• Nitroglycerin, isosorbide dinitrate, and isosorbide 5- mononitrate, an active metabolite of isosorbide dinitrate, are the nitrovasodilators most commonly used in the clinical setting.
  
• All are lipid soluble and readily absorbed via several routes of administration.
  
• Most organic nitrates have very low oral bioavailability due to the presence of high-capacity nitrate reductase enzymes in the liver (exception is isosorbide mononitrate, has nearly 100 percent bioavailability following oral administration).
  
• Most denitrated metabolites are glucuronidated and excreted via the kidney.
• Nitroglycerin may be administered via several routes, including sublingual, buccal, oral, transdermal, and intravenous.
  
• Because of its rapid onset (1-3 minutes) and avoidance of first-pass hepatic metabolism, the sublingual route is preferred.
• Since nitroglycerin is moderately volatile and adsorbs to plastic, the sublingual tablets must be stored in tightly closed glass containers.
  
• The duration of action of sublingual nitroglycerin is relatively brief (~30 minutes).
  
• Nitroglycerin is readily absorbed across the skin and may be applied as either an ointment or transdermal patch.
  
• Intravenous nitroglycerin is used to rapidly attain therapeutic blood levels.
  
• The concentration can be quickly and safely titrated to the desired level, and the hemodynamic effects can be terminated rapidly by stopping the infusion.
  
• Isosorbide dinitrate and isosorbide mononitrate are primarily administered via the oral route.

• Myocardial Oxygen Demand: Nitroglycerin causes relaxation of vascular smooth muscle in both arteries and veins, although the effect on veins predominates at low doses. By dilating veins, nitroglycerin increases venous capacitance and decreases venous return to the heart - decreases preload (as described by the Laplace relationship). Arterial dilation by nitroglycerin decreases peripheral vascular resistance and leads to a reduction in afterload. Reduced preload and afterload result in decreased left ventricular wall tension, a major determinant of myocardial oxygen demand. Thus, the anti-ischemic effects of the nitrovasodilators are largely due to their ability to decrease myocardial work and oxygen consumption.
  
• Myocardial Oxygen supply: The nitrovasodilators have several effects on the coronary circulation, including dilation of large and intermediate-size coronary arteries, increased collateral flow, and redistribution of flow to ischemic regions of the heart. Accordingly, these beneficial effects are primarily responsible for the ability of nitrovasodilators to improve myocardial oxygen supply.

1. Nitrovasodilators are used in the treatment of most forms of angina. Patients with chronic, stable angina often have fixed atherosclerotic lesions that obstruct blood flow in the large coronary arteries. The beneficial effects of nitrovasodilators in stable angina are due primarily to their ability to decrease myocardial oxygen demand. By decreasing preload and afterload, nitrovasodilators reduce ventricular wall tension and myocardial oxygen consumption.
2. In patients with variant (Prinzmetal's) angina, the major underlying cause of angina is vasospasm of one or more coronary arteries. Intense vasoconstriction decreases coronary blood flow, thereby reducing myocardial oxygen supply.By dilating constricted coronary arteries and restoring coronary blood flow, nitrovasodilators increase myocardial oxygen supply and relieve variant angina.
3. Nitrovasodilators are also used in treating patients with unstable angina. The pathophysiology of this condition is often complex and may involve several underlying factors superimposed on one another, including rupture of atherosclerotic plaques and thrombus formation, constriction of coronary arteries, and increased myocardial oxygen demand. In these patients, the beneficial effects of the nitrovasodilators are likely due to both dilation of the coronary arteries and a reduction in myocardial oxygen consumption.
4. Nitrovasodilators are used for the immediate treatment of acute angina, as well as for long-term prevention. Because of its rapid onset of effect, sublingual nitroglycerin is the agent most frequently used to terminate an acute attack of angina. It may be used prophylactically when administered immediately prior to activities known to precipitate an anginal attack (e.g. physical exertion).
   
5. Intravenous nitroglycerin is also used to control acute angina.
   
6. Transdermal nitroglycerin and oral formulations of nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate are widely used in long-term maintenance therapy of angina. Although sustained plasma drug levels can usually be attained with these products, their clinical efficacy may be limited by the development of tolerance.

The most frequently observed adverse effects of the nitrates are a direct result of the vasodilation produced by these drugs. Headache, due to dilation of cranial blood vessels, is common and may be severe. Symptoms of postural hypotension (e.g. dizziness) may also be encountered. Paradoxically, nitrates may increase myocardial oxygen demand in some patients by causing reflex tachycardia.

