Drugs in Obstetrics & Gynecology Ashok Kumar, Krishna Agarwal, Sudha Prasad
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1Principles of drug therapy
CHAPTER
  • 1. Rational Drug Therapy2

Rational Drug TherapyCHAPTER 1

Krishna Agarwal
 
INTRODUCTION
‘Rational drug therapy’ literally means using a right drug in right dose and for right duration. The irrational use of drugs is not only dangerous in short-term but is on its way to cause long-term destructive consequences.
The concept of rational drug use is age old. Reference about ‘rational drug use’ has been made as early as 300 BC by an Alexandrian physician Herophilus who stated that “medicines are nothing by themselves but are the very hands of god if employed with reason and prudence”.
 
Definition
WHO defines rational drug use as “rational use of drug requires that patient receives medication appropriate to their clinical needs in doses that meet their own individual requirements for an adequate period of time, at the lowest cost to them and their community.1
This definition requires following criteria (IA-PIM) to be fulfilled:
  • Appropriate indication: It is based on the medical rationale that the drug is effective and safe in a particular clinical situation.
  • Appropriate agent: Selection of drug is based on the efficacy, safety and cost of the therapy.
  • Appropriate patient: Drug is acceptable to the patient, no contraindications and the possibility of adverse drug reaction is minimum.
  • Appropriate information: Patient should be given information regarding the disease and medicines which are prescribed.
  • Appropriate monitoring: Any unexpected effects of drug should be monitored and appropriate measures taken.
However, more often than not, prescriptions do not follow the steps and are irrational with respect to one or more reasons.
 
Epidemiology
 
Magnitude of Irrational Drug Use
Unfortunately, irrational use of drugs is rampant all over the globe including India. It is estimated that half of the prescriptions are irrational.
Various studies from developing and developed world have revealed the pattern of irrationality such as drug not related to diagnosis, use of costlier drugs when the cheaper and effective drugs are available, polypharmacy (defined as prescription, administration, or use of more medications than are clinically indicated, or when a medical regimen includes at least one unnecessary medication), improper use of antibiotics, irrational self-medication and inadequate dose of medications.2
Studies from Canada, USA, Australia have revealed that the irrational drug use is 4quite prevalent even in the developed world. A Canadian study from a teaching hospital revealed 50% of the prescriptions of antibiotics in gynecologic patients were irrational and of these 86.8% irrational prescriptions were used for prophylaxis.3 Study from USA revealed 41% cases with inappropriately used antibiotics in hospital patients.4
A study from a teaching hospital in South Africa showed 54% irrational drug use in gynecology in patients.5 A study from university care center from Croatia highlighted high prescription rate of antibiotics, concomitant use of antibiotics with a similar spectrum of activity.6
A study on the use of antimicrobials in obstetrics and gynecology in a tertiary care unit of India revealed that antibiotic use was to the tune of 95%. Out of these only 12% (42/340) prescriptions were rational, 33% (112/340) were semirational and 40% (136/340) were irrational.7 Study from city of Jammu showed that drugs used were inappropriate in 33% cases and large number of prescriptions did not confirm to ideal patterns.8
 
Impact on Morbidities, Mortality, Economic Burden and Hospital Stay
Irrational drug use may lead to increase in morbidity and sometimes even mortality tA recent review by Institute of Medicine, USA has estimated that 1 out of 131 outpatients and 1 out of 854 inpatients die due to medication error.9
A few studies from India reveal that antibiotics are being misused which increases the cost of therapy several times resulting in economic burden on already compromised health system. In an Indian study it was estimated that this irrational use had led to 75% extra cost of the treatment.7
In a study from Pakistan, it was seen that after use of antibiotics according to ACOG guidelines, the cost of antibiotics per patient was reduced by 90%. Decrease in the length of hospital stay and workload on nursing staff was also observed.10
 
Common Forms of Irrationality in Drug Use
Antimicrobials, analgesics and supplements are the most commonly used but sadly the most commonly misused drugs.
 
