KD Tripathi Pharmacology Book PDF

SECTION 1 GENERAL PHARMACOLOGICAL PRINCIPLES Chapter 1 Introduction, Routes of Drug Administration INTRODUCTION a vast variety of highly potent and selective new drugs have...

SECTION 1 GENERAL PHARMACOLOGICAL PRINCIPLES Chapter 1 Introduction, Routes of Drug Administration INTRODUCTION a vast variety of highly potent and selective new drugs have been developed. The mechanism of Pharmacology action including molecular target of many drugs Pharmacology is the science of drugs (Greek: has been elucidated. This has been possible due Pharmacon—drug; logos—discourse in). In a to prolific growth of pharmacology which forms broad sense, it deals with interaction of exo- the backbone of rational therapeutics. genously administered chemical molecules with The two main divisions of pharmacology are living systems, or any single chemical substance pharmacodynamics and pharmacokinetics. which can produce a biological response is a ‘drug’. It encompasses all aspects of knowledge Pharmacodynamics (Greek: dynamis—power) about drugs, but most importantly those that are —What the drug does to the body. relevant to effective and safe use for medicinal This includes physiological and biochemical purposes. effects of drugs and their mechanism of action For thousands of years most drugs were crude at organ system/subcellular/macromolecular natural products of unknown composition and levels, e.g.—Adrenaline → interaction with adre- limited efficacy. Only the overt effects of these noceptors → G-protein mediated stimulation of substances on the body were rather imprecisely cell membrane bound adenylyl cyclase → increa- known, but how the same were produced was sed intracellular cyclic 3´,5´AMP → cardiac stimu- entirely unknown. Pharmacology as an experi- lation, hepatic glycogenolysis and hyperglycaemia, etc. mental science was ushered by Rudolf Buchheim who founded the first institute of pharmacology Pharmacokinetics (Greek: Kinesis—move- in 1847 in Germany. In the later part of the 19th ment)—What the body does to the drug. century, Oswald Schmiedeberg, regarded as the This refers to movement of the drug in and altera- ‘father of pharmacology’, together with his many tion of the drug by the body; includes absorption, disciples like J Langley, T Frazer, P Ehrlich, AJ distribution, binding/localization/storage, bio- Clark, JJ Abel propounded some of the fundamen- transformation and excretion of the drug, e.g. tal concepts in pharmacology. Since then drugs paracetamol is rapidly and almost completely have been purified, chemically characterized and absorbed orally attaining peak blood levels at 2 GENERAL PHARMACOLOGY 30–60 min; 25% bound to plasma proteins, widely Chemotherapy It is the treatment of systemic and almost uniformly distributed in the body infection/malignancy with specific drugs that have (volume of distribution ~ 1L/kg); extensively selective toxicity for the infecting organism/ SECTION 1 metabolized in the liver, primarily by glucuronide malignant cell with no/minimal effects on the host and sulfate conjugation into inactive metabolites cells. which are excreted in urine; has a plasma half life (t½) of 2–3 hours and a clearance value of Drugs in general, can thus be divided into: 5 ml/kg/min. Pharmacodynamic agents These are designed to have pharmacodynamic effects in the recipient. Drug (French: Drogue—a dry herb) It is the single active chemical entity present in a medicine Chemotherapeutic agents These are designed that is used for diagnosis, prevention, treatment/ to inhibit/kill invading parasite/malignant cell and cure of a disease. This disease oriented definition have no/minimal pharmacodynamic effects in the of drug does not include contraceptives or use recipient. of drugs for improvement of health. The WHO Pharmacy It is the art and science of compoun- (1966) has given a more comprehensive definition—“Drug is any substance or product ding and dispensing drugs or preparing suitable that is used or is intended to be used to modify dosage forms for administration of drugs to man or explore physiological systems or pathological or animals. It includes collection, identification, states for the benefit of the recipient.” purification, isolation, synthesis, standardization and quality control of medicinal substances. The The term ‘drugs’ is being also used to mean large scale manufacture of drugs is called Phar- addictive/abused/illicit substances. However, this maceutics. It is primarily a technological science. restricted and derogatory sense usage is unfor- tunate degradation of a time honoured term, and Toxicology It is the study of poisonous effect ‘drug’ should refer to a substance that has some of drugs and other chemicals (household, environ- therapeutic/diagnostic application. mental pollutant, industrial, agricultural, homi- Some other important aspects of pharmacology cidal) with emphasis on detection, prevention and are: treatment of poisonings. It also includes the study of adverse effects of drugs, since the same Pharmacotherapeutics It is the application substance can be a drug or a poison, depending of pharmacological information together with on the dose. knowledge of the disease for its prevention, mitigation or cure. Selection of the most appro- priate drug, dosage and duration of treatment DRUG NOMENCLATURE taking into account the specific features of a A drug generally has three categories of names: patient are a part of pharmacotherapeutics. (a) Chemical name It describes the substance Clinical pharmacology It is the scientific chemically, e.g. 1-(Isopropylamino)-3-(1-napht- study of drugs (both old and new) in man. It hyloxy) propan-2-ol for propranolol. This is includes pharmacodynamic and pharmacokinetic cumbersome and not suitable for use in investigation in healthy volunteers and in patients; prescribing. A code name, e.g. RO 15-1788 (later evaluation of efficacy and safety of drugs and named flumazenil) may be assigned by the comparative trials with other forms of treatment; manufacturer for convenience and simplicity surveillance of patterns of drug use, adverse before an approved name is coined. effects, etc. The aim of clinical pharmacology is to (b) Non-proprietary name It is the name accep- generate data for optimum use of drugs and the ted by a competent scientific body/authority, e.g. practice of ‘evidence based medicine’. the United States Adopted Name (USAN) by the  INTRODUCTION, ROUTES OF DRUG ADMINISTRATION 3 USAN council. Similarly, there is the British However, when it is important to ensure Approved name (BAN) of a drug. The non- consistency of the product in terms of quality proprietary names of newer drugs are kept uniform and bioavailability, etc. and especially when CHAPTER 1 by an agreement to use the Recommended official control over quality of manufactured International Nonproprietary Name (rINN) in all products is not rigorous, it is better to prescribe member countries of the WHO. The BAN of older by the dependable brand name. drugs as well has now been modified to be commensurate with rINN. However, many older DRUG COMPENDIA drugs still have more than one non-proprietary These are compilations of information on drugs names, e.g. ‘meperidine’ and ‘pethidine’ or in the form of monographs; without going into ‘lidocaine’ and ‘lignocaine’ for the same drugs. the theoretical concepts, mechanisms of action Until the drug is included in a pharmacopoeia, the and other aspects which help in understanding nonproprietary name may also be called the the subject. Pharmacopoeias and Formularies are approved name. After its appearance in the official broughtout by the Government in a country, hold publication, it becomes the official name. legal status and are called official compendia. In common parlance, the term generic name In addition, some non-official compendia are is used in place of nonproprietary name. Etymolo- published by professional bodies, which are gically this is incorrect: ‘generic’ should be applied supplementary and dependable sources of to the chemical or pharmacological group (or information about drugs. genus) of the compound, e.g. phenothiazines, tricyclic antidepressants, aminoglycoside antibio- Pharmacopoeias They contain description of tics, etc. However, this misnomer is widely chemical structure, molecular weight, physical and accepted and used even in official parlance. chemical characteristics, solubility, identification and assay methods, standards of purity, storage (c) Proprietary (Brand) name It is the name conditions and dosage forms of officially approved assigned by the manufacturer(s) and is his property drugs in a country. They are useful to drug or trade mark. One drug