Most drugs are absorbed from the gastrointestinal tract and because of the convenience, orally administered drugs are widely used over injectable preparations. Some drugs like benzylpenicillin or insulin are destroyed by the acid and enzymes in the gut and therefore have to be administered parenterally.

Drug Absorption At The Small Intestine

Most drugs are absorbed by passive lipid diffusion though there is a degree of carrier-mediated transport. Levodopa, a drug used in Parkinson’s Disease, is transported by the carrier mechanism usually used for phenylalanine. Fluoruracil is a cytotoxic drug that employs the natural pyrimidine transport system. Iron is transported via specific carriers in the jejunal mucosa and calcium by a vitamin D-dependent carrier system. The rate of transfer is determined by the ionisation state and lipid solubility of the drugs. Strong bases with a pK_a of 10 or more or acids with a pK_a of less than 3 are fully absorbed because they are fully ionised.

Factors Affecting GI Absorption

It usually takes 1-3 hours for 75% of an ingested drug to be absorbed. There are several factors which alter this, both physiological and relating to drug formulation.

GI motility has a large effect on the rate of drug absorption. Gastric stasis, which occurs in migraine and diabetic neuropathy, slows drug absorption. However rapid gut movement can also impair absorption. Some drugs have an effect of absorption, metoclopramide is given in migraine to increase GI motility and increase absorption of analgesics. Muscarinic receptor blockers decrease motility.

After a meal, drugs are more slowly absorbed simply because progress to the small bowel is delayed by the presence of food. Exceptions to this are propanolol which has higher concentrations after a meal because of the fact that food increases splanchnic blood flow. Clearly a decrease in splanchnic blood flow, for example in hypovolaemia, slows absorption. Drug particle size also plays a part. It has been observed in the past that different formulations of digoxin resulted in different plasma concentrations despite the fact that digoxin content in the tablets was the same. This was as a result of varying particle size.

Therapeutic drugs are formulated pharmaceutically to produce desired absorption characteristics. Capsules are designed to remain intact for several hours after ingestion with the aim of delaying absorption. Tablets with a resistant coating work on the same principle. Some drug formulations have a mix of slow and fast release in a capsule to achieve rapid and sustained drug action. By manipulating absorption rates, dose intervals can be increased and adverse side effects, associated with high peak plasma levels, reduced.

The physicochemical properties of drugs also play a part in drug absorption. Tetracycline binds to calcium ions and calcium-rich foods, delaying absorption. Bile acid resins such as colestyramine, bind warfarin and thyroxine.

Absorption is also decreased by both increasing age and disease.

Usually drugs that are administered by mouth, pass through the gut wall to the liver in the portal circulation and then into the systemic circulation where they can go about exerting their effects. However some drugs taken by mouth are designed to remain within the gut lumen until they are excreted. An example of this is the antibiotic vancomycin which acts within the gut lumen to eradicate Clostridium Difficile.

Bioavailability

Introduction:

During pregnancy the mother and the fetus form a non-separable functional unit. Maternal well-being is an absolute prerequisite for the optimal functioning and development of both parts of this unit. Consequently, it is important to treat the mother whenever needed while protecting the unborn to the greatest possible extent. Drugs can have harmful effects on the fetus at any time during pregnancy. It is important to remember this when prescribing for a woman of childbearing age. The past use of stilboesterol in pregnant women with threatened abortion has resulted in development of adenocarcinoma of vagina in female children in their teens and early 20s. However, irrational fear of using drugs during pregnancy can also result in harm. This includes untreated illness, impaired maternal compliance, suboptimal treatment and treatment failures.

Such approaches may impose risk to maternal well-being, and may also affect the unborn child. It is important to know the ‘background risk’ in the context of the prevalence of drug-induced adverse pregnancy outcomes. Major congenital malformations occur in 2–4% of all live births. Up to 15% of all diagnosed pregnancies will result in fetal loss. The cause of these adverse pregnancy outcomes is understood in only a minority of the incidents.