The Antimicrobials
Widespread irrational use of antibiotics is a vivid example of irrationality which has started showing off its devastation in form of immerging antimicrobial resistance (AMR).
It has been known that antibiotics affect healthy gut flora and diarrhea is a common side effect of some of the antibiotics. Diarrhea is common with the use of amoxicillin and clavulanic acid. Fluoroquinolone, a commonly used antibiotic, is known to affect the microbiome. Frequent and irrational use of antibiotics has been linked to a change in human microbiome and many diseases. The human microbiome constitutes healthy microorganisms residing in our body—skin, gastrointestinal tract, respiratory tract, genital tract, surface of eyes and others. Recently, this change in microbiome has been even linked with the diabetes, hypertension, asthma and even obesity.11,12
Irrational use of antibiotics is common in obstetrics and gynecology (Table 1.1). We need to base our prescriptions of antibiotics after carefully considering the clinical evidence, sensitivity pattern of the causative agent for a particular condition, local or national guidelines and choosing as far as possible from the essential drug list (prescribed by the hospital, country or World Health Organization).
Use of antimicrobials can be rationalized if the individual hospitals develop their own guidelines based on the national and international guidelines.5
Table 1.1   Antimicrobials in obstetrics and gynecology
S. No.
Clinical situation
Common irrationality
Rational use
1.
Normal vaginal delivery with or without episiotomy
Oral antibiotics such as ampicillin, metrogyl, amoxicillin—clavulanic acid and cephalexin are commonly used for 5–7 days
No prophylactic antibiotic is required. Maintaining proper asepsis is what is sufficient13,14
2.
Elective cesarean section
Injectable antibiotics—ampicillin, gentamicin, metronidazole, cephalosporins, amoxicillin-clavulanic acid given for 5–7 days
Cefazolin 1–2 g IV
or
Clindamycin 600 mg IV
or
Erythromycin 300 mg IV 15–60 minutes before the incision13,14
3.
Emergency cesarean section
Fixed drug combinations—ceftazidime, gentamicin and metronidazole for 7–10 days
Same as above
However, if the procedure extends beyond 3 hours or bleeding more than 1500 mL, one more dose needs to be given13,14
4.
Preterm premature rupture of membrances (PPROM)
Ampicillin + gentamicin + metronidazole for 10–14 days
Ceftazidime + gentamicin + metronidazole for 10–14 days
Erythromycin 250 mg 6 hourly for 10 days
5.
Preterm labor with intact membranes
Ampicillin + gentamicin + metronidazole for 10–14 days
Ceftazidime + gentamicin + metronidazole for 10–14 days
No antibiotics
6.
Elective total abdominal hysterectomy
Ampicillin + gentamicin + metronidazole for 10–14 days
Ceftazidime + gentamicin + metronidazole for 10–14
Single dose of injection cefazolin 1–2 g IV
Or
Clindamycin 600 mg IV
or
Erythromycin 300 mg IV, 15–60 minutes before the incision15
7.
Infertility
Rampant use of ATT on positive polymerase chain reaction (PCR) for tuberculosis (TB) in blood
PCR for TB based on detection of DNA and RNA of tubercular bacillus is a nonspecific test. In a meta-analysis, sensitivity and specificity of PCR for TB ranged from 9% to 100% and from 25% to 100%, respectively.
ATT should be started on only a strong suspicion and in consultation with a DOTS center16
8.
Upper respiratory infection (URI) and viral fevers
Levofloxacin, ceftazidime,
Amoxicillin and clavulanic acid combination for variable duration
No antibiotics required6
 
Analgesics
Use of analgesics is another example of dug misuse (Table 1.2). Analgesics are being given for relief of pain without finding out the cause which may lead to prolongation of disease. Giving long-term analgesics could cause addiction or even have bad effect on the important organs like liver and kidney.
 
Supplements
During pregnancy, supplementation of only iron and folic acid is recommended by World Health Organization and the Government of India. Rest all supplements are of no proven benefit. However, the prescriptions in antenatal patients are replete with all micronutrients and protein powder. These all drastically increase the cost of therapy with possible side effects or harmful effects (Table 1.3).
 
Hormones
Use of various progestogens during pregnancy is quite common (Table 1.4). It is prescribed even to the pregnant women with no high risk factors. This practice of prescribing progestogen thinking that “even if there no benefit it would not cause any harm to the woman,” should be stopped.
Table 1.2   Analgesic use in obstetrics and gynecology
S. No.
Clinical situation
Common irrationality
Rational use
1.
Chronic pelvic pain
Long-term use of NSAIDs (diclofenac) and opioids (tramadol)
Find out the cause of pain (endometriosis), evaluate for depression or sexual abuse and treat the cause
2.
Postoperative pain
Round the clock injectable diclofenac or tramadol for up to 7–10 days
After 48 hours analgesics could be given on demand
Table 1.3   Supplements use during pregnancy
S. No.
Clinical situation
Common irrationality
Rational use
1.
Low risk and high risk pregnancies
Multivitamin commonly prescribed
No proven role and should not be prescribed16
2.
Low risk and high risk pregnancies
Micronutrients which include zinc, copper, magnesium, selenium
No proven role and should not be prescribed17
3.
Pregnancies at risk of pre-eclampsia- history of pre-eclampsia in previous pregnancy or current gestational hypertension
Antioxidants
Role in pre-eclampsia is proposed but not yet proven, should not be prescribed.18
Table 1.4   Progestogen use during pregnancy
S. No.
Common prescribed
Common irrationality
Rational use
1.
Micronized progestogen or hydroxyprogesteron injections in treatment and prophylaxis of threatened miscarriage
No proven role
Should not be prescribed.19,207
 