may have multiple pro- manufacturers and regulatory authorities, but not prietary names, e.g. ALTOL, ATCARDIL, ATECOR, to doctors, most of whom never see a ATEN, BETACARD, LONOL, TENOLOL, TENORMIN for pharmacopoeia. Examples are Indian (IP), British atenolol from different manufacturers. Brand (BP), European (Eur P), United States (USP) names are designed to be catchy, short, easy to pharmacopoeias. remember and often suggestive, e.g. LOPRESOR suggesting drug for lowering blood pressure. Brand Formularies Generally produced in easily names generally differ in different countries, e.g. carried booklet form, they list indications, dose, timolol maleate eye drops are marketed as TIMOPTIC dosage forms, contraindications, precautions, in USA but as GLUCOMOL in India. Even the adverse effects and storage of selected drugs that same manufacturer may market the same drug are available for medicinal use in a country. Drugs under different brand names in different countries. are categorized by their therapeutic class. Some In addition, combined formulations have their own rational fixed-dose drug combinations are multiple brand names. This is responsible for much included. A brief commentary on the drug class confusion in drug nomenclature. and clinical conditions in which they are used There are many arguments for using the generally preceeds specifics of individual drugs. nonproprietary name in prescribing: uniformity, Brief guidelines for treatment of selected convenience, economy and better comprehension conditions are provided. While British National (propranolol, sotalol, timolol, pindolol, Formulary (BNF) also lists brand names metoprolol, acebutolol, atenolol are all β blockers, with costs, the National Formulary of India (NFI) but their brand names have no such similarity). does not include these. Most formularies have 4 GENERAL PHARMACOLOGY informative appendices as well. Formularies can (b) It should be available in a form in which quality, including be considerably helpful to prescribers. bioavailability, and stability on storage can be assured. (c) Its choice should depend upon pattern of prevalent Martindale: The Complete Drug Reference diseases; availability of facilities and trained personnel; SECTION 1 financial resources; genetic, demographic and environmental (Extrapharmacopoeia) Published every 2–3 factors. years by the Royal Pharmaceutical Society of Great (d) In case of two or more similar medicines, choice should Britain, this non-official compendium is an be made on the basis of their relative efficacy, safety, quality, exhaustive and updated compilation of unbiased price and availability. Cost-benefit ratio should be a major consideration. information on medicines used/registered all over (e) Choice may also be influenced by comparative pharma- the world. It includes new launches and contains cokinetic properties and local facilities for manufacture and pharmaceutical, pharmacological as well as storage. therapeutic information on drugs, which can serve (f) Most essential medicines should be single compounds. Fixed ratio combination products should be included only as a reliable reference book. when dosage of each ingradient meets the requirements of Physicians Desk Reference (PDR) and Drug: a defined population group, and when the combination has a proven advantage in therapeutic effect, safety, adherence Facts and Comparisons (both from USA), etc. or in decreasing the emergence of drug resistance. are other useful non-official compendia. (g) Selection of essential medicines should be a continuous process which should take into account the changing priorities for public health action, epidemiological conditions as well ESSENTIAL MEDICINES (DRUGS) as availability of better medicines/formulations and progress CONCEPT in pharmacological knowledge. (h) Recently, it has been emphasized to select essential The WHO has defined Essential Medicines medicines based on rationally developed treatment guidelines. (drugs) as “those that satisfy the priority healthcare To guide the member countries, the WHO needs of the population. They are selected with brought out its first Model List of Essential Drugs due regard to public health relevance, evidence along with their dosage forms and strengths in on efficacy and safety, and comparative cost 1977 which could be adopted after suitable effectiveness. Essential medicines are intended modifications according to local needs. This has to be available within the context of functioning been revised from time to time and the current health systems at all times and in adequate is the 17th list (2011). India produced its National amounts, in appropriate dosage forms, with Essential Drugs List in 1996 and has revised assured quality and adequate information, and at it in 2011 with the title “National List of Essential a price the individual and the community can Medicines”. This includes 348 medicines which afford. are considered to be adequate to meet the priority It has been realized that only a handful of healthcare needs of the general population of the medicines out of the multitude available can meet country. An alphabetical compilation of the WHO the health care needs of majority of the people as well as National essential medicines is presented in any country, and that many well tested and as Appendix-2. cheaper medicines are equally (or more) Adoption of the essential medicines list for efficacious and safe as their newer more expensive procurement and supply of medicines, especially congeners. For optimum utilization of resources, in the public sector healthcare system, has resulted in improved availability of medicines, cost saving governments (especially in developing countries) and more rational use of drugs. should concentrate on these medicines by identifying them as Essential medicines. The Prescription and non-prescription drugs WHO has laid down criteria to guide selection As per drug rules, majority of drugs including of an essential medicine. all antibiotics must be sold in retail only against (a) Adequate data on its efficacy and safety should be available a prescription issued to a patient by a registered from clinical studies. medical practitioner. These are called ‘prescription  INTRODUCTION, ROUTES OF DRUG ADMINISTRATION 5 drugs’, and in India they have been placed in LOCAL ROUTES the schedule H of the Drugs and Cosmetic Rules These routes can only be used for localized lesions (1945) as amended from time to time. However, at accessible sites and for drugs whose systemic CHAPTER 1 few drugs like simple analgesics (paracetamol absorption from these sites is minimal or absent. aspirin), antacids, laxatives (senna, lactulose), Thus, high concentrations are attained at the vitamins, ferrous salts, etc. are considered relatively desired site without exposing the rest of the body. harmless, and can be procured without a Systemic side effects or toxicity are consequently prescription. These are ‘non-prescription’ or ‘over- absent or minimal. For drugs (in suitable dosage the-counter’ (OTC) drugs; can be sold even by forms) that are absorbed from these sites/routes, grocery stores. the same can serve as systemic route of adminis- Orphan Drugs These are drugs or biological products tration, e.g. glyceryl trinitrate (GTN) applied on for diagnosis/treatment/ prevention of a rare disease or the skin as ointment or transdermal patch. The condition, or a more common disease (endemic only in resource poor countries) for which there is no reasonable local routes are: expectation that the cost of developing and marketing it will 1. Topical This refers to external application be recovered from the sales of that drug. The list includes of the drug to the surface for localized action. It sodium nitrite, fomepizole, liposomal amphotericin B, miltefosine, rifabutin, succimer, somatropin, digoxin immune is often more convenient as well as encouraging Fab (digoxin antibody), liothyronine (T3) and many more. to the patient. Drugs can be efficiently delivered Though these drugs may be life saving for some patients, to the localized lesions on skin, oropharyngeal/ they are commercially difficult to obtain as a medicinal nasal mucosa, eyes, ear canal, anal canal or vagina product. Governments in developed countries offer tax benefits and other incentives to pharmaceutical companies for in the form of lotion, ointment, cream, powder, developing and marketing orphan drugs (e.g. Orphan Drug rinse, paints, drops, spray, lozengens, suppositories Act in USA). or pesseries. Nonabsorbable drugs given orally for action on g.i. mucosa (sucralfate, vancomycin), ROUTES OF DRUG ADMINISTRATION inhalation of drugs for action on bronchi (salbutamol, cromolyn sodium) and irrigating Most drugs can be administered by a variety of solutions/jellys (povidone iodine, lidocaine) routes. The choice of appropriate route in a given applied to urethra are other forms of topical situation depends both on drug as well as patient medication. related factors. Mostly common sense consi- 2. Deeper tissues Certain deep areas can be derations, feasibility and convenience dictate the approached by using a syringe and needle, but route to be used. the drug should be in such a form that systemic Routes can be broadly divided into those for absorption is slow, e.g. intra-articular injection (a) Local action and (b) Systemic action. (hydrocortisone acetate in knee joint), infiltration Factors governing choice of route around a nerve or intrathecal injection (lidocaine), retrobulbar injection (hydrocortisone acetate 1. Physical and chemical properties of the drug (solid/ behind the eyeball). liquid/gas; solubility, stability, pH, irritancy). 