Prescribing in Pregnancy:

In the placenta maternal blood is separated from fetal blood by a cellular membrane. Drugs can cross the placenta by active transport or by passive diffusion down the concentration gradient, and it is the latter which is usually involved in drug transfer. Placental function is also modified by changes in blood flow, and drug which reduce placental blood flow can reduce birth weight. This may be the mechanism which causes the small reduction in birth weight following treatment of the mother with b-blockers in pregnancy. Early in embryonic development, exogenous substances accumulate in the neuroectoderm. The blood-brain barrier to diffusion is not developed until the second half of pregnancy, and the susceptibility of the central nervous system (CNS) to developmental toxins may be partly related to this. The human placenta possesses multiple enzymes that are primarily involved with endogenous steroid metabolism but may also contribute to drug metabolism and clearance.

Factors to Consider

In general, most women of child-bearing age are young, fit and healthy. However in some cases the mother is on an established therapy for a pre-existing condition, such as depression or epilepsy, or she may develop a pregnancy-induced medical condition, such as hypertension or gestational diabetes. Therefore the aim of drug therapy is to limit any damage to the growing fetus while still being able to treat the mother appropriately. Ideally a detailed risk:benefit assessment of drug therapy in pregnancy should be conducted.

• The trimester in which the drug is being taken,
  
• What dose of drug is being taken,
  
• If the drug is at the lowest effective dose possible,
  
• How much is being passed through the placenta to the fetus and, consequently,
  
• If the drug is known to be teratogenic

1. Total body water and plasma volume increase during pregnancy. In addition, the concentration of plasma albumin falls, reducing protein binding of drug and consequently increasing drug plasma levels. Hence doses of highly protein-bound drugs might need to be reduced (Phenytoin, Warfarin etc.)
2. Pharmacokinetics of drug metabolism may differ in a woman during pregnancy and consequently this would need to be taken in to account during drug dosing. ( maternal underactive thyroid gland that has previously been controlled by taking levothyroxine at a particular dose may well need to be increased)
3. Drugs taken during pregnancy can act directly on the fetus causing spontaneous abortion, fetal malformations, or have no effect.
4. Drugs can also cause oxidative stress which can result in underdevelopment and malnutrition.
5. Usually very early in pregnancy, before the 20th day, there is an all-or-nothing effect whereby the fetus will abort spontaneously if the drug has caused harm, or there will be no detrimental effects to the developing fetus (Mother is usually unaware).
6. Between days 21 and 56 {approximately), following fertilization, the fetus is very susceptible to birth defects and this is when the mother has usually just realized that she is pregnant. This is the stage of organogenesis and drugs used at this stage may interfere in their development and cause a fetal malformation, or the defect may be more subtle and may not affect function to a debilitating extent or may even lead to a miscarriage.

The stage of gestation influences the effects of drugs on the fetus. It is convenient to divide pregnancy into four stages: fertilization and implatation (<>organogenesis/embryonic stage (17-57 days), the fetogenic stage and delivery.

Effects on fertilization & implantation

The principal mode of contraceptive action of progestrogens is to prevent implantation, which normally occurs 2-3 weeks after fertilization. IUCD have similar effect. Damage to the embryo before implantation results in failure of implantation and is therefore unlikely to cause fetal abnormalities.

Effects on Organogenesis/embryonic stage

The intra-uterine period between 2 weeks – 3 months is when the most serious abnormalities of fetal development can be caused by drugs. It’s during this period that the major organs are being formed. In animal studies, even one dose of a drug administered at the critical time has been shown to have a major effect.

At this stage the fetus is differentiating to form major organs and this is the critical period for teratogenesis. Teratogens cause deviations or abnormalities in the development of the embryo that are compatible with prenatal life and observable postnatally. Drugs that interfere with this process can cause gross structural defects, for example thalidomide phocomelia.

Some drugs are confirmed teratogens, but for many the evidence is inconclusive. Thalidomide was unusual in the way in which a very small dose of the drug given on only one or two occasions between the fourth and seventh weeks of pregnancy produced serious malformations. Despite its wide use it was nearly 4 years before these adverse effects were recognized.

Some drugs that are definitely teratogenic in humans.

Thalidomide Cytotoxic agents Alcohol Warfarin Retinoids Most anticonvulsants

Androgens Progestogens Diethylstilbestrol Radioisotopes Some live vaccines Lithium

Toxicity to the formed fetus

During T2 & T3 of pregnancy, adverse effects on fetus of drugs administered to the mother are generally an exaggeration of the effects seen in the adult. Exception to this rule are the damage to tissues which are still developing e.g. teeth & bones by Tetracycline, and the impairment of brain development by Coumarin anticoagulant.

