By Z. Nemrok. University of Texas at Brownsville.

For example cheap diabecon 60 caps with mastercard, if the drug is 100% absorbed across the gut wall and the liver extracts 70% before it reaches the systemic circulation proven diabecon 60 caps, 30% of the dose finally reaches the bloodstream purchase diabecon 60caps otc. Therefore, we will consider the potential impact that changes in Qh, Fp, and Cli will have on the steady-state concentration of both total and free drug concentration. Remember, we will assume that Cl (totalt body clearance) equals Clh (hepatic clearance) and that steady-state free drug concentration is the major determinant of pharmacologic response. When trying to assess clinical implications, always consider the following: • route of administration (intravenous vs. In the following three examples, we apply the previously described hepatic extraction equation to several cases involving a specific disease state effect or drug interaction. Considerations • Theophylline (in this example) is administered via a constant intravenous infusion (K0). Because theophylline has a low extraction ratio and is not extensively bound to proteins, Clh = Fp × Cl. Impact on Css(free) Because K0 is unchanged and Cl is reduced by 50%,i Css(free) should double. Consequence You should anticipate significant side effects as a consequence of a higher free steady-state concentration of theophylline (Figure 9-8). Figure 9-9 demonstrates changes in plasma theophylline concentrations when enoxacin is begun and then later 1 discontinued. Considerations • Phenytoin is administered by intermittent intravenous administration. Impact on Css(free) BecauseK0 and Cl are unchanged,i Css(free) should remain unchanged. However, the total concentration necessary to achieve this therapeutic unbound concentration will be less than the normal reference range for phenytoin. Myocardial infarctions are known to significantly increase the concentration of alpha-1-acid glycoprotein (a serum globulin) and the protein binding of drugs associated with it. The protein binding of lidocaine is known to be high and primarily dependent on alpha-1-acid glycoprotein. Because lidocaine has a high extraction ratio and binds extensively to alpha-1-acid glycoprotein, Clh = Qh. Substituting for Css(total) Impact on Css(total) Because K0 and Qh are unchanged, Css(total) should remain unchanged. Impact on Css(free) Because K0 and Qh are unchanged and Fp is decreased, Css(free) should decrease, which could result in a reduced pharmacologic response (Figure 9-11). Consequence Because only total (bound and unbound) lidocaine concentrations can be measured clinically, you should anticipate a reduced pharmacologic response despite similar steady-state total lidocaine concentrations. This reduced response may necessitate high total lidocaine concentrations and a higher dose to achieve the desired response. These three examples represent how the well-stirred model and knowledge of the pharmacokinetic characteristics of a drug can be used to predict the effect of changes in hepatic blood flow, protein binding, and intrinsic clearance. These same principles can be used to assess a wide variety of clinically relevant situations. Changes in free and total steady-state plasma theophylline concentrations with the addition of cimetidine. The time period shown (60-360 hours) includes each of the three steady-state periods. Changes in the disposition of theophylline and its metabolites during intermittent administration of enoxacin. Change in free steady-state plasma lidocaine concentrations due to myocardial infarction. Some drugs are primarily excreted unchanged; others are extensively metabolized before excretion. The overall elimination rate is the sum of all metabolism and excretion processes and is referred to as total body elimination: total body elimination = drug excreted unchanged + drug metabolized Excretion is the process that removes a drug from tissues and the circulation. A drug can be excreted through urine, bile, sweat, expired air, breast milk, or seminal fluid. The most important routes of excretion for many drugs and their metabolites are the urine and bile. Excretion may occur for a biotransformed drug or for a drug that remains unchanged in the body. Renal excretion is the net effect of three distinct mechanisms within the kidneys: • glomerular filtration, • tubular secretion, and • tubular reabsorption. With glomerular filtration, blood flows into the capsule of the glomerulus and there is a passive diffusion of fluids and solutes across the porous glomerular membrane (Figure 9-13). In a healthy adult, up to 130 mL of fluid may cross the glomeruli per minute (total of both kidneys). Three factors influence