Drugs Used in Pre-eclampsia and Eclampsia
Pre-eclampsia and eclampsia, which are one of three leading causes of maternal deaths, if not treated properly could lead to maternal mortality. Administration of magnesium sulfate as anticonvulsant and hydralazine or labetalol as antihypertensive is the first drug of choice. Use of diazepam for control of convulsion or frusemide for control of hypertension could result in maternal death (Table 1.5).
 
Drugs During Labor
A woman in labor mostly requires monitoring and no medications. Induction of labor is being performed without any indication. Woman in latent phase or active phase of labor are being started oxytocin infusion and given antispasmodics for pain relief. These medications have no role and may sometimes harm the patient (Table 1.6).
 
Antenatal Steroids
Antenatal steroids are used in women at risk of preterm vaginal delivery. However, multiple courses and its use beyond 34 completed weeks is common (Table 1.7).
 
Drugs Used for Ovulation-induction
As the incidence of infertility is on the rise, there is increase in the rate of complications due to misuse of drugs used for its treatment (Table 1.8).
 
Measures for Promoting Rational Drug Use
To fulfill the IA-PIM criteria for rational drug prescription (WHO), process of prescribing would require stepwise approach in following manner:
  • Defining patient's problem (diagnosis)
  • Defining effective and safe treatment (drugs and nondrugs)
    Table 1.5   Use of anticonvulsants and diuretics in pre-eclampsia and eclampsia
    S. No.
    Clinical situation
    Common irrationality
    Rational use
    1.
    Eclampsia
    Intravenous diazepam for control of convulsions
    Could lead to respiratory depression and death. IV loading dose of magnesium sulfate should be given
    2.
    Pre-eclampsia, eclampsia
    Injectable furosemide for control of blood pressure
    Could lead to shock and death. For control of BP, IV labetalol or nitroglycerine infusion can be used
    Table 1.6   Commonly used drugs during labor
    S. No.
    Clinical situation
    Common irrationality
    Rational use
    1.
    Woman admitted in labor
    Use of enema
    Increases incidence of neonatal infection. Should not be used
    2.
    Woman admitted with labor pains
    Augmentation of labor with oxytocin infusion
    No need for augmentation in a low risk woman, it increases incidence of fetal distress, rate of cesarean section and increased risk of birth asphyxia
    3.
    For relief of pain in labor
    Use of antispasmodics like hyoscine bromide
    No proven role21
    4.
    In advanced labor to increase softness and dilatability of cervix
    Use of valethamate bromide
    No proven role218
    Table 1.7   Use of steroids during pregnancy
    S. No.
    Clinical situation
    Common irrationality
    Rational use
    1.
    Pregnancy before 34 weeks of pregnancy
    Repeated doses of dexamethasone or betamethasone
    Can cause fetal growth restriction, not indicated
    2.
    Preterm labor beyond 34 completed weeks
    Antenatal steroids
    No benefit
    Table 1.8   Ovulation inducing agents for treatment of infertility
    S. No.
    Clinical situation
    Common irrationality
    Rational use
    1.
    Infertility
    Use of clomiphene without ruling out all causes of infertility
    Establish that the couple is infertile and that anovulation is the cause of infertility and all other causes have been ruled out
    2.
    Infertility
    Use of latrozole
    Should not be used, banned by DCGI because of suspicion that it increases risk of congenital malformations
  • Selecting appropriate drug/drugs, dose, and duration
  • Writing the prescription
  • Providing adequate information to the patient
  • Planning for evaluation of treatment response.
 
Defining Patient's Problem
This is the basic requirement for drug prescription. The physician must confirm the diagnosis before prescribing the medicine.
Like in a case of chronic pelvic pain, cause of pain should be established before prescribing her the medicine. Before starting ovulation induction, ensure that the cause for infertility is defective ovulation and all other causes of infertility have been ruled out.
 