2. Site of desired action—localized and approach- 3. Arterial supply Close intra-arterial injec- able or generalized and not approachable. tion is used for contrast media in angiography; 3. Rate and extent of absorption of the drug from anticancer drugs can be infused in femoral or different routes. brachial artery to localise the effect for limb 4. Effect of digestive juices and first pass metabolism on the drug. malignancies. 5. Rapidity with which the response is desired (routine treatment or emergency). SYSTEMIC ROUTES 6. Accuracy of dosage required (i.v. and inhalational can provide fine tuning). The drug administered through systemic routes 7. Condition of the patient (unconscious, vomiting). is intended to be absorbed into the blood stream 6 GENERAL PHARMACOLOGY and distributed all over, including the site of action, inconvenient and embarrassing; absorption is through circulation (see Fig. 1.1). slower, irregular and often unpredictable, though diazepam solution and paracetamol suppository 1. Oral SECTION 1 are rapidly and dependably absorbed from the Oral ingestion is the oldest and commonest mode rectum in children. Drug absorbed into external of drug administration. It is safer, more convenient, haemorrhoidal veins (about 50%) bypasses liver, does not need assistance, noninvasive, often but not that absorbed into internal haemorrhoidal painless, the medicament need not be sterile and veins. Rectal inflammation can result from irritant so is cheaper. Both solid dosage forms (powders, drugs. Diazepam, indomethacin, paracetamol, tablets, capsules, spansules, dragees, moulded ergotamine and few other drugs are some times tablets, gastrointestinal therapeutic systems— given rectally. GITs) and liquid dosage forms (elixirs, syrups, emulsions, mixtures) can be given orally. 4. Cutaneous Highly lipid soluble drugs can be applied over Limitations of oral route of administration the skin for slow and prolonged absorption. The Action of drugs is slower and thus not suitable for liver is also bypassed. The drug can be incorpo- emergencies. rated in an ointment and applied over specified Unpalatable drugs (chloramphenicol) are difficult to administer; drug may be filled in capsules to area of skin. Absorption of the drug can be circumvent this. enhanced by rubbing the preparation, by using May cause nausea and vomiting (emetine). an oily base and by an occlusive dressing. Cannot be used for uncooperative/unconscious/ vomiting patient. Transdermal therapeutic systems (TTS) Absorption of drugs may be variable and erratic; These are devices in the form of adhesive patches certain drugs are not absorbed (streptomycin). Others are destroyed by digestive juices (penicillin G, of various shapes and sizes (5–20 cm2) which insulin) or in liver (GTN, testosterone, lidocaine). deliver the contained drug at a constant rate into systemic circulation via the stratum corneum (Fig. 2. Sublingual (s.l.) or buccal 1.2). The drug (in solution or bound to a polymer) The tablet or pellet containing the drug is placed is held in a reservoir between an occlusive backing under the tongue or crushed in the mouth and film and a rate controlling micropore membrane, spread over the buccal mucosa. Only lipid soluble the under surface of which is smeared with an and non-irritating drugs can be so administered. adhesive impregnated with priming dose of the Absorption is relatively rapid—action can be pro- drug. The adhesive layer is protected by another duced in minutes. Though it is somewhat incon- film that is to be peeled off just before applica- venient, one can spit the drug after the desired tion. The drug is delivered at the skin surface effect has been obtained. The chief advantage by diffusion for percutaneous absorption into is that liver is bypassed and drugs with high first circulation. The micropore membrane is such that pass metabolism can be absorbed directly into rate of drug delivery to skin surface is less than systemic circulation. Drugs given sublingually the slowest rate of absorption from the skin. This are—GTN, buprenorphine, desamino-oxytocin. offsets any variation in the rate of absorption according to the properties of different sites. As 3. Rectal such, the drug is delivered at a constant and Certain irritant and unpleasant drugs can be put predictable rate irrespective of site of application. into rectum as suppositories or retention enema Usually chest, abdomen, upper arm, lower back, for systemic effect. This route can also be buttock or mastoid region are utilized. used when the patient is having recurrent vomiting Transdermal patches of GTN, fentanyl, or is unconscious. However, it is rather nicotine and estradiol are available in India, while  INTRODUCTION, ROUTES OF DRUG ADMINISTRATION 7 CHAPTER 1 Fig. 1.1: Vascular pathway of drugs absorbed from various systemic routes of administration and sites of first pass metabolism Note: Total drug absorbed orally is subjected to first pass metabolism in intestinal wall and liver, while approximately half of that absorbed from rectum passes through liver. Drug entering from any systemic route is exposed to first pass metabolism in lungs, but its extent is minor for most drugs. 8 GENERAL PHARMACOLOGY drugs like insulin, as well as to bypass the blood- brain barrier. 7. Parenteral SECTION 1 (Par—beyond, enteral—intestinal) Conventionally, parenteral refers to administration by injection which takes the drug directly into the tissue fluid or blood without having to cross the enteral mucosa. The limitations of oral administration are circumvented. Fig. 1.2: Illustration of a transdermal drug delivery system Drug action is faster and surer (valuable in emergencies). Gastric irritation and vomiting are those of isosorbide dinitrate, hyoscine, and not provoked. Parenteral routes can be employed clonidine are marketed elsewhere. For different even in unconscious, uncooperative or vomiting drugs, TTS have been designed to last for patient. There are no chances of interference by 1–3 days. Though more expensive, they provide food or digestive juices. Liver is bypassed. smooth plasma concentrations of the drug without Disadvantages of parenteral routes are—the fluctuations; minimize interindividual variations preparation has to be sterilized and is costlier, (drug is subjected to little first pass metabolism) the technique is invasive and painful, assistance and side effects. They are also more convenient— of another person is mostly needed (though self many patients prefer transdermal patches to oral injection is possible, e.g. insulin by diabetics), tablets of the same drug; patient compliance is there are chances of local tissue injury and, in better. Local irritation and erythema occurs in general, parenteral route is more risky than oral. some, but is generally mild; can be minimized The important parenteral routes are: by changing the site of application each time by rotation. Discontinuation has been necessary in (i) Subcutaneous (s.c.) The drug is deposited 2–7% cases. in the loose subcutaneous tissue which is richly supplied by nerves (irritant drugs cannot be 5. Inhalation injected) but is less vascular (absorption is slower Volatile liquids and gases are given by inhalation than intramuscular). Only small volumes can be for systemic action, e.g. general anaesthetics. injected s.c. Self-injection is possible because deep Absorption takes place from the vast surface of penetration is not needed. This route should be alveoli—action is very rapid. When administra- avoided in shock patients who are vasocons- tion is discontinued the drug diffuses back and tricted—absorption will be delayed. Repository is rapidly eliminated in expired air. Thus, control- (depot) preparations that are