glomerular filtration: • molecular size, • protein binding, and • glomerular integrity and total number of functioning nephrons. Drugs dissolved in the plasma may be filtered across the glomerulus; drugs that are protein bound or have a molecular weight greater than 60,000 are not filtered. Some drugs are actively secreted from the blood into the proximal tubule, which contains urine. These drugs (primarily weak organic acids and some bases) are excreted by carrier-mediated active processes that may be subject to competition from other substances in the body due to broad specificity of the carriers. If given together, probenecid competes with penicillin for secretion, so penicillin is secreted less rapidly (it has a longer half-life). This particular relationship can be used in therapeutic situations to extend the duration of penicillin action. This process occurs passively in the distal tubules for drugs that are lipid soluble or not highly ionized. For other agents, it can occur as an active process and (as with tubular secretion) is subject to competition from other agents. An example of reabsorption is glucose, which normally undergoes 100% reabsorption in the distal tubules of the kidneys. With renal dysfunction, glucose often is not reabsorbed and may appear in the urine. Other examples of agents that are actively reabsorbed include endogenous substances such as vitamins, electrolytes, and amino acids. Tubular reabsorption is dependent on the physical and chemical properties of the drug and the pH of the urine. Drugs that are highly ionized in the urine have less tubular reabsorption; they tend to stay in the urine and are excreted. Urea, for example, has a high tubular reabsorption at low urine flow rates and a low tubular reabsorption at high urine flow rates. Because renal clearance is determined by filtration, active secretion, and reabsorption, it is fairly complicated. However, because it is not easy to differentiate these processes when measuring the amount of drug in the urine, renal clearance is calculated from the ratio of the urine excretion rate to the drug concentration in plasma: There are several different methods to calculate renal drug clearance.

Precautons Pregnancy (Appendix 7c); lactaton (Appendix 7b); broken skin (see below); renal impairment; avoid contact with eyes; neonates order diabecon 60 caps. The applicaton of povidone iodine to large wounds or severe burns may produce systemic adverse efects such as metabolic acidosis; hypernatraemia; and impairment of renal functon generic 60 caps diabecon with amex. Adverse Efects Irritaton of skin and mucous membranes; may interfere with thyroid functon tests; systemic efects (see under Precautons) buy discount diabecon 60 caps online. Disinfectants do not necessarily kill all organ- isms but reduce them to a level, which does not harm health or the quality of perishable goods. Disinfectants are applied to inanimate objects and materials such as instruments and surfaces to control and prevent infecton. They may also be used to disinfect skin and other tssues prior to surgery (see also Antseptcs, above). Where water is not disinfected at source it may be disin- fected by boiling or by chemical means for drinking, cleaning teeth and food preparaton. It is highly corrosive in concentrated soluton and splashes can cause burns and damage the eyes. Appropriate precautons must be taken when concentrated chlorine solutons or powders are handled. The chlorinated phenolic compound, chloroxylenol, is efec- tve against a wide range of Gram-positve bacteria. It is less efectve against staphylococci and Gram-negatve bacteria; it is ofen inefectve against Pseudomonas spp. The aldehyde bactericidal disinfectant, glutaraldehyde, is strongly actve against both Gram-positve and Gram-negatve bacteria. A 2% w/v aqueous alkaline (bufered to pH 8) glutaral soluton can be used to sterilize heat-sensitve pre-cleansed instruments and other equipments. Dose Surface disinfecton (minor contaminaton): apply solutons containing 1000 parts per million. Instrument disinfecton: soak in soluton containing 1000 parts per million for a minimum of 15 min; to avoid corrosion do not soak for more than 30 min; rinse with sterile water. Chloroxylenol Pregnancy Category-C Indicatons Antseptc; disinfecton of instruments and surfaces. Dose Antseptc (wounds and other skin damage): apply a 1 in 20 diluton of 5% concentrate in water. Disinfecton of instruments: use a 1 in 20 diluton of 5% concentrate in alcohol (70%). Precautons Aqueous solutons should be freshly prepared; appropriate measures required to prevent contaminaton during storage or diluton; pregnancy (Appendix 7c); lactaton. Precautons Signifcant peripheral neuropathy; patents with