Defining Effective and Safe Treatment (Drugs and Nondrugs)
Once diagnosis is established, next step is to know what would be the effective as well as safe treatment for the patient. Use of a drug should be based on the clinical guidelines which may be hospital based, national or international guidelines. In the absence of any such guidelines, the treatment may be based on the evidences which may be in the form of meta-analysis, systematic reviews, well conducted randomized controlled trials or sometimes the cohort studies.
 
Selecting Appropriate Drug(s), Dose and Duration
The knowledge regarding the available drugs for a particular condition and choosing amongst them the first drug of choice after excluding the contraindications for that drug would constitute the rational use.
Use of hospital drug formulary, national drug formulary or even choosing from the WHO essential drug list would take care of this aspect of rational drug therapy. WHO essential drug list enlists the most suitable drugs to be used in common clinical conditions of different specialties. Sometimes if the guidelines are not available or the drug is not included in the essential drug list then, drug treatment should be based on the clinical evidences.9
 
Writing the Prescription
This step in drug therapy is very important. Literature is full of untoward incidences due dispensing of wrong drugs because the prescription was not written clearly. Even MCI has given directions to practitioners to use capital letters while writing the names of the drugs. The MCI directs to write generic names. It has been proven that when generic names are used, it has helped in rationalizing the drug use by directly linking the disease and the drug.22
The prescription should be written on a proper drug slip meant for writing a prescription. For a private practitioner, the prescription slip carries name, address and phone numbers of the prescriber.
Patient's name, age, address and date should be written. Symbol Rx is written before writing the drug name. This is an abbreviation for a Latin phrase that means “take thou.” Dose of the drug, frequency, route of administration and duration of the drug intake should be clearly mentioned. In the end the prescriber should sign the prescription. Every aspect of prescription writing is important and the clinician must master the art of prescription writing during their training.
 
Providing Adequate Information to the Patient
Patient is provided with the information about what would be the effect of drug, how to take the medicine and for how much duration. The patient should be warned about the side effects of a particular drug and what to do if patient has some side effects.
 
Planning for Evaluation of Treatment Response
This step should always be a part of drug therapy and evaluation may be planned in a way which is convenient to the patient. Quality improvement (QI) initiatives at national and hospital level could provide guidance on the rationality of drug use. A QI in a tertiary care hospital in Pakistan has proved to effectively decrease the use of irrational antibiotics. This study revealed that use of antibiotics according to ACOG guidelines led to decrease in the use of antibiotics from 97% to 8% and surgical site infections rates came down to less than 5%.11
 
Regulatory Body for Promotion of Rational Use
There is a national regulatory body in India that guides us about the use of drugs and provides some safeguard in case of an untoward adverse drug reaction.
 
Central Drug Standard Control Organization (CDSCO)
It is the national regulatory agency for Indian pharmaceuticals and medical devices. It serves same function in India as the Food and Drug Administration (FDA) in United States.
It is headed by Drug Controller General of India (DCGI). DCGI is responsible for approval of new drugs, conduct of clinical trials in the country, laying down standards for drugs, controls the quality of imported drugs, coordination of the activities of State Drug Control Organizations and provision of expert opinion about the enforcement of Drugs and Cosmetics Act. The office of CDSCO is located at FDA Bhawan, Kotla Road, New Delhi 110002 and functions under the Directorate General of Health Services.
The Central Government has established four zonal offices of the Central Drug Standard Control Organization at Mumbai, Kolkata, Chennai, and Ghaziabad. The zonal offices work in close collaboration with the State Drug Control Administration and assist them in securing uniform enforcement of the Drug Act and other connected legislations, on all India basis.
 
Pharmacovigilance
This is a relatively new concept for enhancing the rational drug use.2310
WHO defines pharmacovigilance (PV) as the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug-related problem. It established its International pharmacovigilance program after the Thalidomide disaster detected in 1961. It promotes PV at country level and by the end of 2010, 134 countries including India were part of WHO PV program.
The Pharmacovigilance Program of India (PVPI) was started in India in July 2010 by CDSCO under the aegis of Ministry of Health and Family Welfare. At present the national coordinating center for PVPI is Indian Phamacopoeia Commisssion (IPC), Ghaziabad, UP. Any adverse drug reaction should be informed to the office of PvPI on following address:
Secretary-cum-Scientific Director
Indian Pharmacopoeia Commission
Ministry of Health & Family Welfare
Government of India
Sector-23, Raj Nagar, Ghaziabad-201 002
Telephone: 0120-2783400, 2783401, 2783392,
FAX: 0120-2783311
E-mail: ipclab@vsnl.net
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