious diseases, skindiseases, lung diseases, neurological disorders, kidney diseases, heart diseases, liverdiseases, cancer, HIV andAIDS, reproductive diseases, ocular diseases, diabetes, anddrug-resistance management. Therefore, this monograph will be a welcome additionto the subject’s literature. To the best of my knowledge, the topics covered in thismonograph provide deeper insights into drug resistance and encourage readers tolearn more about this fascinating phenomenon. I highly appreciate and congratulateeditors for their diligent work and devotion in making this valuable contribution inthe field of drug resistance.

Narowal, Pakistan Sarfraz Ahmed

v

Preface

Resistance to drugs continues to have a substantial global impact on public healthand economic development. Apart from death and injury, chronic illness results inmore extended hospital stay, the need for more expensive medications, and financialproblems for those affected. Without effective antimicrobials, the advancement ofmodern medicine in treating diseases, including major non-infectious diseases andcancer chemotherapy, will be at greater risk. The constant need to develop newantimicrobial drugs that function against multi-drug resistant pathogens has spurredresearchers on their investment in various drug development techniques, includingdiscovering new applications for existing drugs. Albeit the process is especiallypromising for fast-tracking compounds in clinical trials, it nevertheless has significantbarriers to success.

This book’s framework comes into being as we progressively began to speak withpeers from diverse backgrounds, many of whomwere or had heard of drug resistancewithin their respective specialties.We realized that enormous informationondifferentaspects of drug resistancewas straggly available to the researchers and academicians.Also, drug resistance literature across disciplines was scarcely accessible or highlydispersed without any meaningful interpretation. Therefore, there was an immenseneed for a comprehensive collection of knowledge on drug resistance, biochemistry,kinetics, dynamics, and management.

This book is a compilation of the scientific work carried out by dedicated teamsof scientists devoted to human well-being. This book discusses recent advances indrug resistance that can facilitate young minds to turn their ideas into discoveringnew medicines for the benefit of society. The central focus of this book is to covercritical issues in drug resistance biochemistry. All chapters are logically chosenand structured to provide detailed state-of-the-art information on drug resistance’sbroad aspects. Its detailed chapter list includes almost all issues, including drugresistance to bacterial diseases, viral diseases, parasitic diseases, fungal diseases,ENT infectious diseases, skin diseases, lung diseases, neurological disorders, kidneydiseases, heart diseases, liver diseases, cancer, HIV andAIDS, reproductive diseases,ocular diseases, diabetes, and drug-resistance management. All chapters and theircontents are supported by thorough citations of available literature, estimates, andconclusions based on practical facts of current research and development in this area.

vii

viii Preface

We hope readers will find Biochemistry of Drugs Resistance enjoyable to readand useful for gaining deeper insights into drug resistance. This book provides awealth of information based on a realistic evaluation of modern drug resistance withan emphasis on biochemistry. Many chapters in the book are written at a reason-ably advanced level and should be of interest to graduate students and practitioners.It highlights the prospects of the drug mode of action, dynamics, and all possibleresistance mechanisms. We hope readers will take the time to read all of the chap-ters, no matter which medical or scientific discipline you practice. We encouragereaders to do so because, first of all, each chapter is super interesting. Secondly,because learning how drug resistance evolves may awaken you to explore its use innovel ways. We genuinely hope that one of the advantages of this book will be toencourage responsible research to resolve drug resistance and support patients bymaking research therapy accessible.

Narowal, PakistanLuzhou, ChinaMultan, PakistanNarowal, PakistanIslamabad, Pakistan

Sarfraz AhmedSuvash Chandra Ojha

Muhammad Najam-ul-HaqMuhammad Younus

Muhammad Zaffar Hashmi

Acknowledgements Thanks to Higher Education Commission of Pakistan NRPU projects 7958and 7964; Pakistan Science Foundation project PSF/Res/CP/C-CUI/Envr (151). Furthermore,thanks are due to Pakistan Academy of Sciences project 3-9/PAS/98 for funding.

Contents

1 Introduction to Drugs, Drug Targets and Drug Resistance . . . . . . . . 1Saima Ashraf, Nabila Bashir, Nadia Rashid,Adeel Hussain Chughtai, Khalid Mahmood Zia,Saadat Majeed, Muhammad Naeem Ashiq, Ghulam Murtaza,and Muhammad Najam-ul-Haq

2 Drugs Resistance in Bacterial Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . 33Muhammad Zeeshan Ahmed, Tazeen Rao, Waqas Ahmad,Shahzeb Hameed, Samrana Anayat, Asma Altaq, Wafa Iqbal,Muhammad Younus, Ali Ahmad, Suvash Chandra Ojha,Atif Liaqat, Rahat Naseer, Shehla Munir, Muhammad Ibrahim,and Sarfraz Ahmed

3 Drugs Resistance Against Viral Diseases . . . . . . . . . . . . . . . . . . . . . . . . . 57Atif Liaqat, Muhammad Farhan Jahangir Chughtai,Adnan Khaliq, Tariq Mehmood, Samreen Ahsan, Kanza Saeed,Syed Junaid Ur Rahman, Nimra Sameed, Shoaib Aziz,Rabia Iqba, Waqas Ahmad, and Saeed Ur Rahman

4 Drug Resistance in Protozoal Infections . . . . . . . . . . . . . . . . . . . . . . . . . 95Hafiz Muhammad Rizwan, Haider Abbas,Muhammad Sohail Sajid, Mahvish Maqbool, Malcolm K. Jones,Muhammad Irfan Ullah, and Nabeel Ijaz

5 Antifungal Drugs: Mechanism of Action and Resistance . . . . . . . . . . 143Muhammad Zeeshan Ahmed, Tazeen Rao, Ali Saeed,Zeeshan Mutahir, Shahzeb Hameed, Samrana Inayat,Haseeba Shahzad, Najeeb Ullah, Muhammad Abaid-Ullah,Muhammad Ibrahim, Shehla Munir, Asghar Javed, Jallat Khan,Muhammad Khalid, and Sarfraz Ahmed

ix

x Contents

6 Drug Resistance in Ear, Nose, and Throat Infections . . . . . . . . . . . . . . 167Muhammad Zeeshan Ahmed, Zeeshan Mutahir, Tazeen Rao,Arshad Islam, Nayyab Hameed, Saifullah Shakeel,Haseeba Shahzad,Mazhar Ali, Shahzeb Hameed, Syed Hizbullah,and Saeed Ur Rahman

7 Drug Resistance in Skin Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197Humaira Shah and Sher Zaman Safi

8 Drugs Resistance in Lungs Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235Muhammad Salman Sajid, Shafaq Saleem, Fahmida Jabeen,Batool Fatima, Adeela Saeed, Dilshad Hussain, Saadat Majeed,Muhammad Naeem Ashiq, and Muhammad Najam-ul-Haq

9 Neurological Disorders: Biochemistry of Drug Resistanceand Future Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255Muhammad Sheeraz Ahmad, Salma Batool, Arshad Islam,Ammara Jabeen, Azka Noureen, Sana Shamshad,Tayyaba Zainab, Maryam Shahid, and Warda Ahmed

10 Drug Resistance in Kidney Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279Nadia Rashid, Dilshad Hussain, Saima Ashraf,Nabila Bashir, Saadat Majeed, Muhammad Naeem Ashiq,and Muhammad Najam-ul-Haq