Particular care must be taken with drugs given shortly before delivery. Analgesics, e.g. Meperidine (Pethidine), and tranquillizers e.g. (Benzodiazepines) may severely impair neonatal respiration. In addition, the newborn lacks many enzyme necessary for the efficient metabolism of drugs.

Adverse effects of drugs on fetal growth and development.

- Drugs used to tread maternal hyperthyroidism can cause fetal and neonatal hypothyroidism - Tetracycline antibiotics inhibit growth of fetal bones and stain teeth - Aminoglycosides cause fetal VIIIth nerve damage - Opioids and cocaine taken regularly during pregnancy can lead to fetal drug dependency

Delivery

Some drugs given late in pregnancy or during delivery may cause particular problems. Pethidine, regularly administered as an analgesic can cause fetal apnea (which is reversed with naloxone). Anesthetic agents given during Cesarian section may transiently depress neurological, respiratory and muscular functions. Warfarin given in late pregnancy causes a hemostasis defect in the baby and predisposes to cerebral hemorrhage during delivery.


Prescribing in Lactation:

During breast feeding unintentional passage of any drug to the baby through the breast milk and the effects on the newborn must be considered. In pregnancy the mother's circulation eliminates the drug for the fetus, but once born the neonate has to clear any drug itself when the organs for drug elimination (liver and kidney) are more fragile and not functioning optimally.

It is preferable that the mother stays on stabilized medication during pregnancy and continues while breastfeeding to avoid adverse or other side-effects from changing to another drug, such as with antidepressants. However, in some cases otherwise acceptable drugs used in pregnancy are contraindicated after delivery or in breastfeeding, and prescribing an alternative, more appropriate drug would be considered at this stage. For example, methyldopa is the drug of choice for high blood pressure in pregnancy and although it is also safe in lactation, there is an increased risk of postnatal depression in women taking methyldopa; therefore it would be changed to an alternative drug postnatally.

Other factors to consider in prescribing in lactating mothers is the percentage of the drug passed into breast milk, its half-life, and whether the baby was born at term and is healthy and able to tolerate this drug, which would depend on its gestational age. Drugs taken by the mother may not be absorbed - Fybogel, Lactulose, some antibiotics such as oral vancomycin, or the antifungal, nystatin, Insulin and heparin are too large to pass into breast milk and these are usually safe. Some drugs pass in to breast milk in small amounts. In some cases this would be below therapeutic levels in the baby so would not appear to cause any adverse effects. However, a neonates organs are not fully functioning in the first few weeks of life meaning a drug could potentially accumulate over days in the neonates bloodstream, which may cause adverse side- effects. In other cases even small amounts of a drug can be harmful to the neonate, e.g. methotrexate and should therefore be avoided altogether, or the mother should consider not breastfeeding.



Specific scenarios:

1. Analgesia in pregnancy and lactation:
   
• The drug of choice for pain relief in pregnancy is paracetamol.
• Weak opioids like codeine may be used if pain is not manageable.
• Pethidine is used as analgesia in labour as it is short- acting and its effects can be controlled.
• NSAIDs are altogether avoided because of risk to premature closure of ductus arteriosus, high risk of miscarriage due to inhibition of prostaglandin synthesis - however low dose aspirin might be used in women with PIH, umbilical placental insufficiency and clotting disorders such as lupus coagulant, Factor V Leiden and protein C deficiency, or pre-eclampsia.
• Drug of choice for pain relief during lactation is paracetamol. Tn the case of more severe pain, NSAIDs such as ibuprofen and diclofenac, are preferred. Although aspirin passes into breast milk in only small amounts, it should be avoided to prevent the risk of Reye's syndrome in children.
• Weak opiates, such as codeine and dihydrocodeine, may be used in lactation but can cause colic and constipation in the infant.
2. Antihypertensives in pregnancy and lactation:
• Angiotensin II receptor antagonists, angiotensin converting enzyme (ACE) inhibitors and the beta blocker, atenolo!, are contraindicated in pregnancy because of their adverse effects on the fetus and fetal growth.
• Drugs of choice to lower high blood pressure in pregnancy are methyldopa, labetalol or nifedipine, all of which have been used safely previously.
• Some beta blockers that have low protein binding, e.g. atenolol and acebutolol, increase bioavailability of the drug in breast milk and should be avoided because of the effects of neonatal bradycardia, otherwise all anti-hypertensives are safe during lactation.
3. Antidepressants in pregnancy and lactation:
• The SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) are now most commonly prescribed to new patients as they are better tolerated than other classes of antidepressants.
• Fluoxetine has been the most extensively studied of the SSRIs in pregnancy and offers no increased risk of miscarriage, malformation or neurodevelopment to the fetus and long term.
• The SSRIs of choice for lactating women are those with the shortest half-life, i.e. tluvoxamine, paroxetine or sertraline with half lives between 17 and 26 hours. However, infants should be monitored for symptoms (owing to drug accumulation) such as excessive crying, poor sleep, irritability and colic.
4. Anticonvulsants in pregnancy and lactation:
• Epilepsy in pregnancy can lead to fetal and maternal morbidity/mortality through convulsions whilst all the anticonvulsants used have been associated with teratogenic effects, for example phenytoin is associated with cleft palate and congenital heart disease.
  