diabetes at risk of neuropathic ulcers; protect surrounding skin and avoid broken skin; not suitable for applicaton to face; anogenital region; or large areas; increased levels of serum aminotransferase. Glutaraldehyde* Indicatons Disinfecton and sterilizaton of instruments and surfaces; conditons like warts and hyperhidrosis of palms and soles. Dose Disinfecton of clean instruments - immerse in undiluted soluton for 10 to 20 min; up to 2 h may be required for certain instruments (for example bronchoscopes with possible mycobacterial contaminaton); rinse with sterile water or alcohol afer disinfecton. Sterilizaton of clean instruments - Immerse in undiluted soluton for up to 10 h; rinse with sterile water or alcohol afer disinfecton. Precautons Minimize occupatonal exposure by adequate skin protecton and measures to avoid inhalaton of vapour; lung damage; oral and nasal lesions, if swallowed do not induce vomitng. Adverse Efects Nausea (occupatonal exposure); headache; airway obstructon; asthma; rhinits; eye irritaton and dermatts and skin discolouraton. Management depends on the type of angina and may include drug treatment, coronary artery bypass surgery, or percuta- neous transluminal coronary angioplasty. Stable Angina: Drugs are used both for the relief of acute pain and for proph- ylaxis to reduce further atacks; they include organic nitrates, beta-adrenoceptor antagonists (beta-blockers) and calcium- channel blockers. Nitrates: Organic nitrates have a vasodilatng efect; they are some- tmes used alone, especially in elderly patents with infre- quent symptoms. Tolerance leading to reduced antanginal efect is ofen seen in patents taking prolonged-acton nitrate formulatons. Evidence suggests that patents should have a ‘nitrate-free’ interval to prevent the development of toler- ance. Adverse efects such as fushing, headache and postural hypotension may limit nitrate therapy but tolerance to these efects also soon develops. The short-actng sublingual formulaton of glyceryl trinitrate is used both for preventon of angina before exercise or other stress and for rapid treat- ment of chest pain. A sublingual tablet of isosorbide dinitrate is more stable in storage than glyceryl trinitrate and is useful in patents who require nitrates infrequently; it has a slower onset of acton, but efects persist for several h. Beta-blockers are frst-line therapy for patents with efort-induced chronic stable angina; they improve exercise tolerance, relieve symp- toms, reduce the severity and frequency of angina atacks and increase the anginal threshold. Beta-blockers should be withdrawn gradually to avoid precipi- tatng an anginal atack; they should not be used in patents with underlying coronary vasospasm (Prinzmetal’s angina). Beta-blockers may precipitate asthma and should not be used in patents with asthma or a history of obstructve airways disease. Some, including atenolol, have less efect on β2 (bronchial) receptors and are therefore relatvely cardioselec- tve. Although they have less efect on airways resistance they are not free of this efect and should be avoided. Beta-blockers slow the heart and may induce myocardial depres- sion, rarely, precipitatng heart failure. They should not be given to patents who have incipient ventricular failure, second-or third- degree atrioventricular block, or peripheral vascular disease. Beta-blockers should be used with cauton in diabetes since they may mask the symptoms of hypoglycaemia, such as rapid heart rate. Beta-blockers enhance the hypoglycaemic efect of insulin and may precipitate hypoglycaemia. Calcium-Channel Blockers: A calcium-channel blocker, such as verapamil, is used as an alternatve to a beta-blocker to treat stable angina. Calcium- channel blockers interfere with the inward movement of calcium ions through the slow channels in heart and vascular smooth muscle cell membranes, leading to relaxaton of vascular smooth muscle. Myocardial contractlity may be reduced, the formaton and propagaton of electrical impulses within the heart may be depressed and coronary or systemic vascular tone may be diminished. Calcium-channel blockers are used to improve exercise tolerance in patents with chronic stable angina due to coronary atherosclerosis or with abnor- mally small coronary arteries and limited vasodilator reserve. Calcium-channel blockers can also be used in patents with unstable angina with a vasospastc origin, such as Prinzmetal’s angina and in patents in whom alteratons in cardiac tone may infuence the angina threshold. Unstable Angina: Unstable angina requires prompt aggressive treatment to prevent progression to myocardial infarcton. Inital treatment is with acetylsalicylic acid to inhibit platelet aggregaton, followed by heparin.