11 Drugs Resistance in Heart Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 295Adeel Mahmood, Maryam Eqan, Saher Pervez, Rimsha Javed,Rizwan Ullah, Arshad Islam, Ajmal Khan, Atif Amin Baig,Gotam Kumar, Muhammad Abaid-Ullah, and Muhammad Rafiq

12 Drug Resistance in Liver Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335Shehla Munir, Muhammad Ibrahim, Nor Hayati Othman,Atif Amin Baig, Mogana Das Murti, Nik Soriani,Muhammad Zeeshan Ahmed, Farhan Younus, and Sarfraz Ahmed

13 Drug Resistance in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367Batool Fatima, Maryam Jamil, Dilshad Hussain,Adeela Saeed, Fahmida Jabeen, Muhammad Salman Sajid,and Muhammad Najam-ul-Haq

14 Drugs Resistance and Treatment Failure in HIV and/or AIDS . . . . . 387Fahmida Jabeen, Muhammad Salman Sajid, Adeela Saeed,Batool Fatima, Dilshad Hussain, Saadat Majeed,Muhammad Naeem Ashiq, and Muhammad Najam-ul-Haq

15 Drug Resistance in Reproductive Diseases . . . . . . . . . . . . . . . . . . . . . . . 405Dilshad Hussain, Adeela Saeed, Hafiza Nadia Rashid,Batool Fatima, Muhammad Salman Sajid, Fahmida Jabeen,and Muhammad Najam-ul-Haq

Contents xi

16 Drug Resistance in Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 423Adnan Khaliq, Muhammad Farhan Jahangir Chughtai,Javed Iqbal, Haq Nawaz, Samreen Ahsan, Tariq Mehmood,Atif Liaqat, Muhammad Nadeem, Nimra Sameed, Kanza Saeed,Syed Junaid-ur-Rahman, Ayesha Ali, and Shoaib Aziz

17 Drug Resistance in Rheumatological Diseases . . . . . . . . . . . . . . . . . . . 461Hassan Waqar, Ammar Arshad, Muhammad Asad Raza,Mohammad Qamar Nasir, Ahmed Shams Nasir, Arshad Islam,Ifra Idrees, Sarfraz Ahmed, Khalid Muhammad, and Atif Amin Baig

18 Pherotypes in Streptococcus Pneumoniae and Role of CSP-1and CSP-2 in Antibiotic Susceptibility and Resistance;Towards Development of Live Attenuated Vaccine Candidatesin Inducing Netosis Based Acquired Immune Response . . . . . . . . . . . 475Saima Iqbal, Muhammad Hassan, Hassan Waqar, Sarfraz Ahmed,Arshad Islam, Ahmed Zubaidi Abd Latiff, Nordin Simbak,Shehla Munir, and Atif Amin Baig

19 Hypoxia, Obesity and Drug Resistance; Towards SustainableDevelopment Goals and Globalization . . . . . . . . . . . . . . . . . . . . . . . . . . . 489Farwa Munir, Fizza Maqbool, Shahzaib Naeem, Shaharbano,Mavra Riaz Atif, Asad Ur Rehman, Sarfraz Ahmed,Faheem Mustafa, Muhammad Hassan, Shehla Munir,and Atif Amin Baig

20 Genetic and Molecular Mechanisms of Multidrug-Resistancein Uropathogens and Novel Therapeutic Combat . . . . . . . . . . . . . . . . . 505Muhammad Mubashar Idrees and Ali Saeed

21 Drugs Resistance Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 539Nabila Bashir, Saima Ashraf, Nadia Rashid,Syed Tayyab Raza Naqvi, Saadat Majeed, Ghulam Murtaza,Muhammad Naeem Ashiq, and Muhammad Najam-ul-Haq

Chapter 1Introduction to Drugs, Drug Targetsand Drug Resistance

Saima Ashraf, Nabila Bashir, Nadia Rashid, Adeel Hussain Chughtai,Khalid Mahmood Zia, Saadat Majeed, Muhammad Naeem Ashiq,Ghulam Murtaza, and Muhammad Najam-ul-Haq

Abstract Drugs are the moieties used in treating diseases. Drugs include vaccines,antidepressants, antibiotics, antiviral, anesthetics, stimulants, and inhibitors. Drugsperform functions in the living system and are associated with the change in bodymetabolism. Various mechanisms are linked to drug distribution and drug action.Mechanisms are specific and they target specific regionor process in the body.Mecha-nisms for antibiotic resistance includemodification of bacterial proteinswhich are thetargets of antibiotics, enzymaticmodification of antibiotics, reduction in drug uptake,efflux pump modification, plasmid modification, and inhibition of metabolic path-ways. Drugs are used individually or in combinations tomaximize each other’s effectand minimize the risk. Factors defining drugs efficiency include nature of disease,medical history, drug dosage, treatment time, age, and environmental factors. Drugresistance is the ineffectiveness of drug against a disease after specific period. Factorsassociatedwith drug resistance are the excessive or inappropriate use of drugs and themodification in target sites including genetic mutations. Genetic mutations lead totherapeutic and economic problems as new therapies and drug combinations requiretime and resources. Some pathogens are resistant to multiple drugs known as multi-drug resistance. Drugs designing by considering these challenges can minimize thedrug resistance.

S. Ashraf · N. Bashir · N. Rashid · A. H. Chughtai · S. Majeed · M. N. Ashiq ·M. Najam-ul-Haq (B)Institute of Chemical Sciences, Bahauddin Zakariya University, Multan 60800, Pakistane-mail: najamulhaq@bzu.edu.pk

K. M. ZiaDepartment of Chemistry, Government College University, Faisalabad, Pakistan

G. MurtazaDepartment of Pharmacy, COMSATS University Islamabad (CUI), Lahore Campus, Lahore,Pakistan

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021S. Ahmed et al. (eds.), Biochemistry of Drug Resistance,https://doi.org/10.1007/978-3-030-76320-6_1

1

2 S. Ashraf et al.

1.1 Drugs

A drug is a chemical substance when consumed causes change in organism’s bodyfunctions both physically and psychologically (Rajesh, 2015). It can be used for thetreatment, prevention, diagnosis, or cure of diseases and to enhance/effect the cellularfunctions. Drugs can be consumed via inhalation, injection, ingestion, smoking,absorption, and patch on skin. A drug produces pharmacological effect by interactingwith specific biological sites or cell components in the body. Drug interactions occurvia physical and chemical bonds like hydrogen, ionic, covalent and van der Waalsforces (Sarker & Nahar, 2007). Drugs with short period of interaction form weakbonds while long actions produce strong and irreversible bonds with their targets.There are many types of target molecules showing interactions with drugs.

1.1.1 Classification of Drugs

1.1.1.1 Classification Based on Pharmacological Effect

Pharmacological effect shows how a drug effects cells of an organism. Various drugshave different pharmacological effects on the body and thus categorized on this basis.