• However, there is not doubt the benefits of good seizure control outweigh the drug-induced teratogenic risk.
  
• Thorough explanation to the mother, ideally before a planned pregnancy, is essential and it must be emphasized that the majority of epileptic mothers haver normal babies (>90%). (The usual risk of fetal malformation is about 2%. In epileptic mothers it is up to 10%).
  
• In view of the association of spina bifida with sodium valproate and carbamazepine therapy it is often recommended that the standard dose of folic acid be increased to 4-5 mg daily. Both these anticonvulsants cause hypospadias.
  
• As in non-pregnant epilepsy single drug therapy is preferable.
  
• Plasma concentration monitoring is particularly relevant for phenytoin because the decrease in plasma protein binding and the increase in hepatic metabolism may cause considerable changes in the plasma concentration of free (active.
5. Antiemetics in pregnancy and lactation:

• Nausea and vomiting are common in early pregnancy but are usually self-limiting and ideally should be managed with reassurance and non-drug strategies such as small frequent meals, avoiding large volumes of fluid and raising the head of the bed.
  

• If symptoms are prolonged or severe, drug treatment may be effective.

• Meclozine and cyclizine are commonly used although both have been weakly associated with an increased risk of congenital malformations.

• Metoclopramide is considered safe and efficacious in labor and before anesthesia in late pregnancy but its routine use in early pregnancy cannot be recommended because of lack of controlled data, and a significant incidence of dystonic reactions in young women.

6. Drugs for Acid-peptic and constipation during pregnancy and lactation:

• The high incidence of dyspepsia due to gastro-esophageal reflux in the second and third trimesters is probably related to the reduction in lower esophageal sphincter pressure.
  

• Non-drug treatment - reassurance, small frequent meals and advice on posture - should be pursued in the first instance particularly in the first trimester. Fortunately most cases occur later in pregnancy when non-absorbable antacids such as alginates should be used.
  

• In late pregnancy metoclopramide is particularly effective as it increases lower esophageal sphincter pressure.

• There are inadequate safety data on the use of H₂-receptor blockers and omeprazole in pregnancy.
  

• Sucralfate has been recommended for use in pregnancy in the USA and is rational as it is not systemically absorbed.
• Misoprostol, a prostaglandin which stimulates the uterus, is contraindicated because it causes abortion.
  

• Constipation should be managed with dietary advice. Stimulant laxatives may be uterotonic and should be avoided if possible.

7. Anticoagulants in pregnancy and lactation:

• Warfarin has been associated with nasal hypoplasia and chondrodysplasia when given in the first trimester and CNS abnormalities after administration in later pregnancy, as well as a high incidence of hemorrhagic complications towards the end of pregnancy. Neonatal hemorrhage is difficult to prevent because of the immature enzymes in fetal liver and low stores of vitamin K.

• Heparin, which does not cross the placenta, is the anticoagulant of choice in pregnancy although chronic use can cause maternal osteoporosis.
  

• Women on long-term oral anticoagulants should be warned that these drugs are likely to affect the fetus in early pregnancy.
  

• Subcutaneous heparin (usually self-administered) must be substituted for warfarin as soon as possible, well before the critical period of 6-9 weeks´ gestation. Subcutaneous heparin can be continued throughout pregnancy but due to the risk of maternal osteoporosis and thrombocytopenia warfarin may be considered as an alternative during the second trimester changing back to heparin at 36 weeks.
  

• Patients with prosthetic heart values present a special problem: in these patients in spite of the risk to the fetus warfarin is often given up to 36 weeks.

• The prothrombin time/international normalized ratio (INR) (warfarin) or APTT (activated partial thromboplastin time) (heparin) should be monitored closely.