aqueous suspensions led administration is possible with moment to can be injected for prolonged action. Some special moment adjustment. Irritant vapours (ether) cause forms of this route are: inflammation of respiratory tract and increase (a) Dermojet In this method needle is not used; secretion. a high velocity jet of drug solution is projected 6. Nasal from a microfine orifice using a gun like imple- The mucous membrane of the nose can readily ment. The solution passes through the superficial absorb many drugs; digestive juices and liver are layers and gets deposited in the subcutaneous bypassed. However, only certain drugs like GnRH tissue. It is essentially painless and suited for mass agonists and desmopressin applied as a spray or inoculations. nebulized solution have been used by this route. (b) Pellet implantation The drug in the form This route is being tried for some other peptide of a solid pellet is introduced with a trochar and  INTRODUCTION, ROUTES OF DRUG ADMINISTRATION 9 cannula. This provides sustained release of the drug reaches directly into the blood stream and drug over weeks and months, e.g. DOCA, effects are produced immediately (great value in testosterone. emergency). The intima of veins is insensitive CHAPTER 1 (c) Sialistic (nonbiodegradable) and bio- and drug gets diluted with blood, therefore, even degradable implants Crystalline drug is highly irritant drugs can be injected i.v., but hazards packed in tubes or capsules made of suitable are—thrombophlebitis of the injected vein and materials and implanted under the skin. Slow and necrosis of adjoining tissues if extravasation occurs. uniform leaching of the drug occurs over months These complications can be minimized by diluting providing constant blood levels. The nonbio- the drug or injecting it into a running i.v. line. degradable implant has to be removed later on Only aqueous solutions (not suspensions, because but not the biodegradable one. This has been tried drug particles can cause embolism) are to be for hormones and contraceptives (e.g. NORPLANT). injected i.v. and there are no depot preparations for this route. Chances of causing air embolism (ii) Intramuscular (i.m.) The drug is injected is another risk. The dose of the drug required in one of the large skeletal muscles—deltoid, is smallest (bioavailability is 100%) and even large triceps, gluteus maximus, rectus femoris, etc. volumes can be infused. One big advantage with Muscle is less richly supplied with sensory nerves (mild irritants can be injected) and is more this route is—in case response is accurately measur- vascular (absorption of drugs in aqueous solution able (e.g. BP) and the drug short acting (e.g. is faster). It is less painful, but self injection is sodium nitroprusside), titration of the dose with often impracticable because deep penetration is the response is possible. However, this is the most needed. Depot preparations (oily solutions, risky route—vital organs like heart, brain, etc. aqueous suspensions) can be injected by this route. get exposed to high concentrations of the drug. Intramuscular injections should be avoided in (iv) Intradermal injection The drug is anticoagulant treated patients, because it can injected into the skin raising a bleb (e.g. BCG produce local haematoma. vaccine, sensitivity testing) or scarring/multiple (iii) Intravenous (i.v.) The drug is injected puncture of the epidermis through a drop of the as a bolus (Greek: bolos–lump) or infused slowly drug is done. This route is employed for specific over hours in one of the superficial veins. The purposes only. ) PROBLEM DIRECTED STUDY 1.1. A 5-year-old child is brought to the hospital with the complaint of fever, cough, breathlessness and chest pain. On examination he is found to be dull, but irritable with fast pulse (116/min), rapid breathing (RR 50/min) and indrawing of lower chest during inspiration, wheezing, crepitations and mild dehydration. Body temperature is 40°C (104°F). The paediatrician makes a provisional diagnosis of acute pneumonia and orders relevant haematological as well as bacteriological investig- ations. He decides to institute antibiotic therapy. (a) In case he selects an antibiotic which can be given orally as well as by i.m. or i.v. injection, which route of administration will be most appropriate in this case? (b) Should the paediatrician administer the antibiotic straight away or should he wait for the laboratory reports? (see Appendix-1 for solution)  Chapter 2 Pharmacokinetics: Membrane Transport, Absorption and Distribution of Drugs Pharmacokinetics is the quantitative study of drug group of cholesterol) of these are oriented at the movement in, through and out of the body. The two surfaces and the nonpolar hydrocarbon chains overall scheme of pharmacokinetic processes is are embedded in the matrix to form a continuous depicted in Fig. 2.1. The intensity of response sheet. This imparts high electrical resistance is related to concentration of the drug at the site and relative impermeability to the membrane. of action, which in turn is dependent on its Extrinsic and intrinsic protein molecules are pharmacokinetic properties. Pharmacokinetic adsorbed on the lipid bilayer (Fig. 2.2). Glyco- considerations, therefore, determine the route(s) proteins or glycolipids are formed on the surface of administration, dose, latency of onset, time by attachment to polymeric sugars, aminosugars of peak action, duration of action and frequency or sialic acids. The specific lipid and protein of administration of a drug. composition of different membranes differs All pharmacokinetic processes involve trans- according to the cell or the organelle type. The port of the drug across biological membranes. proteins are able to freely float through the membrane: associate and organize or vice versa. Biological membrane This is a bilayer (about Some of the intrinsic ones, which extend through 100 Å thick) of phospholipid and cholesterol the full thickness of the membrane, surround fine molecules, the polar groups (glyceryl phosphate aqueous pores. Paracellular spaces or channels attached to ethanolamine/choline or hydroxyl also exist between certain epithelial/endothelial Fig. 2.1: Schematic depiction of pharmacokinetic processes  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 11 CHAPTER 2 Fig. 2.2: Illustration of the organisation of biological membrane cells. Other adsorbed proteins have enzymatic, Fig. 2.3: Illustration of passive diffusion and filtration across the lipoidal biological membrane with aqueous carrier, receptor or signal transduction properties. pores Lipid molecules also are capable of lateral move- ment. Thus, biological membranes are highly ionized at acidic as well as alkaline pH). The dynamic structures. ionization of a weak acid HA is given by the Drugs are transported across the membranes by: equation: (a) Passive diffusion and filtration [A¯ ] (b) Specialized transport pH = pKa + log —–—...(1) [HA] Passive diffusion The drug diffuses across the membrane in the pKa is the negative logarithm of acidic disso- direction of its concentration gradient, the ciation constant of the weak electrolyte. If the membrane playing no active role in the process. concentration of ionized drug [A¯ ] is equal to This is the most important mechanism for majority concentration of unionized drug [HA], then of drugs; drugs are foreign substances [A¯ ] (xenobiotics), and specialized mechanisms are —–— = 1 [HA] developed by the body primarily for normal metabolites. since log 1 is 0, under this condition Lipid soluble drugs diffuse by dissolving in pH = pKa...