Vaccines

Vaccination is a cost-effective measure for controlling infectious diseases. Thediscovery of vaccines was a critical point in the war between human and microbes.Vaccination has protected mankind from diseases like smallpox and measles etc.Till now 27 vaccines have been developed to prevent and control infections (Vartak& Sucheck, 2016). Vaccines are the biological preparations made of small amountof attenuated or dead pathogens (virus or bacterium) that elicit immunity to targetpathogens (Pulendran & Ahmed, 2011). Vaccine sparks body’s immune responseto fight off, destroy and memorize pathogens if they ever encounter again andcause infections. By injecting vaccine, some minor infections with fever may occur.Fever is caused as immunity requires few days or sometime weeks to produce anti-bodies. To understand the working of vaccines, lets first look at how the bodyfights against illness. Pathogens enter in the body and multiply to cause infec-tion leading to illness. Body’s Defense System (Immune System) fights againstsuch infections through white blood cells also known as immune cells present inblood. Macrophages, B-lymphocytes, and T-lymphocytes are the components ofwhite blood cells. Macrophages swallow and digest germs, and dead or dying cells.The macrophages leave behind parts of invading germs called antigens. Body iden-tifies antigens as danger and stimulates antigen-specific antibodies to attack them.B-lymphocytes are defensive white blood cells which produce antibodies that attack

1 Introduction to Drugs, Drug Targets and Drug Resistance 3

antigens. T-lymphocytes are another type of defensive white blood cell which attackthe infected cells present in the body. Immune system through T-lymphocytes andB-lymphocytes remembers how to fight the same pathogen in future (Vetter et al.,2018). Vaccines have thus rapid effect, save life, and promote health.

Types of Vaccines

(i) Live Attenuated VaccineLive vaccine consists of antigenic substance containing living microorgan-isms cultivated under controlled conditions in culture or embryo that makethem less virulent. When administered, they show protective and long-lastingimmune response in host against pathogens. Viral vaccines protect againstdiseases like measles, rubella, varicella-zoster, oral poliovirus, chickenpox,mumps, rotavirus and yellow fever (Victoria et al., 2010). For example, thelive attenuated mycobacterium vaccine containing virulently modified strainsof “BCG” cures deadly and infectious Tuberculosis disease. Live attenuatedvaccines have disadvantages like they are not given to immunocompromisedindividuals as small quantity of live pathogens can produce infections. Some-times these vaccines mutate to virulent form and cause health problems (Sinha& Bhattacharya, 2014).

(ii) Inactivated VaccinesInactivated vaccines are created by inactivating the propagated pathogensvia treating them in culture with chemicals like binary ethyleneimine, radi-ations or heat. Inactivated vaccines provide weaker immunity as comparedto live vaccines, therefore immunological adjuvant and booster shots arerequired periodically after vaccination. These vaccines immune against polio,influenza, plague, cholera, typhoid and pertussis (Sanders et al., 2015).

(iii) ToxoidsToxoid vaccines are inactivated toxins made by inactivating bacterial toxins(exotoxin) through treatment with heat or chemicals (formaldehyde). Thesevaccines induce anti-toxoid antibodies capable to bind with toxin andneutralize them. This vaccination is effective for diseases caused by secretedtoxins like tetanus and diphtheria (Hermanson, 2013; Yadav et al., 2014).

(iv) Subunit/Recombinant VaccinesSubunit vaccines use only a fragment of target pathogens (e.g. proteins,polysaccharides) which provoke immune response. Subunit vaccines areproduced either by well-established expression systems or by conventionalbiochemical technologies. These vaccines are cost-effective compared totraditional vaccines (Tan & Jiang, 2017). Subunit vaccines are used againsthepatitis b, human papillomavirus and pneumococcal disease (Schiller &Lowy, 2018).

(v) Conjugate VaccinesConjugate vaccines induce immune response against polysaccharides capsulepresent as an external layer on range of bacteria. Bacteria can synthesizevariety of polysaccharides. Antibodies against polysaccharides of pathogenicbacteria like Hib, pneumococcus and meningococcus protect from diseases

4 S. Ashraf et al.

(Rappuoli et al., 2019). Example of this type of vaccine is Haemophilusinfluenza type B (Hib) (Goldblatt, 2000) (Table 1.1).

Antidepressants

Hypertension is a medical condition where arteries have elevated pressure. Factorslike blood plasma levels, hormonal activity, environmental conditions (stress) arefew of the reasons of primary hypertension. Secondary hypertension can result dueto diabetes, kidney disease, hyperthyroidism, pregnancy, obesity, and sleep apnea(Charles et al., 2017). There are several classes of antihypertensive drugs used tocontrol, treat, and prevent hypertension. Diuretics, Angiotensin-converting enzyme(ACE) inhibitors and calcium channel blockers are used as the first line treatment(Khalil & Zeltser, 2020). Thiazide diuretics work by inhibiting reabsorption of salts(sodium) in the convoluted tubule of kidneys and thus promote diuresis and natri-uresis. Commonly used thiazide diuretics are hydrochlorothiazide (HCTZ), inda-pamide and Chlorthalidone (Akbari & Khorasani-Zadeh, 2019). Calcium is the mainreason of contraction of arteries and heart cells. CCBs help in lowering blood pres-sure by preventing calcium entry into the heart cells and arteries walls through L-type calcium channels (Ozawa et al., 2006). ACE inhibitors prevent angiotensinconverting enzyme toproduce angiotensin II, a strongvasoconstrictor.ACE inhibitorsthus lower blood pressure and prevent contraction of cardiac myocytes and smoothmuscles (Herman &Bashir, 2019). Table 1.2 shows antidepressant drugs, their modeof actions and side effects.

Antibiotics

Antibiotics slowdown the growth or destroy bacteria. Penicillin’s discovery byAlexander Fleming in 1928 as first antibioticwas a breakthrough inmodernmedicine.Penicillin prevents cross-linking of peptidoglycan in the cell wall of bacteria byinhibiting transpeptidase enzyme and results in bursting of bacterium. Penicillin isclassified with regard to the chemical substitution of side chain attached with (4membered) beta lactam ring (Lobanovska & Pilla, 2017). Types of penicillin antibi-otics include penicillinV, penicillinG, amoxicillin, and ampicillin.Another antibioticis tetracycline used for treating infections caused by bacteria (both gram-negativeand gram-positive), mycoplasmas, protozoans, chlamydiae or rickettsia. Tetracyclineinhibits protein synthesis by reversibly binding with receptors on microbial RNA.They are bacteriostatic and thus prevent bacteria from multiplying. Chlortetracy-cline, Doxycycline and Oxytetracycline belong to this class (Chopra & Roberts,2001). Cephalosporins are the β-lactam antibiotics working like penicillin for rangeof bacteria.Cephalosporins treat diseases like bacteremia, pneumonia,meningitis andsoft tissue infections (Marshall & Blair, 1999). Other antibiotics include glycopep-tides (Kang & Park, 2015), aminoglycosides (Krause et al., 2016), sulfonamides(Kleiner, 2018) and quinolone (Aldred et al., 2014).

1 Introduction to Drugs, Drug Targets and Drug Resistance 5

Table1.1

Typesof

vaccines

Vaccine

type

Detail

Advantages

Disadvantages

Disease

Liveattenu

ated

Vaccine

strainsarecultivatedin

controlledconditionsof

cultu

reor

embryo

thatmakethem

less

virulent

Inductionof

long-lastin

gim

muneresponse

inhost

Adverse

effectin

immunocom

prom

ised

individuals.Mutateto

virulent

form

Tub

erculosis,Measles,

Smallpox

,Oralp

olio

vaccine,

Mum

ps,R

otavirus,Y

ellow

fever

Inactiv

ated

vaccines

Pathog

enskille

din

cultu

rethroughradiations,chemical

treatm

ent,or

heat

Canno

treplic

ate

Shorterlength

response.