8. Hormones in pregnancy and lactation:
   

• Progestogens, particularly synthetic ones, can masculinize the female fetus. There is no evidence that this occurs with the small amount of progestogen (or estrogen) in the oral contraceptive: the risk applies to large doses.
• Corticosteroids do not appear to give rise to any serious problems when given via inhalation or in short courses. Transient suppression of the fetal hypotlalamic-pituitary-adrenal axis has been reported. Rarely cleft palate and congenital cataract have been linked with steroids in pregnancy but the benefit of treatment usually outweighs any such risk.

• A detailed risk:benefit assessment of drug therapy in pregnancy should be conducted.
• There are altered pharmacokinetics in the pregnant woman affecting drug metabolism and elimination.
• It is important to consider the trimester of pregnancy when prescribing.
• Known teratogenic drugs must be avoided in pregnancy.
• Some acceptable drugs used in pregnancy may be contraindicated after delivery or in breastfeeding and vice versa; the two should be considered independently.
• Drug prescribing in the breastfeeding mother depends on the percentage of drug passed in to breast milk, the drug half-life, and whether the baby was born at term and is healthy.

Essential drugs are those that satisfy the health care needs of the majority of the population; they should therefore be available at all times in adequate amounts and in the appropriate dosage forms.

The first WHO model list of essential drugs was published in 1975.Since 1977, WHO has promoted the use of limited Essential Drug Lists (EDL) as part of Essential Drug Concept. Initially drugs were selected on the basis of experience. Recently WHO has begun to advocate a change towards an “evidence-based” approach. The Indian government published its first National Essential Drugs list (EDL) in 1996, and some state governments have also adopted an EDL. It is believed that only about 250 drugs are essential to treat the majority of diseases in a country. Selecting some drugs as part of the EDL does not lower the importance of other drugs - a list of essential drugs is a positive list, mainly intended to define priority drugs for public procurement and reimbursement, and for training of health personnel


Selection of Drugs in EDL

1. Pattern of prevalent diseases
• Drugs required for national programs given priority
  
2. Treatment facilities available
3. Training and experience of available personnel
4. Safety, Efficacy, Cost and Ease of administration
• Generics are cheaper
• Newer is not always better
  
5. Storage conditions
• Good manufacturing processes
  
6. Patient acceptability
7. Medicine Surveys
• To measure effects of information/regulation on drug usage pattern
• To study absolute/relative efficacy and safety
• To indicate overuse/under use or misuse of drug/drug classes
  

1. Use of medicine when no drug therapy is needed (antibiotics in viral upper respiratory tract infections)
2. Use of wrong medication for conditions requiring specific drug therapy (Fixed drug combination of Norfloxacin and Metronidazole in diarrhea)
3. Use of medicine of doubtful or unproven efficacy (Vitamins in the absence of deficiency)
4. Use of medicine of uncertain safety (ayurvedic bhasmas)
5. Failure to prescribe available, safe and effective agents (Under use of antidepressants or antihypertensives)
6. Incorrect administration, dosages or duration.
7. Use of too many drugs per patient (Polypharmacy)
8. Use of injections when oral formulations available
9. Inappropriate self-medication, often of prescription only medicine
10. Incorrect treatment of disorders
11. Poor compliance

1. Misinformation, misleading beliefs or inability to communicate symptoms correctly on part of the patient.
• Wants quick response - believes injections work faster
• Unhappy if no medicine prescribed
• compliance is big problem - once symptoms subside, stops treatment
• Adherence of patients to a treatment program is necessary for the success of the program. Non-adherence or non compliance results from factors related to the drug, the patient, the prescriber and the environment.
  
• Almost all drugs available OTC
  
2. Lack of accurate and correct information of newer agents, workload and pressure to prescribe on part of the prescribers
• Poor diagnostic support - empirical treatment
  
• No evidence based guidelines readily available
• Continuing education programmes
  
3. Poor medical facilities and supply of drugs
• Vaccines and many other drugs not stored at required temparature
• Over 80,000 formulations in the country, many doubtful value
  
4. Inadequate drug regulation -
• Process for marketing approval of new drugs
• Controls on OTC drugs
• More effective definition of prescriber
• Quality assurance of products
• good drug distribution systems
• availability and price control of essential drugs
• Unbiased drug information
• Unethical promotion of drugs
  

• Poor quality of health care delivery - Increased morbidity and mortality
• Waste of scant resources on using wrong medicine
• Irrational drug use leads to ineffective and unsafe treatment, worsening or prolonging of illness and adverse drug reactions.
  