If there is no prior history of vaccinaton discount diabecon 60 caps without a prescription, 2 doses are administered buy 60caps diabecon with amex, the frst in 2nd trimester and the second dose one month later buy 60caps diabecon amex. Variatons in drug responses amongst fraternal twins (dizygotc) may be relatvely wide when compared to identcal (monozygotc) twins. Importance of Pharmacogenetcs lies in the development of new drugs from informaton available from human genome project. The variaton to drug response can also be brought about by: • Metabolic variaton • Idiosyncratc reacton As an example metabolic variaton can be best explained by the varied metabolic response exhibited to the anttubercular drug Isoniazid due to the presence of two diferent pheno- types in a populaton. These varied phenotypes are expressed as larger or smaller amount of enzyme N- acetylase in liver, and the populaton being termed as rapid acetylators and slow acetylators respectvely. Calcium re- 1:20,000 Halothane Malignant lease channel hyperthermia, (ryanodine receptor) 6. Altered recep- 2 large Warfarin Warfarin resist- tor or enzyme pedigrees ance in liver with in- creased afnity for vitamin K 10. Mixed functon Only 1 Dicoumarol Dicoumarol oxidase in liver small Phenacetn sensitvity microsomes pedigree Methemoglob- hydroxylaton inemia d-ethylaton 11. Mixed functon 25% Tolbutamide Tolbutamide oxidase induced cardio- vascular death 13. Cytochrome Ondansetron Ondansetron P450 2D6 - lesser efcacy in ultrarapid metabolisers Tramadol Lesser efcacy of tramadol Codeine Codeine - poor analgesia Tamoxifen Therapeutc failure of Tamoxifen in poor metabo- lisers ~ 7% cau- Debrisoquine Poor metabo- casians lism of Debriso- quine 14. Cytochrome Warfarin Longer tmes to P450 2C9 dose stabilisa- and Vitamin ton and higher K epoxide re- risk of serious ductase com- and life threat- plex subunit 1 ening bleeding 16. Increased Chloroquine, an- Development of expression of – tcancer drugs resistance p-glycoprotein 17. An enzyme or Rare Simultaneous Warfarin resist- receptor site administraton ance with altered of inducing afnity for agents with vitamin K warfarin 18. Thiopurine 3% Azathioprine Risk of bone methyl trans- 6- mercaptopu- marrow sup- ferase enzyme rine pression 19. Uridine-5- 61% Cau- Irinotecan Risk of induc- diphosphoglu- casians ton of neu- curosyl trans- 84% tropenia and ferase 1A1 Asians diarrhoea 47% Afri- can ameri- cans 20. The mission of the programme is to ensure that the benefts of use of medicine outweigh the risk and thus safeguard the health of the Indian populaton. Integrated eforts from the regulatory authorites, pharmaceutcal industry and healthcare workers are necessary for the success and efec- tveness of this programme. Therefore the actve partcipa- ton of the all concerned in this programme will not only be useful for Indian health care system but also facilitate ratonal prescribing globally. While there has not been any natonal standard of pictorial label adopted so far, based on a project by Delhi Pharmaceutcal Trust, in collaboraton with Apothecaries Foundaton the following pictorial labels that were developed and used and found appropriate,are recommended for use. Such labels can be pre-printed using self-adhesive stcker label and made available in Pharmacies. Pharmacists should paste relevant pictorial label either on the botle/pack of the drugs dispensed or on the prescripton sheet against each drugs prescribed. Based on the most commonly needed instructons, 11 types of messages were identfed and pictorial labels have been developed. More instructons if required can be added to this list and additonal labels need to be developed. Dosing consideratons for the pediatric patent Determinaton of a safe and efectve drug dose for the pedi- atric patent is essental for the treatng physician. Doses and dosing intervals in children