Booster

shotsare

required

forlong

term

immun

ity

Influ

enza,P

lague,Cholera,

Typhoid,

WholecellPertussis

Toxoid

vaccine

Inactiv

ated

toxins.T

hey

generatestrong

immune

response

againsttoxins

Excellent

stability,H

ighly

effic

ient

Not

highly

immunogenic

Tetanustoxoid,D

iphteria

toxoid

Subunit/recom

binant

vaccine

Purifiedantig

ens.Fragments

(polysaccharides,p

roteins)of

virusor

bacteria

Safe

andnon-replicating

vaccine

Repeatedvaccinationor

boosterarerequired

Smallpox

,HepatitisB,

Haemophilusinflu

enza

type

B,P

neum

ococcal(PC

V-7,

PCV-10,

andPC

V-13)

Con

jugatevaccine

Antigensenclosed

inpolysaccharides’coating

Improved

immuneresponse,

longer

protectio

n,herd

immun

ity

The

lack

ofprotectiv

eim

muneresponse

inyoungchild

ren

Haemophilusinfl

uenzae

type

B(H

ib)

6 S. Ashraf et al.

Table 1.2 Antidepressant drugs

Drugs Mechanism of action Side effects Examples

Thiazide diuretics Inhibit Na/Clsymporter

Dizziness, blurredvision, stomach upset,weakness

Chlorothiazide,Hydrochlorothiazide,Chlorthalidone,Indapamide

Calcium channelblockers

Prevent Ca2+ entry incell

Constipation, fatigue,headache, nausea, fastheartbeat

Amlodipine,Isradipine, Nifedipine

ACE inhibitors Inhibit conversion ofangiotensin I toangiotensin II

Cough, fatigue,hypotension, azotemia

Benazepril,Perindopril, Lisinopril,Captopril

Beta blockers Blocking effect ofepinephrine hormone

Bradycardia,depression, fatigue,constipation, sexualdysfunction

Atenolol, Nadolol,Propranolol,Metoprolol

Loop diuretics Inhibit Na+, Ca2+,and K+ reabsorption

Electrolyte imbalance,dehydration,hyperlipidemia,hyperuricemia

Bumetanide,Furosemide,Torsemide,Bumetanide

Potassium sparingdiuretics

Na+ channel inhibitor,Reduced K+ secretion

Muscles cramp, skinrashes, aches and pain,headache

Amiloride,Triamterene,Eplerenone

Alpha-blockers Blockage of alpha-1receptor

Orthostatic hypotensionand Tachycardia

Prazosin, Doxazosin

Angiotensin IIReceptor Blockers(ARBs)

Blocking of type 1angiotensin IIreceptors on arteries

Angioedema, renalfailure

Losartan, Irbesarten,Telmisartan

Drugs for Specific Disease Manifestations

This class of drugs target the specific cells hampered because of any disorder in thebody. These drugs alter themechanismof disease either by inhibition of diseased cellsor regulationof healthy cells, for example, antipsychotics also referred as neuroleptics(Finkel et al., 2009). These drugs target the mental disorders including psychosis,primarily in bipolar disorder and schizophrenia (Lally & MacCabe, 2015). Theirlong-termusemayproduce adverse effects like gynecomastia,weight gain,metabolicsyndrome, and impotence. In 1940s, typical antipsychotics were discovered as first-generation while the second generation of atypical antipsychotics like Clozapine wasdeveloped in 1960s (Hippius, 1989). Both generations block the dopamine recep-tors however some atypical medications also operate via serotonin receptors. Thesemedications are employed in schizoaffective disorderswithmood stabilizer or antide-pressant. Atypicalmedications are prescribed in psychotic depression in combinationwith an antidepression. These medications work by blocking dopamine D2 recep-tors to reduce its effect in brain dopaminergic pathways, as psychotic effects are

1 Introduction to Drugs, Drug Targets and Drug Resistance 7

produced due to excess dopamine release. These medications impact the activity ofneurotransmitters in the brain.

Drugs for Non-specific Diseases

These drugs treat disorders like runny nose, nasal congestion, sneezing, fever,influenza, and sinus. These medications do not contain cough relieving ingredi-ents. This class includes analgesics also referred as pain relievers or painkillers.They act without inducing sleep or unconsciousness. Analgesics function on bothcentral and peripheral nervous systems (CNSandPNS).Analgesics are different fromanesthetics which temporarily or sometimes permanently affect the sensation. Anal-gesics include drugs like NSAID’s (non-steroidal anti-inflammatory drugs), parac-etamol and opioids as oxycodone and morphine. The extent of pain suggests theuse of analgesics. Traditional drugs are not effective in neuropathic pain and benefitcan come from drugs like anticonvulsants and tricyclic anti-depressants which arenot the normal analgesics (Dworkin et al., 2003). Analgesics work by blocking thepain signals of brain or disrupt the brain’s interpretation of those signals. In somecases, they terminate the synthesis of prostaglandins by enzyme inhibition. They alsostimulate opioid receptors which relieve the chronic pain (Smith et al., 2014).

Antihistamine is a group of drugs for relieving allergies and allergic rhinitis.They are inexpensive, over the counter, and generic medicines that treat skin rashes,sneezing and nasal congestion. Antihistamines are for short term processes whereaschronic allergies like sinusitis and asthma cannot be treated. They function byopposing the histamine receptors and thus categorized as e.g. H1-antihistamine andH2-antihistamine. H1-antihistamine acts by the attachment of H1 receptors in cellsto cure problems associated with nose, inner ear, sneezing, motion sickness andinsomnia. H2 receptors bind cells in gastrointestinal tract for treating ulcers andgastric acid issues (Panula et al., 2014).

Anesthetics, Muscle Relaxants and Diagnostic Agents

(a) AnestheticsThey make humans unconscious in controlled manner. Anesthetics are diver-sified compounds which perform via neuronal passages. They cause reducedconsciousness, immobility, decreased responsiveness and amnesia (Chou et al.,2002). They are administered through inhalation and injection. Sometimes,anesthetics are given in combination with other drug to avoid side effects oruncontrolled consciousness. Anesthetics agonize GABA receptors for theireffect, e.g. benzodiazepines, isoflurane, etomidate and propofol (Louis, 2011).

(b) Muscle RelaxantsThey deal with skeletal muscles and reduce muscle tone. Spasmolytic andneuromuscular blockers are the muscle relaxants. Neuromuscular blockershinder the transmission atNMJ (Neuromuscular junction) and cause no activity

8 S. Ashraf et al.

in CNS and induce temporary paralysis in intensive care and surgical opera-tions. Spasmolytics as “centrally acting” muscle relaxants alleviate muscu-loskeletal pain and decrease spasticity in neurological conditions (Bowman,2006). Baclofen, metaxalone, methocarbamol and cyclobenzaprine are theexamples of muscle relaxants.