• It also unnecessarily adds to the economic burden of the patients, the government or the insurance system.
  
• The widespread antibiotic resistance is also partly a result of irrational use of antibiotics.
  

1. Define the patient's problem - define the therapeutic objective

2. Use drug only when indicated and when potential benefits outweigh any risks

1. seriousness of the problem to be treated
   
2. efficacy of the drug to be used
   
3. severity and incidence of possible ADRs
   
4. safety and efficacy of alternative drugs if any
   
• e.g., phenylbutazone, commonly used in the treatment of osteoarthritis in the past, because of its high benefit-to-risk ratio, is currently replaced with safer drugs.
5. Assessment of benefit-to-risk ratio may not always be easy. The following examples show this problem:
• The benefit of adding digoxin to a diuretic and vasodilator vis- à-vis the risk of its toxicity in the treatment of congestive cardiac failure. This might depend on the cause of the heart failure, patient compliance, renal function and ease of monitoring of plasma digoxin concentration
  
• The benefit from a course of antibiotic in treating urinary tract infection in two months pregnant as compared to the risk of treatment to the fetus. Here the risk of teratogenesis needs to be compared to the risk of renal damage to the mother as a result of untreated infection
  

3. Choose a drug of proven efficacy and safety, which is suitable and affordable for the patient

• The use of International Non Proprietary Names (INN) or generic names of drugs in prescribing is an essential component of good prescribing practice. This is because generic drugs are less costly, an important factor in our country, and for a generic prescription any suitable product can be dispensed hence avoiding delay while looking for a specific brand.
  
• Avoid same class drug

4. Choose suitable dose

1. Route of administration: e.g.,
   
• Crystalline penicillin is given by intravenous route for severe infections; Intramuscular benzathine penicillin monthly or oral penicillin daily can be given for rheumatic fever prophylaxis.
  
• Beta agonists like salbutamol are given through nebulizers or inhalers in acute asthmatic attack for fast action.
2. Formulations : e.g.,
   

• Timing of drug administration: The following are examples where timing is very important
  
• To minimize ADR: tricyclic antidepressants to avoid dry mouth and drowsiness better to take it at bed time; potent diuretics better be given in the morning to avoid disturbance during the night
  
• Timing of symptoms: e.g., anginal attack, use of antacids
  
• Timing in relation to meals: penicillin to be administered before meal; aspirin to be administered with meal
• Inform the patient - dose, duration, adverse effects if any
• Monitor treatment
• If drug ineffective find reason, any changes needed or monitoring required
• Whether to continue drug or stop

• Depends on the nature of the disease or symptom: e.g., A single dose of aspirin for headache;Insulin for chronic therapy; treatment with H₂ blockers require six weeks as healing occurs with in this period, but longer periods of nightly administration may be required to prevent recurrence.
• Duration of treatment of infection depends on: The infecting organisms , Site of infection, Response to treatment, Dosage of antibiotics

• Informing and persuading prescriber - from students to practicing clinicians and community (teaching, seminars, face to face talks, distribution of printed matter, television etc)

Factors to consider when prescribing drugs dependent on hepatic elimination

• Ascertain how much the drug depends on hepatic metabolism for its elimination from the body.
• Determine the degree of hepatic impairment using the Child-Pugh classification, hepatic enzyme levels and possibly an ultrasound of the liver with portal vein Doppler study.
• If there is doubt about the degree of hepatic impairment or the drug has a narrow therapeutic index (that is, the upper dose range for efficacy is close to the lower concentration range of toxicity), then lower the recommended starting dose by approximately 50%, and titrate to effect under careful supervision – 'start low and go slow'.
• Determine possible interactions between the new drug and any drugs the patient is already taking.

Conclusion:

Historically, herbs and drugs have been two very different treatment modalities, which have rarely been used together. The line that separates herbs and drugs, however, has been blurred in recent decades with the increased accessibility to the lay public of different treatment modalities. Even though herbal products are available without prescription, medical guidance is necessary because of the adverse effects of these products and the potential for drug interaction.

The solution to this situation lies in the understanding of drug-drug and drug-herb interaction in detail with scientific evidence. With understanding of these mechanisms, one can recognize potential interactions and take proper steps to prevent their occurrence.