(2) the lipoidal matrix of the membrane (Fig. 2.3), Thus, pKa is numerically equal to the pH at which the rate of transport being proportional to the the drug is 50% ionized. lipid : water partition coefficient of the drug. A more lipid-soluble drug attains higher concentra- If pH is increased by 1 scale, then— tion in the membrane and diffuses quickly. Also, log [A¯ ]/[HA] = 1 or [A¯ ]/[HA] = 10 greater the difference in the concentration of the drug on the two sides of the membrane, faster Similarly, if pH is reduced by 1 scale, then— is its diffusion. [A¯ ]/[HA] = 1/10 Influence of pH Most drugs are weak electro- Thus, weakly acidic drugs, which form salts lytes, i.e. their ionization is pH dependent (contrast with cations, e.g. sod. phenobarbitone, sod. strong electrolytes that are nearly completely sulfadiazine, pot. penicillin-V, etc. ionize more at 12 GENERAL PHARMACOLOGY alkaline pH and 1 scale change in pH causes 10 Lipid-soluble nonelectrolytes (e.g. ethanol, fold change in ionization. diethyl-ether) readily cross biological membranes Weakly basic drugs, which form salts with and their transport is pH independent. SECTION 1 anions, e.g. atropine sulfate, ephedrine HCl, chloroquine phosphate, etc. conversely ionize Filtration more at acidic pH. Ions being lipid insoluble, Filtration is passage of drugs through aqueous do not diffuse and a pH difference across a pores in the membrane or through paracellular membrane can cause differential distribution of spaces. This can be accelerated if hydrodynamic weakly acidic and weakly basic drugs on the two flow of the solvent is occurring under hydrostatic sides (Fig. 2.4). or osmotic pressure gradient, e.g. across most capillaries including glomeruli. Lipid-insoluble drugs cross biological membranes by filtration if their molecular size is smaller than the diameter of the pores (Fig. 2.3). Majority of cells (intestinal mucosa, RBC, etc.) have very small pores (4 Å) and drugs with MW > 100 or 200 are not able to penetrate. However, capillaries (except those in brain) have large paracellular spaces (40 Å) and most drugs (even albumin) can filter through these (Fig. 2.8). As such, diffusion of drugs across capillaries is dependent on rate of blood flow through them rather than on lipid solubility of Fig. 2.4: Influence of pH difference on two sides of a the drug or pH of the medium. biological membrane on the steady-state distribution of a weakly acidic drug with pKa = 6 Specialized transport Implications of this consideration are: This can be carrier mediated or by pinocytosis. (a) Acidic drugs, e.g. aspirin (pKa 3.5) are largely Carrier transport unionized at acid gastric pH and are absorbed All cell membranes express a host of transmem- from stomach, while bases, e.g. atropine (pKa 10) are largely ionized and are absorbed only brane proteins which serve as carriers or when they reach the intestines. transporters for physiologically important ions, (b) The unionized form of acidic drugs which nutrients, metabolites, transmitters, etc. across the crosses the surface membrane of gastric mucosal membrane. At some sites, certain transporters also cell, reverts to the ionized form within the cell translocate xenobiotics, including drugs and their (pH 7.0) and then only slowly passes to the metabolites. In contrast to channels, which open extracellular fluid. This is called ion trapping, for a finite time and allow passage of specific i.e. a weak electrolyte crossing a membrane to ions, transporters combine transiently with their encounter a pH from which it is not able to escape substrate (ion or organic compound)—undergo easily. This may contribute to gastric mucosal a conformational change carrying the substrate cell damage caused by aspirin. to the other side of the membrane where the (c) Basic drugs attain higher concentration substrate dissociates and the transporter returns intracellularly (pH 7.0 vs 7.4 of plasma). back to its original state (Fig. 2.5). Carrier (d) Acidic drugs are ionized more in alkaline transport is specific for the substrate (or the type urine—do not back diffuse in the kidney tubules of substrate, e.g. an organic anion), saturable, and are excreted faster. Accordingly, basic drugs competitively inhibited by analogues which utilize are excreted faster if urine is acidified. the same transporter, and is much slower than  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 13 CHAPTER 2 Fig. 2.5: Illustration of different types of carrier mediated transport across biological membrane ABC—ATP-binding cassettee transporter; SLC—Solute carrier transporter; M—Membrane A. Facilitated diffusion: the carrier (SLC) binds and moves the poorly diffusible substrate along its concentration gradient (high to low) and does not require energy B. Primary active transport: the carrier (ABC) derives energy directly by hydrolysing ATP and moves the substrate against its concentration gradient (low to high) C. Symport: the carrier moves the substrate ‘A’ against its concentration gradient by utilizing energy from downhill movement of another substrate ‘B’ in the same direction D. Antiport: the carrier moves the substrate ‘A’ against its concentration gradient and is energized by the downhill movement of another substrate ‘B’ in the opposite direction the flux through channels. Depending on to high), resulting in selective accumulation of requirement of energy, carrier transport is of two the substance on one side of the membrane. Drugs types: related to normal metabolites can utilize the a. Facilitated diffusion The transporter, transport processes meant for these, e.g. levodopa belonging to the super-family of solute carrier and methyl dopa are actively absorbed from the (SLC) transporters, operates passively without gut by the aromatic amino acid transporter. In needing energy and translocates the substrate in addition, the body has developed some relatively the direction of its electrochemical gradient, i.e. nonselective transporters, like P-glycoprotein from higher to lower concentration (Fig. 2.5A). (P-gp), to deal with xenobiotics. Active transport It mearly facilitates permeation of a poorly can be primary or secondary depending on the diffusible substrate, e.g. the entry of glucose into source of the driving force. muscle and fat cells by the glucose transporter i. Primary active transport Energy is GLUT 4. obtained directly by the hydrolysis of ATP (Fig. b. Active transport It requires energy, is 2.5B). The transporters belong to the superfamily inhibited by metabolic poisons, and transports the of ATP binding cassettee (ABC) transporters solute against its electrochemical gradient (low whose intracellular loops have ATPase activity. 14 GENERAL PHARMACOLOGY They mediate only efflux of the solute from the saturable and follows the Michaelis-Menten cytoplasm, either to extracellular fluid or into an kinetics. The maximal rate of transport is intracellular organelli (endoplasmic reticulum, dependent on the density of the transporter in SECTION 1 mitochondria, etc.) a particular membrane, and its rate constant (Km), Encoded by the multidrug resistance 1 (MDR1) gene, i.e. the substrate concentration at which rate of P-gp is the most well known primary active transporter transport is half maximal, is governed by its expressed in the intestinal mucosa, renal tubules, bile canaliculi, choroidal epithelium, astrocyte foot processes affinity for the substrate. Genetic polymorphism around brain capillaries (the blood-brain barrier), testicular can alter both the density and affinity of the and placental microvessels, which pumps out many drugs/ transporter protein for different substrates and thus metabolites and thus limits their intestinal absorption, affect the pharmacokinetics of drugs. Moreover, penetration into brain, testes and foetal tissues as well as promotes biliary and renal elimination. Many xenobiotics tissue specific drug distribution can occur due which induce or inhibit P-gp also have a similar effect on to the presence of specific transporters in certain the drug metabolizing isoenzyme CYP3A4, indicating their cells. synergistic role in detoxification of xenobiotics. Other primary active transporters of pharmacological Pinocytosis It is the process of transport across the cell in significance are multidrug resistance associated protein 2 particulate form by formation of vesicles. This is applicable to (MRP 2) and breast cancer resistance protein (BCRP). proteins and other big molecules, and contributes little to ii. Secondary active transport In this type transport of most drugs, barring few like vit B12 which is absorbed from the gut after binding to intrinsic factor (a protein). of active transport effected by another set of SLC transporters, the energy to pump one solute is derived from the downhill movement of another ABSORPTION solute (mostly Na+). When the concentration Absorption is movement of the drug from its site gradients are such that both the solutes move in of administration into the circulation. Not only the same direction (Fig. 2.5C), it is called symport the fraction of the administered dose that gets or cotransport, but when they move in opposite directions (Fig. 2.5D), it is termed antiport or absorbed, but also the rate of absorption is exchange transport. Metabolic energy (from important. Except when given i.v., the drug has hydrolysis of ATP) is spent in maintaining high to cross biological membranes; absorption is transmembrane electrochemical gradient of the governed by the above described principles. Other second solute (generally Na +). The SLC factors affecting absorption are: transporters mediate both uptake and efflux of Aqueous solubility Drugs given in solid form drugs and metabolites. must dissolve in the aqueous biophase before they The organic anion