difer from that of an adult because of age-related variatons in drug absorpton, distri- buton, metabolism, and eliminaton. Drugs like phenytoin and chloramphenicol are absorbed slowly and erratcally whereas penicillin and ampicillin are absorbed more ef- ciently than in the adults because of a higher gastric pH in the neonates. Most drug metabolizing enzymes are expressed at low levels at birth followed by postnatal inducton of specifc isoenzymes. For most drugs including phenytoin, barbiturates, digoxin and analgesics the plasma half lives are 2-3 tmes longer in neonates as compared to adults. As a result, neonatal dosing regimens for a number of drugs must be reduced to avoid toxicity. Similarly, specifc drug toxicites may be unique to this age group as evident in case of tetracyclines afectng teeth and glucocortcoids reducing linear growth of bones. Because of these maturatonal diferences in infants and chil- dren, simple proportonate reducton in the adult dose may not be adequate to determine an optmal pediatric dose. The most reliable dose informaton is usually the one provided by the drug manufacturer in the package insert or pediatric doses listed in the formulary. However, such informaton is not avail- able for the majority of drugs since proper dose optmizaton studies are ofen not performed in the pediatric age range. Consequently, inital doses are derived by scaling down the dosages used in adults and then ttratng according to clinical response. In the absence of specifc pediatric dose recommendatons, an estmate can be made by any of several methods based on age, weight, or surface area. Clark ( known as the Clark’s rule) introduced weight proportonal regimen for drug therapy. The above mentoned rules are helpful in situatons requiring the use of a drug that is unlicensed in children and for which no pediatric prescribing informaton is available. However, these rules are not precise and doses should not be calculated if it is possible to obtain the actual pediatric dose. Whatever be the method chosen to calculate the child’s dose, it should never exceed that of the adult. Dosing consideratons for the geriatric patent Aging is a natural process of human development and is char- acterized by a progressive loss of physiologic and reproductve functons. Altered response to drugs with aging occurs at both pharmacokinetc and pharmacodynamic levels. Pharmacokinetc changes occur with the age as a result of the inevitable anatomical and physiological changes which occur with tme, such as loss of an organ’s functonal units (neph- rons, neurons) and distrupton of some regulatory processes between cells and organs, resultng in decrease in functon of body systems. For example, frst pass metabolism decreases due to decrease in liver mass and blood fow, resultng in an increase in bioavailability of drugs which undergo extensive frst pass metabolism, for example, propranolol. Another example of a pharmacokinetc change is the reduced clear- ance of renally-cleared drugs due to reduced renal plasma fow and glomerular fltraton. This increases the potental for toxic efects partcularly with those drugs where even marginal accumulaton can have toxic efects, for example digoxin and lithium. Changes in body compositon such as increase in body fat proporton and decrease in total body water result in a decreased volume of distributon for water soluble drugs such as digoxin, which increases their serum concentratons and potental for adverse efects. Geriatric patents are much more “sensitve” to the acton of many drugs, implying a change in the pharmacodynamic inter- actons of the drugs with their receptors. Since homeostatc responses are ofen important components of the total response to a drug, these physiolog- ical alteratons may change the patern or intensity of drug response.

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