(c) Diagnostic AgentsDiagnostic agents help in diagnosing diseases and their causes. They are termedas “helping aids” in detecting abnormalities in cells, tissues, or organs. Theirdose depends on the type of test and can be administered via injection, mouth,eye etc. In radiopharmaceuticals, the radioactive isotope is employed to deter-mine the disorder. For example, I-131 detects goiter in thyroid gland, P-32and Sr-90 diagnose skin and other cancers, N-13, Rb-82 and Tl-201 detectheart disorders. Their composition and activity differ because of their workingnature, e.g. sulphobromophthalein sodium detects liver disorder whereasp-amino hippuric acid, phenosulphophthalein and inulin determine kidneydysfunction (Sano et al., 2001). Rose Bengal targets serum albumin for findingabnormalities. Protirelin targets thyrotropin releasing hormone receptor, i.e.GPCRwhich activates intracellular signalingmolecules and respond regardingthe function of cells.Enlon and tensilon containing Edrophonium, are acetylcholinesteraseinhibitors. They detect muscle disorder referred as myasthenia gravis. Somemedications in surgical operations cause muscle contractions which canbe reversed by edrophonium. Acetylcholine in the body inhibits acetyl-cholinesterase by stimulating themuscarinic and nicotinic receptors (Caliandroet al., 2009).

1.1.1.2 Classification Based on Drug Action

Immune Response

The immune system is activated against pathogens to avoid disorders in the body.Longer presence of pathogens causes more damage. Immune response can be innateand adaptive. The innate part responds immediately to every pathogen and is non-specific. Adaptive part includes cells like antibodies, B cells and T cells that arespecific to the pathogen.

Some drugs are immuno suppressant and can be advantageous in organ trans-plantation where they reduce the probability of organ rejection. Immune responsivedrugs include cortisone, hydrocortisone, prednisone and triamcinolone (Demirkiranet al., 2009). Some drugs are immunostimulant which activate the immune system towork against pathogens (Rich et al., 2012). Immunosuppressants work by consumingbody healthy tissues and weaken the immune system while immuno stimulantsinduce pathogen-linked patterns recognized by the receptors for quick recovery.Cytokines (signaling channels of immune system) can also activate the immunesystem. Example of immune response is the histamine which reacts differently to

1 Introduction to Drugs, Drug Targets and Drug Resistance 9

an injury or infection. Mast cells and basophils produce histamine in response toinfection. Histamine enhances capillaries permeability to platelets and restrict someproteins to pathogens in the infected part. In injury, mast cells in injured part releasehistamine which broadens nearby blood vessels for enhanced permeability.

Protease Inhibitors

Protease inhibitors inhibit proteins cleavage to small peptide chains and thus areantiviral. The antiviral drugs block virus replication instead of destroying or deac-tivating the viruses by inhibiting the cleavage of proteins into peptides (Daniels &Nicoll, 2011). These proteins also contain virus, and the cleavage inhibition stopstheir replication. Some of the protease inhibitor antiviral drugs are atazanir, indivanir,ritonavir and fosamprevanir (Madruga et al., 2007).

Dihydropteroate Synthetase (DPHS) Inhibitors

DHPS enzyme assists the synthesis of dihydropteroate in bacteria. The anti-diabeticdrug (sulphonamide) binds with DHPS and inhibits this enzyme. DHPS enzyme isessential for the folate synthesis in bacteria. Inhibition of folate synthesis inhibitsthe amino acids synthesis which are crucial for bacterial functioning. Sulphonamidethus inhibits the reproduction of bacteria rather than killing them (Bauman, 2015).

1.1.1.3 Classification Based on Chemical Structure

Opioids

They include illegal drugs like heroin, synthetic opioids like fentanyl (50–100%morepotent than morphine and given in extreme pain conditions), and legally prescribedpain relievers such as oxycodone, hydrocodone, codeine, and morphine (Strømgaardet al., 2017). These drugs act on opioid receptors to produce morphine like effectsand relieve pain. Sometimes body becomes opioid tolerant due to internalization,downregulation, and desensitization of opioid receptors (Gudin, 2012).Opioid addic-tion must not be confused with opioid tolerance as both phenomena are different.Patients using opioids for non-cancer or cancer pain may become tolerant (Adesoye&Duncan, 2017). The homeostatic mechanisms of body counteract the effect of drugresulting in opioid tolerance. Opioids also include some abuse deterrent formulationswhich are given in Table 1.3.

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Table 1.3 Abuse deterrentOpioids (2015)

Brand name Generic name Abuse deterrentmechanism

Oxaydo Oxycodone Crush/extractionresistant

Zohydro ER Hydrocodone Crush/extractionresistant

Emdeda ER Morphine-naltrexone Agonist-antagonist

Troxyca ER Oxycodone-naltrexone Agonist-antagonist

Morpha bond Morphine Crush/extractionresistant

Xtampza ER Oxycodone Crush/extractionresistant

Hysingla ER Hydrocodone Crush/extractionresistant

Arymo ER Morphine Crush/extractionresistant

Opana ER Oxymorphone HCl Crush/extractionresistant

Er = Extended release, HCl = Hydrogen chloride

Alcohol

This class of drugs are antiseptic and used in many situations. Alcohol in the formof wine was initially prescribed to aid digestion, for the stimulation of appetite andas general tonic (Williams, 1980). However, it was banned in many countries dueto harmful effects (O’Connell et al., 2003). Epidemiological researches show thatalcohol is beneficial in moderate levels and prevents heart disease (Corrao et al.,2000), diabetes (Koppes et al., 2005) and stroke (Reynolds et al., 2003). Evidencefrom red wine suggests that antioxidants are responsible for its beneficial effects (StLeger, 1979). Later studies proved that alcohol modifies the fat content and bloodcoagulation factors (Rimm et al., 1996). The use of alcoholic medications varieswith age as risk factor must be considered in aged people because of physiologicalchanges occurring due to the prescribed and non-prescribed medicines (Aira et al.,2005).

Alcohol interacts with medicines and changes their effects. Even the moderatealcohol levels interfere the activity of a medicine (Tapert et al., 2002). Drug-alcoholinteractions can be explained as pharmacokinetic and pharmacodynamic interac-tions. The medication metabolism is harmed by the interference of alcohol andis termed as pharmacokinetic interaction. These interactions are observed in liveras the metabolism of both alcohol and drug occurs in liver by the same enzymes.Alcohol enhances the medication effects in some cases, specifically in CNS i.e. seda-tion (Carrière et al., 1996). Negative effects are observed when herbal medicines

1 Introduction to Drugs, Drug Targets and Drug Resistance 11

interact with alcohols. The drugs interacting with alcohols are e.g. muscle relax-ants, barbiturates, antidepressants, histamineH2 receptor antagonists, antihistamines,anti-inflammatory agents, opioids, and antibiotics (Weathermon & Crabb, 1999).

Benzodiazepines and Barbiturates

Benzodiazepines consist of fused diazepine and benzene rings. Benzodiazepines arepsychoactive drugs also termed as ‘benzos’ (Shorter, 2005). Benzodiazepines werethemost prescribedmedications in 1977 (Washton&Zweben, 2006). They belong toa group of medicines known as minor tranquilizer (Haverkampf, 2017). They workby increasing the gamma-aminobutyric acid (GABA, a neurotransmitter) effect atGABAA receptor which results in anxiolytic, hypnotic/sleep inducing, and musclerelaxant properties (Page, 2002). So, seizures, agitation, insomnia, muscle spasms,anxiety and the issues of alcohol withdrawal can be resolved by using benzodi-azepines. They can be the potential pre-medicines in medical and dental procedures(Olkkola & Ahonen, 2008). Benzodiazepines drugs are alprazolam, clorazepate,diazepam, lorazepam (Ativan), and chlordiazepoxide (Librium).