transporting polypeptide (OATP) and organic cation transporter (OCT), highly expressed in liver are absorbed. For poorly water soluble drugs canaliculi and renal tubules, are secondary active transporters (aspirin, griseofulvin) rate of dissolution governs important in the metabolism and excretion of drugs and rate of absorption. Ketoconazole dissolves at low metabolites (especially glucuronides). The Na+,Cl– dependent pH: gastric acid is needed for its absorption. neurotransmitter transporters for norepinephrine, serotonin and dopamine (NET, SERT and DAT) are active SLC Obviously, a drug given as watery solution is transporters that are targets for action of drugs like tricyclic absorbed faster than when the same is given in antidepressants, selective serotonin reuptake inhibitors solid form or as oily solution. (SSRIs), cocaine, etc. Similarly, the Vesicular monoamine transporter (VMAT-2) of adrenergic and serotonergic storage Concentration Passive diffusion depends on vesicles transports catecholamines and 5-HT into the vesicles concentration gradient; drug given as concentrated by exchanging with H+ions, and is inhibited by reserpine. The absorption of glucose in intestines and renal tubules solution is absorbed faster than from dilute is through secondary active transport by sodium-glucose solution. transporters (SGLT1 and SGLT2). As indicated earlier, carrier transport (both Area of absorbing surface Larger is the facilitated diffusion and active transport) is surface area, faster is the absorption.  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 15 Vascularity of the absorbing surface Blood sustained release preparations (drug particles circulation removes the drug from the site of coated with slowly dissolving material) can be absorption and maintains the concentration used to overcome acid lability, gastric irritancy CHAPTER 2 gradient across the absorbing surface. Increased and brief duration of action. blood flow hastens drug absorption just as wind The oral absorption of certain drugs is low hastens drying of clothes. because a fraction of the absorbed drug is extru- ded back into the intestinal lumen by the efflux Route of administration This affects drug transporter P-gp located in the gut epithelium. absorption, because each route has its own The low oral bioavailability of digoxin and cyclo- peculiarities. sporine is partly accounted by this mechanism. Oral Inhibitors of P-gp like quinidine, verapamil, The effective barrier to orally administered drugs erythromycin, etc. enhance, while P-gp inducers is the epithelial lining of the gastrointestinal tract, like rifampin and phenobarbitone reduce the oral which is lipoidal. Nonionized lipid soluble drugs, bioavailability of these drugs. e.g. ethanol are readily absorbed from stomach Absorption of a drug can be affected by other as well as intestine at rates proportional to their concurrently ingested drugs. This may be a luminal lipid : water partition coefficient. Acidic drugs, effect: formation of insoluble complexes, e.g. e.g. salicylates, barbiturates, etc. are predominantly tetracyclines and iron preparations with calcium unionized in the acid gastric juice and are absorbed salts and antacids, phenytoin with sucralfate. Such from stomach, while basic drugs, e.g. morphine, interaction can be minimized by administering the quinine, etc. are largely ionized and are absorbed two drugs at 2–3 hr intervals. Alteration of gut flora only on reaching the duodenum. However, even by antibiotics may disrupt the enterohepatic cycling for acidic drugs absorption from stomach is of oral contraceptives and digoxin. Drugs can also slower, because the mucosa is thick, covered with alter absorption by gut wall effects: altering motility mucus and the surface area is small. Absorbing (anticholinergics, tricyclic antidepressants, opioids, surface area is much larger in the small intestine metoclopramide) or causing mucosal damage due to villi. Thus, faster gastric emptying (neomycin, methotrexate, vinblastine). accelerates drug absorption in general. Dissolution is a surface phenomenon, therefore, particle size Subcutaneous and Intramuscular of the drug in solid dosage form governs rate By these routes the drug is deposited directly in of dissolution and in turn rate of absorption. the vicinity of the capillaries. Lipid soluble drugs Presence of food dilutes the drug and retards pass readily across the whole surface of the absorption. Further, certain drugs form poorly capillary endothelium. Capillaries having large absorbed complexes with food constituents, e.g. paracellular spaces do not obstruct absorption of tetracyclines with calcium present in milk; even large lipid insoluble molecules or ions (Fig. moreover food delays gastric emptying. Thus, 2.8A). Very large molecules are absorbed through most drugs are absorbed better if taken in empty lymphatics. Thus, many drugs not absorbed orally stomach. However, there are some exceptions, are absorbed parenterally. Absorption from s.c. site e.g. fatty food greatly enhances lumefantrine is slower than that from i.m. site, but both are absorption. Highly ionized drugs, e.g. gentamicin, generally faster and more consistent/ predictable neostigmine are poorly absorbed when given than oral absorption. Application of heat and orally. muscular exercise accelerate drug absorption by Certain drugs are degraded in the gastrointes- increasing blood flow, while vasoconstrictors, e.g. tinal tract, e.g. penicillin G by acid, insulin by adrenaline injected with the drug (local anaesthetic) peptidases, and are ineffective orally. Enteric retard absorption. Incorporation of hyaluronidase coated tablets (having acid resistant coating) and facilitates drug absorption from s.c. injection by 16 GENERAL PHARMACOLOGY promoting spread. Many depot preparations, e.g. benzathine penicillin, protamine zinc insulin, depot progestins, etc. can be given by these routes. SECTION 1 Topical sites (skin, cornea, mucous membranes) Systemic absorption after topical application depends primarily on lipid solubility of drugs. However, only few drugs significantly penetrate intact skin. Hyoscine, fentanyl, GTN, nicotine, testosterone, and estradiol (see p. 8) have been used in this manner. Corticosteroids applied over extensive areas can produce systemic effects and pituitary-adrenal suppression. Absorption can be Fig. 2.6: Plasma concentration-time curves depicting promoted by rubbing the drug incorporated in bioavailability differences between three preparations of a drug containing the same amount an olegenous base or by use of occlusive dressing Note that formulation B is more slowly absorbed than A, which increases hydration of the skin. Organo- and though ultimately both are absorbed to the same phosphate insecticides coming in contact with skin extent (area under the curve same), B may not produce can produce systemic toxicity. Abraded surfaces therapeutic effect; C is absorbed to a lesser extent— lower bioavailability readily absorb drugs, e.g. tannic acid applied over burnt skin has produced hepatic necrosis. Incomplete bioavailability after s.c. or i.m. Cornea is permeable to lipid soluble, unioni- injection is less common, but may occur due to zed physostigmine but not to highly ionized local binding of the drug. neostigmine. Drugs applied as eye drops may get absorbed through the nasolacrimal duct, e.g. Bioequivalence Oral formulations of a drug timolol eye drops may produce bradycardia and from different manufacturers or different batches precipitate asthma. Mucous membranes of mouth, from the same manufacturer may have the same rectum, vagina absorb lipophilic drugs: estrogen amount of the drug (chemically equivalent) but cream applied vaginally has produced gynaeco- may not yield the same blood levels—biologically mastia in the male partner. inequivalent. Two preparations of a drug are considered bioequivalent when the rate and extent BIOAVAILABILITY of bioavailability of the active drug from them is not significantly different under suitable test Bioavailability refers to the rate and extent of conditions. absorption of a drug from a dosage form as Before a drug administered orally in solid determined by its concentration-time curve in dosage form can be absorbed, it must break into blood or by its excretion in urine (Fig. 2.6). It individual particles of the active drug (disinte- is a measure of the fraction (F ) of administered gration). Tablets and capsules contain a number dose of a drug that reaches the systemic circulation of other materials—diluents, stabilizing agents, in the unchanged form. Bioavailability of drug binders, lubricants, etc. The nature of these as injected i.v. is 100%, but is frequently lower after well as details of the manufacture process, e.g. oral ingestion because— force used in compressing the tablet, may affect (a) the drug may be incompletely absorbed. disintegration. The released drug must then (b) the absorbed drug may undergo first pass dissolve in the aqueous gastrointestinal contents. metabolism in the intestinal wall/liver or be The rate of dissolution is governed by the inherent excreted in bile. solubility, particle size, crystal form and other  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 17 physical properties of the drug. Differences in dose administered i.v. bioavailability may arise due to variations in V = —————————...