Barbiturates act as depressant in Central Nervous System and are active ashypnotics, anxiolytics, and anticonvulsants. Barbiturates are prescribed in clusterheadache/acute migraines, treatment of epilepsy and as general anesthesia (Vaux &Golder, 2003). Phenobarbital (a barbiturate medication) treats epilepsy, anxiety, andhypnotics. Sodium thiopental is a general anesthetic and primidone an anticonvul-sant (Johns, 1975). Barbiturates bind to GABA receptor as agonist and response isproduced.GABA is the inhibitory neuro receptor inCNSofmammalian cell. Barbitu-rates inhibit CNS by stimulating the inhibitory GABA receptor and cause depressionin CNS (Löscher & Rogawski, 2012). GABA is a chloride containing channel. WhenGABA binds to chloride, it alters the voltage in brain cells by increasing the numberof negative charges. Brain cells become resistant to nerve impulses and depress them.Sometimes barbiturates resistance is due to the enhanced p450 cytochrome contentwhich is followed by reduction in sleep (Chiara et al., 2013).

Cocaine and Other Stimulants

Cocaine is a stimulant employed as recreational drug. It enters the body by injection,snorting and smoking (Pomara et al., 2012). It exerts physical and mental disor-ders. Physical effects include large pupils, sweating and fast heart rate while mentalsymptoms include loss of agitation and restlessness (Harper & Jones, 2006). Highblood pressure and high body temperature is observed with the large dose. It medi-cally diminishes bleeding in nasal treatment and in numbing. Cocaine increases theamount of three neurotransmitters in brain cells. They are dopamine, serotonin, andnorepinephrine. Dopamine activates brain cells for muscle mobility and the mind to

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work faster (Kalivas &McFarland, 2003). Cocaine can cross by breaking the blood–brain barrier. It stops the uptake of these neurotransmitters and thus hampers CNS(Karch, 2009).

Sulfonamides

Sulfonamides known as sulfa drugs contain sulfonamide functional group. Theyare antibacterial (Henry, 1943) with antimalarial and antifungal properties and treatcough and allergies. Sulfonamide drugs include sulfadimethoxine (long-acting),sulfadimidine, sulfacetamide, sulfisomidine, sulfafurazole (short-acting), sulfani-tran, sulfamoxole, and sulfamethoxazole (intermediate-acting). Sulfonamides alsocontain a group of sulfonylyreas (anti-diabetic agents), diuretics, antiretrovirals, anddermatologicals (Pelet & Matheux, 2011). Sulfa drugs bind with DHPS and inhibitthis enzyme which is essential for folate synthesis in bacteria. Side effects of sulfadrugs are dizziness, headache, rash, folate deficiency, gastrointestinal disorders suchas diarrhea, stomach upset, vomiting and fatigue (Chung, 2016). Sulfa drugs can alsoaccelerate DHPS synthesis leading to the resistance of sulfonamides. This mecha-nism is mediated by the mutations in DHPS genes which can be isolated to explorethis mechanism (Zhang et al., 2009).

Amphetamines

Amphetamine is branded as Evekeo and used as a stimulant in CNS. The chemicalname of amphetamine is α-methylphenethylamine (Klee, 1997). It treats ADHD(attention deficit hyperactivity disorder), obesity and narcolepsy (Rasmussen, 2006).Amphetamine therapeutic effect in the form of euphoria and weakness. It improvesmuscle strength, fatigue resistance and reaction time (Carvalho et al., 2012). Sideeffects include nausea, increase in heart rate, blood pressure, abdominal crampsand vomiting (Adler et al., 2008). Primary mechanism for amphetamines is therelease of dopamine, serotonin and norepinephrine from nerve terminals (Biaggioni&Robertson, 2009).Abuse or unprescribed use of amphetamines disturb the reuptakeof neurotransmitters leading to amphetamine resistance.

1.1.1.4 Classification Based on Molecular Targets

Enzymes

Enzymes also termed as biological catalysts which speed up the biochemical reac-tions. They are proteins acting on substrate for conversion into products. Everymetabolic action requires enzyme for the fast completion (Buchner). Enzymaticstudy is referred as enzymology and pseudoenzyme analysis emphasizes enzymeswhich have lost activity in the evolutionary processes (Murphy et al., 2017). Their

1 Introduction to Drugs, Drug Targets and Drug Resistance 13

catalytic activity has been affected because of change in their amino acid sequence(Murphy et al., 2014).

(a) Protein KinasesThese enzymes cause phosphorylation by chemically adding phosphate groupsto proteins. Phosphorylation affects the enzyme activity which in turn altersthe function of target protein. About 500 protein kinases are found in humangenome (Manning et al., 2002). Plants and bacteria also contain kinases.Kinases may modify 30% of human proteins and regulate cellular pathways,especially the signal transduction. They remove phosphate moiety form ATPfollowed by its attachment to one of the three amino acids (Serine, Tyrosine andThreonine). Majority of kinases operate on threonine and serine while otherswork on tyrosine. Some kinases work on all three amino acids (Dhanasekaran& Reddy, 1998). Histidine residues are phosphorylated by histidine kinase(Besant et al., 2003).

(b) ProteasesProtease also termed as proteinase or peptidase, catalyzes the breakdown oflarge proteins into small peptide chains or in single amino acids. They performcleavage through hydrolysis (King et al., 2014). Proteases also have func-tions like ingested proteins digestion, cell signaling and proteins catabolism(Shen et al., 2006). Protease activates a nucleophile that attacks peptide carbonfollowed by the migration of electrons of C–O bond to oxygen. This produceshigh energy intermediate and protease stabilizes it by splitting into small chainpeptides (Berg et al., 2012).

(c) EsterasesEsterase is a hydrolase enzyme that converts ester into alcohol and acid viahydrolysis. Esterases have activity based on the nature of substrate, biologicalaction, and protein structure.

(d) PhosphatasePhosphatase detaches phosphate group or performs opposite to that of kinase.It splits phosphoric acid into alcohol and phosphate ion via hydrolysis. Asphosphatase catalyzes hydrolysis, it can be categorized as hydrolase. Phospho-rylation (by kinases) followed by dephosphorylation (by phosphatases) haverole in signaling and cellular regulation (Liberti et al., 2013). Phosphatasesare different from phosphorylases which are responsible for phosphate grouptransfer (from hydrogen phosphate) to acceptor.

Structural Proteins

These proteins develop protective capsid or capsule. They constitute cell shape,compose vertebral bone and cartilage in connective tissues. For example, tubulin viapolymerization forms long chains and assists the skeletal system.Tubulin after certainstructural changes formsmicrotubules that regulate transport in the cell (Jenkins et al.,2002).

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Membrane Transport Proteins

These proteins involve themovement ofmolecules, ions, macromolecules, andmicromolecules across the membrane. They are found in the cell and perform the functionof transport. Diffusion is also supported by these proteins. The binding of transportproteins to solutes bring them to one side of membrane and their release to otherend is accomplished by alteration in conformation of transport proteins (Medicine,2000).

Nucleic Acids

Macro biomolecules or biopolymers are referred as DNA or RNA. They consist ofnucleotides formed by the combination of 5-carbon sugar, nitrogenous base, and aphosphate group. DNA is formed in the presence of deoxyribose sugar and RNA inthe presence of ribose. DNA serves as the “life genetic code” for information storagewhile RNA is involved in proteins synthesis. Nucleic acids have the potential ofgenetic level cure to the diseases (Elson, 1965).

1.2 Receptors (Drug Targets)

Receptors are the protein molecules within or on the cell that recognize and bindwith ligands (e.g. hormones, chemical messenger substances or particular drugs) andregulate the cellular process (Currie, 2018). Drug-receptor interaction is importantin biological functions such as drug delivery, cell proliferation and immune response(Ma et al., 2018). Drug molecules upon interaction with receptor may activate orinactivate a receptor. Activation of receptor may enhance or diminish a biologicalfunction. Few drugs show specific binding with receptors and thus are selective.Selectivity is the ability of a drug to bind with specific receptor.

Potency of a drug is determined by its affinity and efficacy. The term affinityis the ability of drug to affect a receptor and intrinsic efficacy is the potential ofdrug-receptor complex to initiate a cellular process (Lambert, 2004). Drug mayact as agonist or antagonist based on the difference in efficacy. An agonist is adrug which activates receptor and produces functional response. The neurotrans-mitters (e.g. histamine, acetylcholine, and norepinephrine), hormones and drugs(e.g. phenylephrine, isoproterenol, and morphine) act as agonist. Antagonist is adrug which prevents receptor activation. Neutral antagonist prevents the action of anagonist. There are reversible and irreversible types of antagonists. Reversible formsweak bond and dissociates from receptor while irreversible makes stable chemicalbond with receptors. Antagonism can be competitive or non-competitive. In compet-itive antagonism, antagonist competes with agonist for the same binding site. Forexample, a competitive antagonist for all opioid receptors like morphine is naloxone.

1 Introduction to Drugs, Drug Targets and Drug Resistance 15

In non-competitive antagonism, simultaneous binding of both agonist and antagonistreduce the effect of agonist.

Alfred Joseph Clark proposed receptor theory which informs about drug receptorinteraction and cellular functions altered thereof. Rate of formation of drug-receptorcomplex is proportional to the dose of drug (Zhu, 1993).

Drug+Receptor � Drug-Receptor complex

Above equation is derived from Langmuir isotherm which shows effect of drugreceptor interaction on forward (k1) and backward (k2) reaction constants.

1.2.1 Types of Receptors

There are four types of receptors based on molecular structures.

1.2.1.1 Ion Channels

(a) Ligand Gated and Voltage GatedLigand gated ion channels are the pore like transmembrane proteins which bindwith ligands and change the permeability of cell membrane to provide gatewayfor selective ions to move across the membrane (Abdul Kadir, 2018). Theseare proteins spread around the membrane and are responsible for ions channelswhich can be categorized based on the cause of channel opening and closing.So, ion channels are either ligand-gated or voltage-gated. Opening and closingof voltage-gated channels correspond to variation in membrane potential. Acti-vation of this channel occurs in the presence of ligand and no other biologicalintermediates are involved. Sometimes amino acids side chains may block thepores. Binding of receptors to the extracellular part of channel causes confor-mational changes and opens the pore for flow of ions like calcium, sodium,chlorine, magnesium and hydrogen (Hanukoglu, 2017). Receptors activationunlocks the transmembrane ion channel and potential of the cell changes dueto flow of ions across the membrane and cause activation or prevention ofelectrical impulses. Examples of this channel include acetylcholine, GABAAreceptor, glycine, Glutamate and serotonin (Suvarna, 2011) (Fig. 1.1).

(b) G-protein Linked ReceptorsG protein-linked receptor also termed as heptahelical receptor binds withextracellular substances and activates intracellular molecule called G-protein(guanine nucleotide-binding protein), also referred as 7TM receptors (α-helices transmembrane receptors). There are various types of GPCRs—humangenome has 1000 types of encoded receptors. Theymediate responses to signalmolecules including amines, amino acids, neurotransmitters, lipids, hormones,

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Fig. 1.1 Ligand gated ion channel (Pacheco, 2007)

proteins, local mediators, and also to the derivatives of fatty acids and aminoacids (Gether, 2000). GPCRs are titled because of their binding ability andregulation of G protein activity. They also mediate the activities like kidneyfunction, immune response, visual control, tumorigenesis, and inflammation.In 2007, β2 adrenergic receptor was analyzed as first human GPCR. Its crystalstructure is similar to bovine rhodopsin (mammalian GPCR) discovered inyear 2000 (Strader et al., 1994). Many receptors are activated by the sameligand like adrenaline activates 9 GPCRs, acetylcholine 5 receptors and sero-tonin 15 receptors (Alberts et al., 2002). For example, epinephrine binds withbeta-adrenergic receptors of GPCRs, rhodopsin and prostaglandins which areinflammatory substances binding with prostaglandin E2 receptors.GPCRs are involved in two signal transduction mechanisms (Gilman, 1987).First is the Adenosine 3’,5’-cyclic monophosphate (cAMP), a nucleotidethat works as 2nd messenger and controls cellular actions like cell differ-entiation and growth, gene transcription followed by protein expression.In second mechanism, extracellular signal binds with receptor convertingphosphatidylinositol-(4, 5)-bisphosphate (PIP2) to two messengers (diacyl-glycerol), DAG and IP3 (inositol triphosphate) which produce the intracellularresponse from extracellular signal.

1 Introduction to Drugs, Drug Targets and Drug Resistance 17

GPCRs are important drug targets and 50%ofUSFDAapproved drugs are fromthis class (Nuez Veulens and Rodríguez, 2009). GPCRs work by GTP-GDPexchangewhereGPCRsbindGDP in inactive formonplasmamembrane insidethe cell. It binds GTP upon becoming active. Signal molecule attachment withGPCRs changes its shape and receptor gets activated for binding with inactiveG protein. Replacement of GDP with GTP activates G protein (Brass, 2003).GPCRs also control homeostasis. Brain depends on GPCRs for their prac-tical expression. Synaptic transmission mechanisms including major sensesare affected by the activation of relevant GPCRs (Oliveira et al., 1993). Newlyapproved drugs for psychiatric, metabolic, oncologic, neurodegenerative, andcardiovascular diseases are based on GPCR.

(c) Receptor Tyrosine Kinases (RTKs)Biochemical signalling pathways initiate through ligand binding with receptor.Insulin and other peptide growth factors adhere with receptor proteins havingC-terminal domains of tyrosine kinase activity. Receptor tyrosine kinases havesingle transmembrane segment and are monomers without ligand. Bindingof ligand to extracellular domain induces conformational change in intra-cellular domain. Mechanism for activation of RTKs seems dimerization ofreceptor proteins by ligand binding as with the growth hormone receptor.Insulin receptor however exists in dimer statewithout ligand and ligand bindinginduces structural change. Upon RTK dimer formation, its cytoplasmic proteintyrosine kinase (PTK) domains cross-phosphorylate on specific Tyr residues.Autophosphorylation triggers PTK to phosphorylate other protein substrates(Voet et al., 2013).