(3) plasma concentration disintegration and dissolution rates. CHAPTER 2 Differences in bioavailability are seen mostly Since in the example shown in Fig. 2.7, the drug with poorly soluble and slowly absorbed drugs. does not actually distribute into 20 L of body Reduction in particle size increases the rate of water, with the exclusion of the rest of it, this absorption of aspirin (microfine tablets). The is only an apparent volume of distribution which amount of griseofulvin and spironolactone in the can be defined as “the volume that would tablet can be reduced to half if the drug particle accommodate all the drug in the body, if the is microfined. There is no need to reduce the concentration throughout was the same as in particle size of freely water soluble drugs, e.g. plasma”. Thus, it describes the amount of drug paracetamol. present in the body as a multiple of that contained Bioavailability variation assumes practical in a unit volume of plasma. Considered together significance for drugs with low safety margin with drug clearance, this is a very useful (digoxin) or where dosage needs precise control pharmacokinetic concept. (oral hypoglycaemics, oral anticoagulants). It may Lipid-insoluble drugs do not enter cells— also be responsible for success or failure of an V approximates extracellular fluid volume, e.g. antimicrobial regimen. streptomycin, gentamicin 0.25 L/kg. However, in the case of a large number of Distribution is not only a matter of dilution, drugs bioavailability differences are negligible and but also binding and sequestration. Drugs the risks of changing from branded to generic extensively bound to plasma proteins are largely product or to another brand of the same drug restricted to the vascular compartment and have have often been exaggerated. low values, e.g. diclofenac and warfarin (99% bound) V = 0.15 L/kg. A large value of V indicates that larger quantity DISTRIBUTION of drug is present in extravascular tissue. Drugs Once a drug has gained access to the blood stream, sequestrated in other tissues may have, V much it gets distributed to other tissues that initially more than total body water or even body mass, had no drug, concentration gradient being in the direction of plasma to tissues. The extent and pattern of distribution of a drug depends on its: lipid solubility ionization at physiological pH (a function of its pKa) extent of binding to plasma and tissue proteins presence of tissue-specific transporters differences in regional blood flow. Movement of drug proceeds until an equilibrium is established between unbound drug in the plasma and the tissue fluids. Subsequently, there is a parallel decline in both due to elimination. Apparent volume of distribution (V) Presuming Fig. 2.7: Illustration of the concept of apparent volume of distribution (V). that the body behaves as a single homogeneous In this example, 1000 mg of drug injected i.v. produces compartment with volume V into which the drug steady-state plasma concentration of 50 mg/L, apparent gets immediately and uniformly distributed volume of distribution is 20 L 18 GENERAL PHARMACOLOGY e.g. digoxin 6 L/kg, propranolol 4 L/kg, morphine Factors governing volume of drug distribution 3.5 L/kg, because most of the drug is present Lipid: water partition coefficient of the drug in other tissues, and plasma concentration is low. pKa value of the drug SECTION 1 Therefore, in case of poisoning, drugs with large Degree of plasma protein binding volumes of distribution are not easily removed Affinity for different tissues Fat: lean body mass ratio, which can vary by haemodialysis. with age, sex, obesity, etc. Pathological states, e.g. congestive heart Diseases like CHF, uremia, cirrhosis failure, uraemia, cirrhosis of liver, etc. can alter the V of many drugs by altering distribution of Anaesthetic action of thiopentone sod. injected body water, permeability of membranes, binding i.v. is terminated in few minutes due to proteins or by accumulation of metabolites that redistribution. A relatively short hypnotic action displace the drug from binding sites. lasting 6–8 hours is exerted by oral diazepam More precise multiple compartment models or nitrazepam due to redistribution despite their for drug distribution have been worked out, but elimination t ½ of > 30 hr. However, when the the single compartment model, described above, same drug is given repeatedly or continuously is simple and fairly accurate for many drugs. over long periods, the low perfusion high capacity sites get progressively filled up and the drug Redistribution Highly lipid-soluble drugs get becomes longer acting. initially distributed to organs with high blood flow, i.e. brain, heart, kidney, etc. Later, less vascular Penetration into brain and CSF The but more bulky tissues (muscle, fat) take up the capillary endothelial cells in brain have tight drug—plasma concentration falls and the drug junctions and lack large paracellular spaces. is withdrawn from the highly perfused sites. If Further, an investment of neural tissue (Fig. 2.8B) the site of action of the drug was in one of the covers the capillaries. Together they constitute highly perfused organs, redistribution results in the so called blood-brain barrier (BBB). A similar termination of drug action. Greater the lipid blood-CSF barrier is located in the choroid solubility of the drug, faster is its redistribution. plexus: capillaries are lined by choroidal Fig. 2.8: Passage of drugs across capillaries A. Usual capillary with large paracellular spaces through which even large lipid-insoluble molecules diffuse B. Capillary constituting blood brain or blood-CSF barrier. Tight junctions between capillary endothelial cells and investment of glial processes or choroidal epithelium do not allow passage of non lipid-soluble molecules/ions  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 19 epithelium having tight junctions. Both these Some influx transporters also operate at the barriers are lipoidal and limit the entry of nonlipid- placenta. Thus, it is an incomplete barrier and soluble drugs, e.g. streptomycin, neostigmine, etc. almost any drug taken by the mother can affect CHAPTER 2 Only lipid-soluble drugs, therefore, are able to the foetus or the newborn (drug taken just before penetrate and have action on the central nervous delivery, e.g. morphine). system. In addition, efflux transporters like P-gp and anion transporter (OATP) present in Plasma protein binding brain and choroidal vessels extrude many drugs Most drugs possess physicochemical affinity for that enter brain by other processes and serve to plasma proteins and get reversibly bound to these. augment the protective barrier against potentially Acidic drugs generally bind to plasma albumin and harmful xenobiotics. Dopamine does not enter basic drugs to α1 acid glycoprotein. Binding to brain but its precursor levodopa does; as such, albumin is quantitatively more important. Extent the latter is used in parkinsonism. Inflammation of binding depends on the individual compound; of meninges or brain increases permeability of no generalization for a pharmacological or these barriers. It has been proposed that some chemical class can be made (even small chemical drugs accumulate in the brain by utilizing the change can markedly alter protein binding), for transporters for endogenous substances. example the binding percentage of some benzo- There is also an enzymatic BBB: Monoamine diazepines is: oxidase (MAO), cholinesterase and some other Flurazepam 10% Alprazolam 70% enzymes are present in the capillary walls or in Lorazepam 90% Diazepam 99% the cells lining them. They do not allow Increasing concentrations of the drug can pro- catecholamines, 5-HT, acetylcholine, etc. to enter gressively saturate the binding sites: fractional brain in the active form. binding may be lower when large amounts of the The BBB is deficient at the CTZ in the medulla drug are given. The generally expressed percen- oblongata (even lipid-insoluble drugs are emetic) tage