(d) Nuclear ReceptorsNuclear receptors are also known as steroid receptors. Ligand like estrogenbinds to receptor influencing the rate of transcription and translation of specificgenes to form cellular proteins. Steroid hormones are ligand activated for theregulation of gene expression. They bind to targetedDNAcomprised of specificgenes sequences for controlling functions like skin differentiation and devel-opment, behavioral brain centers, bone development and reproductive tissuesregulation (Kosztin et al., 1999).

Steroid hormones (such as cortisol, estrogen, and progesterone) are hydrophobicand do not readily dissolve in blood. They are transported through specific carrierproteins to their target site from point of synthesis. In target cells, these hormonescross plasma membranes through diffusion and bind to receptor proteins in thenucleus inducing conformational changes in receptor proteins. The receptors theninteractwith specific regulatory sequences inDNAcalledhormone response elements(HREs). Consequently, gene expression is altered. The receptor-hormone complexeither suppresses or enhances the expression of specific genes. The regulators takeeffect in hours or days resulting in alterations of RNA synthesis and consequentprotein synthesis is evident from altered metabolism (Nelson & Cox, 2009).

Nuclear receptors (NRs) also categorized as ligand-regulated transcription factorsare another class of therapeutic drug receptor target. The nuclear receptors act for

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biological ligands like lipids, fatty acids, and steroid hormones. Approved drugsfor nuclear receptors include steroidal contraceptives, anti-inflammatory glucocor-ticoids, lipid lowering agents, hormone replacement therapies and drugs related toestrogen and thyroid receptors (Kojetin & Burris, 2014). Until now 48 types of NRshad been recognized in humans (Kronenberger et al., 2015).

1.2.1.2 Functional Macromolecules

Drugs combine with targets like proteins and enzymes other than the specificreceptors. Proteins function in signaling pathways, subcellular transport, structuralstability, and translation. Proteins are the targets for drug action where they bind withlower molecular weight drug molecules (Makley & Gestwicki, 2013). Drugs inhibitenzymes by interacting receptors like Donepezil for inhibiting acetylcholinesterasewhich inactivates acetylcholine neurotransmitter for delaying the removal of amyloidplague and also cause symptomatic effect in Alzheimer’s disease (Colovic et al.,2013). Transport proteins transport endogenous compounds like drugs across epithe-lial barriers for therapeutic functions at the site of action. These proteins are the phar-macological targets in increasing drug absorption at target site. Transport proteinslike P-glycoprotein, apical sodium-dependent transporter and the peptide transporterpepT1 enhance bioactivity and the drug absorption (Swaan, 2003).

1.2.1.3 Four Phases of Pharmacokinetics

Pharmacokinetics is the study of drug in body which include four phases ofdrug absorption, distribution, metabolic changes, and excretion (ADME). Drugadministration is categorized into two groups.

(a) Enteral RouteEnteral administration delivers medication via gastrointestinal (GI) tract whereboth ends, mouth and the anus can be used. Enteral route involves esophagus,stomach, and gastrointestinal tract. Enteral administration can be oral (throughmouth), sublingual (under tongue), buccal (between gums and teeth) and rectal(into the rectum).

(b) Parental RouteParental route delivers compounds (food & drug) via intravenous (throughveins), subcutaneous (under the skin), intramuscular (through muscles),pulmonary (inhaled via lungs) and percutaneous (absorption via intact skin)(Kapalka, 2009).

Drug Absorption

Absorption is the process of transferring drug from its site of administration to bloodstream (Devadasu et al., 2018). Oral route is convenient and the common path of

1 Introduction to Drugs, Drug Targets and Drug Resistance 19

administeringmedication. Oral absorption involves two processes, (a) drug dissolvesin gastrointestinal fluid, and (b) dissolved drug goes into bloodstream throughintestinal walls. Absorption of oral drug encounters GI secretions like degradingenzymes and low pH which decrease the bioavailability of drug. Peptide drug (i.e.insulin) is thus not given orally as it is susceptible to degradation. The process iscontrolled by physiochemical properties of drugs like permeability and solubility.Oral absorption is a lengthy process and its efficacy depends on various steps (Lin& Wong, 2017). Other methods of drug absorption (inhalation, intravenous, intra-muscular) take few seconds to minutes. Absorption further depends on drug charac-teristics like molecular size, particle shape, physical form, concentration, chemicalnature, lipid solubility, concentration gradient and degree of ionization (Chillistone& Hardman, 2017).

Drug Distribution

Drug distributes to body tissues from blood stream. Drug distribution is controlled byphysiological factors which effect degree and rate of distribution. The rate is affectedby blood perfusion and degree by plasma protein binding, lipid solubility, pH-pKa ofdrug and tissue protein binding (Maheshwari et al., 2018). Cell membrane composedof phospholipids is the barrier in drug distribution across the cell. Hydrophobic drugs(lipid soluble) cross the barrier whereas movement of hydrophilic drugs depends onthe molecular size of drugs (Kelley et al., 2017).

Metabolism

Chemical alteration of pharmaceutical substances in the body is drug metabolism.Most drugs metabolize in liver as enzymes catalyze reactions including deamina-tion, N-dealkylation, alkyl chain oxidation, azo-link cleavage, glucuronide forma-tion and nitro-group reduction. These reactions help in drug excretion (Conney &Bubns, 1962). Rate of drug metabolism differs among patients because of variationsin drug interaction, genetic factors, and coexisting disorders. In 20–95% patients,genetic factors are responsible for variation in drug responses. Cytochrome P450 2C9(CYP2C9) enzyme metabolizes drugs like glipizide, losartan, warfarin, phenytoinand tolbutamide (Belle & Singh, 2008).

Elimination

Controlled removal of drug either as metabolite or as intact drug from the body isreferred as drug elimination. Excretion paths include bile, urine, sweat, tears, andsaliva. Excretion is mostly carried out by liver and kidney. Hydrophilic or polar drugsexcrete by kidneys while hydrophobic ones undergo biotransformation (primary siteof biotransformation is liver) before excretion (Garza et al., 2019). Factors affecting

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Kidneys An�bio�cs,

Beta blockers, Diure�cs, and

Cime�dine Lungs

Volatile drugs like gaseous Anesthetics and Alcohol

Saliva Caffeine, Iodide, Phenytoin and Theophylline

Milk Antibiotics and Morphine Intestine

Laxative

Skin Benzoic acid, Salicylic acid, Heavy metals (Pb,Hg & As)

Bile Phenobarbitone.

Hairs Methoxyphenamine

Elimination routes

Fig. 1.2 Excretion routes

excretion through kidneys involve kidney function, glomerular filtration rate, urinepH, protein binding and urine flow (Fig. 1.2).

1.2.1.4 Drug-Drug Interactions (DDIs)

Drug interaction is defined as change in pharmacodynamic effect of one drug due tointeraction with another. Two or more drugs taken together change the efficiency orpotency of one drug modified due to the presence of another drug. These interactionscan enhance or diminish the effect of either drug. Adverse drug interactions causepatient morbidity, increased malpractice claims and medical costs (Goldberg et al.,1996). Concomitant intake of drugs increases the chance of drugs interaction. Factorscontributing in drug interactions aremultiple drug therapy, poor patient compliances,patient’s age, drug related factors, multiple diseases, multiple prescribers and somesocial factors (alcohol intake) (Alomar, 2014). Favorable interactions enhance drugeffectiveness allowing the use of small doses and reducing the chance of severeaction. Unfavorable interactions produce toxic effects on body (Baxter & Preston,