binding refers to the usual therapeutic plasma and at certain periventricular sites—(anterior concentrations of a drug. The clinically significant hypothalamus). Exit of drugs from the CSF and implications of plasma protein binding are: brain, however, is not dependent on lipid-solubility (i) Highly plasma protein bound drugs are largely and is rather unrestricted. Bulk flow of CSF restricted to the vascular compartment because (alongwith the drug dissolved in it) occurs through protein bound drug does not cross membranes the arachnoid villi. Further, nonspecific organic (except through large paracellular spaces, such anion and cation transport processes (similar to those in renal tubule) operate at the choroid plexus. Drugs highly bound to plasma protein Passage across placenta Placental membra- nes are lipoidal and allow free passage of lipo- To albumin To α1-acid glycoprotein philic drugs, while restricting hydrophilic drugs. The placental efflux P-gp and other transporters Barbiturates β-blockers like BCRP, MRP3 also serve to limit foetal Benzodiazepines Bupivacaine NSAIDs Lidocaine exposure to maternally administered drugs. Valproic acid Disopyramide Placenta is a site for drug metabolism as well, Phenytoin Imipramine which may lower/modify exposure of the foetus Penicillins Methadone to the administered drug. However, restricted Sulfonamides Prazosin amounts of nonlipid-soluble drugs, when present Tetracyclines Quinidine in high concentration or for long periods in Tolbutamide Verapamil Warfarin maternal circulation, gain access to the foetus. 20 GENERAL PHARMACOLOGY as in capillaries). They tend to have smaller into account while relating these to concentrations volumes of distribution. of the drug that are active in vitro, e.g. MIC of (ii) The bound fraction is not available for action. an antimicrobial. SECTION 1 However, it is in equilibrium with the free drug (v) One drug can bind to many sites on the in plasma and dissociates when the concentration albumin molecule. Conversely, more than one drug of the latter is reduced due to elimination. Plasma can bind to the same site. This can give rise to protein binding thus tantamounts to temporary displacement interactions among drugs bound to storage of the drug. the same site(s). The drug bound with higher affinity will displace that bound with lower affinity. (iii) High degree of protein binding generally If just 1% of a drug that is 99% bound is displaced, makes the drug long acting, because bound fraction the concentration of free form will be doubled. is not available for metabolism or excretion, unless This, however, is often transient because the it is actively extracted by liver or by kidney tubules. displaced drug will diffuse into the tissues as well Glomerular filtration does not reduce the as get metabolized or excreted: the new steady- concentration of the free form in the efferent state free drug concentration is only marginally vessels, because water is also filtered. Active higher unless the displacement extends to tissue tubular secretion, however, removes the drug binding or there is concurrent inhibition of without the attendant solvent → concentration of metabolism and/or excretion. The overall impact free drug falls → bound drug dissociates and is of many displacement interactions is minimal; eliminated resulting in a higher renal clearance clinical significance being attained only in case value of the drug than the total renal blood flow of highly bound drugs with limited volume of (see Fig. 3.3). The same is true of active transport distribution (many acidic drugs bound to albumin) of highly extracted drugs in liver. Plasma protein and where interaction is more complex. Moreover, binding in this situation acts as a carrier mechanism two highly bound drugs do not necessarily displace and hastens drug elimination, e.g. excretion of each other—their binding sites may not overlap, penicillin (elimination t½ is 30 min); metabolism e.g. probenecid and indomethacin are highly of lidocaine. Highly protein bound drugs are not bound to albumin but do not displace each other. removed by haemodialysis and need special Similarly, acidic drugs do not generally displace techniques for treatment of poisoning. basic drugs and vice versa. Some clinically (iv) The generally expressed plasma concentra- important displacement interactions are: tions of the drug refer to bound as well as free Aspirin displaces sulfonylureas. drug. Degree of protein binding should be taken Indomethacin, phenytoin displace warfarin. Drugs concentrated in tissues Skeletal muscle, heart — digoxin, emetine (bound to muscle proteins). Liver — chloroquine, tetracyclines, emetine, digoxin. Kidney — digoxin, chloroquine, emetine. Thyroid — iodine. Brain — chlorpromazine, acetazolamide, isoniazid. Retina — chloroquine (bound to nucleoproteins). Iris — ephedrine, atropine (bound to melanin). Bone and teeth — tetracyclines, heavy metals (bound to mucopolysaccharides of connective tissue), bisphosphonates (bound to hydroxyapatite) Adipose tissue — thiopentone, ether, minocycline, phenoxybenzamine, DDT dissolve in neutral fat due to high lipid-solubility; remain stored due to poor blood supply of fat.  MEMBRANE TRANSPORT, ABSORPTION AND DISTRIBUTION OF DRUGS 21 Sulfonamides and vit K displace bilirubin Tissue storage Drugs may also accumulate (kernicterus in neonates). in specific organs by active transport or get bound Aspirin displaces methotrexate. to specific tissue constituents (see box). CHAPTER 2 (vi) In hypoalbuminemia, binding may be redu- Drugs sequestrated in various tissues are ced and high concentrations of free drug may unequally distributed, tend to have larger volume be attained, e.g. phenytoin and furosemide. Other of distribution and longer duration of action. Some diseases may also alter drug binding, e.g. may exert local toxicity due to high concentration, phenytoin and pethidine binding is reduced in e.g. tetracyclines on bone and teeth, chloroquine uraemia; propranolol binding is increased in on retina, streptomycin on vestibular apparatus, pregnant women and in patients with inflammatory emetine on heart and skeletal muscle. Drugs may disease (acute phase reactant α1 acid-glycoprotein also selectively bind to specific intracellular increases). organelle, e.g. tetracycline to mitochondria, chloroquine to nuclei. ) PROBLEM DIRECTED STUDY 2.1 A 60-year-old woman complained of weakness, lethargy and easy fatigability. Investigation showed that she had iron deficiency anaemia (Hb. 8 g/dl). She was prescribed cap. ferrous fumarate 300 mg twice daily. She returned after one month with no improvement in symptoms. Her Hb. level was unchanged. On enquiry she revealed that she felt epigastric distress after taking the iron capsules, and had started taking antacid tablets along with the capsules. (a) What could be the possible reason for her failure to respond to the oral iron medication? 2.2 A 50-year-old type-2 diabetes mellitus patient was maintained on tab. glibenclamide (a sulfonylurea) 5 mg twice daily. He developed toothache for which he took tab. aspirin 650 mg 6 hourly. After taking aspirin he experienced anxiety, sweating, palpitation, weakness, ataxia, and was behaving abnormally. These symptoms subsided when he was given a glass of glucose solution. (a) Waht could be the explanation for his symptoms? (b) Which alternative analgesic should have been taken? (see Appendix-1 for solutions)  Chapter 3 Pharmacokinetics: Metabolism and Excretion of Drugs, Kinetics of Elimination BIOTRANSFORMATION Active drug Active metabolite (Metabolism) Chloral hydrate — Trichloroethanol Biotransformation means chemical alteration of Morphine — Morphine-6-glucuronide Cefotaxime — Desacetyl cefotaxime the drug in the body. It is needed to render Allopurinol — Alloxanthine nonpolar (lipid-soluble) compounds polar (lipid- Procainamide — N-acetyl procainamide insoluble) so that they are not reabsorbed in the Primidone — Phenobarbitone, renal tubules and are excreted. Most hydrophilic phenylethylmalonamide Diazepam — Desmethyl-diazepam, drugs, e.g. streptomycin, neostigmine, pancuro- oxazepam nium, etc. are little biotransformed and are largely Digitoxin — Digoxin excreted unchanged. Mechanisms which meta- Imipramine — Desipramine bolize drugs (essentially foreign substances) have Amitriptyline — Nortriptyline Codeine — Morphine developed to protect the body from ingested Spironolactone — Canrenone toxins. Losartan — E 3174 The primary site for drug metabolism is liver; others are—kidney, intestine, lungs and plasma. Biotransformation reactions can be classified Biotransformation of drugs may lead to the into: following. (a) Nonsynthetic/Phase I/Functionali