Drugs Used in Pregnancy

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Drugs Used In Pregnancy
PHARMACOKINETIC CONSIDERATIONS •most drugs can cross the placenta •risk of pharmacologic and teratogenic effects •critical factors affecting placental drug transfer and drug effects on the foetus include •the physicochemical properties of the drug •the rate at which the drug crosses the placenta and the amount of drug reaching the foetus •the duration of exposure to the drug •distribution characteristics in different foetal tissues •the stage of placental and foetal development at the time of exposure to the drug •the effects of drug interaction •lipid solubility •lipophilic drugs diffuse readily and rapidly across the placenta and enter the foetal circulation •intravenous anaesthetic agents cross the placenta almost immediately and can produce sedation or apnoea in newborn •small amounts of unionised salicylate is highly lipid soluble and crosses placenta rapidly •ionization •highly ionised drugs crosses the placenta slowly and achieve very low concentrations in the foetus •muscle relaxants - succinylcholine, tubocurarine •impermeability of the placenta to polar compounds is relative rather than absolute •can be influenced by high enough concentration gradients •molecular size •molecular weights •250-500 D : cross placenta easily depending on their lipid solubility and degree of ionization •500-1000 D: cross the placenta with more difficulty •>1000 D : cross the placenta very poorly •applications •choice of anticoagulant in pregnant women •heparin (large molecular weight, polar) •warfarin is contraindicated •exceptions to the size rule •maternal antibody globulins and certain polypeptides cross the placenta by unidentified selective mechanisms •protein binding •degree of binding to plasma proteins affects the rate of transfer and the amount transferred across placenta •transfer of poorly lipid soluble and ionised drug will be slow if also highly bound to maternal plasma proteins •very lipid soluble compounds will not be greatly affected by protein binding •transfer of such drugs dependent on and proportionate to placental blood flow

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•foetal proteins have lower binding affinity for •sulphonamides, barbiturates, phenytoin, and local anaesthetic agents •drugs which are least protein bound cross the placenta more readily resulting in a higher UV/MV ratio •UV/MV ratio (pKa) •lignocaine 0.52-0.69 (pKa 7.85) •mepivacaine 0.69-0.71 (pKa 7.65) •bupivacaine 0.31-0.44 (pKa 8.05) •low foetal α1-acid glycoprotein concentrations lead to low plasma binding of drugs •placental drug metabolism •placenta has monoamine oxidase, cholinesterase, microsomal drug-metabolising enzyme systems •metabolic activities include oxidation, reduction, hydroxylation, N-dealkylation, demethylation (pentobarbitone is metabolised here), hydrolysis, and conjugation •toxic metabolites may result (ethanol, benzpyrenes) •foetal drug metabolism •40-60% of umbilical venous blood enters foetal liver, a drug that enters the liver may be partially metabolised before reaching the circulation •active metabolites may adversely affect the foetus •foetal hepatic extraction of drugs protects the brain and myocardium of the foetus to some extent against high circulating drug concentrations •at third month of gestation, cytochrome P450 is present in foetal liver •glucuronyl transferase activity extremely low •drug uptake and distribution in mother •biochemical and physiological changes •gastrointestinal motility is decreased, gastric emptying time may increase by 30-50% •will alter the rate of drug absorption from GIT •during later stage in labour, drug absorption from GIT is greatly delayed after receiving opioids (pethidine, heroin, pentazocine, but not by epidural analgesia •hypoproteinaemia, modifying drug binding during pregnancy •blood volume increases by 30-40% during pregnancy •proliferation of smooth endoplasmic reticulum •indicating an increase in hepatic microsomal enzyme activity •renal plasma flow and glomerular filtration rates increase •renal clearance of drugs may be modified .

Drugs Used In Pregnancy
FDA PREGNANCY CATEGORY LABELING OF DRUGS Category A •Description: Controlled studies show no risk-Adequate, well-controlled studies in pregnant women have failed to demonstrate a risk to the foetus in any trimester of pregnancy. Category B •Description: No evidence of risk in humans-Adequate, well controlled studies in pregnant women have not shown increased risk of foetal abnormalities despite adverse findings in animals, or In the absence of adequate human studies, animal studies show no foetal risk. The chance of foetal harm is remote, but remains a possibility. Category C •Description: Risk can not be ruled out- Adequate, wellcontrolled human studies are lacking, and animal studies have shown a risk to the foetus or are lacking as well. There is a chance of foetal harm if the drug is administered during pregnancy; but the potential benefits may outweigh the potential risk. Category D •Description: Positive evidence of Risk-Studies in humans, or investigational or post marketing data, have demonstrated foetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life threatening situation or serious disease for which safer drugs cannot be used or are ineffective. Category X •Description: Contraindicated in Pregnancy- Studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of foetal abnormalities or risk which clearly outweighs any possible benefit to the patient EFFECTS OF DRUGS IN THE FOETUS •therapeutic drug actions •corticosteroids are used to stimulate foetal lung maturation when premature birth is expected •phenobarbitone when administered to the mother near term, •can induce foetal hepatic enzymes responsible for the glucuronidation of bilirubin •has been shown to decrease the risk of intracranial bleeding in preterm infants •antiarrhythmic agents have been given to mothers for treatment of foetal arrhythmias •toxic drug actions •chronic use of opioids •may produce dependence in the foetus and newborn •may manifest after delivery as neonatal withdrawal syndrome

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•high doses of ethanol (especially during 1st and 2nd trimesters) •foetal alcohol syndrome, central nervous system, growth and facial development may be affected •angiotensin-converting enzyme inhibitor •can result in irreversible renal damage in the foetus (contraindicated in pregnant women) •diethylstilbestrol •at risk for adenocarcinoma of vagina after puberty •teratogenic drug actions •teratogen •causes a characteristic set of malformations, indicating a selectivity for certain target organs •exerts its effects during organogenesis •shows a dose-dependent incidence •mechanisms •a direct effect on maternal tissues with secondary or indirect effects on foetal tissues •interfere with the passage of oxygen or nutrients through the placenta and therefore have effects on the most rapidly metabolising tissues of the foetus •direct actions on the processes of differentiation in developing tissues •a single intrauterine exposure to a drug can affect the foetal structures undergoing rapid development at the time of exposure •thalidomide phocomelia risk occurs during the 4th to the 7th week of gestation because it is during this time that the arms and legs develop •neural tube defects occur with carbamazepine use (T1) •warfarin causes hypoplastic nasal bridge and chondrodysplasia (T1), central nervous system malformations (T2), risk of bleeding (T3) AGENTS ALTERING UTERINE TONE AND CONTRACTION •uterine tone increased by •α-adrenoceptor agonists •oxytocin •ergometrine •PGE2 •PGF2 •(acetylcholine, bradykinin, histamine, serotonin) •uterine tone decreased by •β2-adrenoceptor agonists •volatile anaesthetics •nitroglycerin •magnesium sulphate •Ca++ channel blockers •prostaglandin synthase inhibitors •alcohol (by suppressing oxytocin secretion)

Drugs Used In Pregnancy
DRUGS THAT INCREASE UTERINE CONTRACTION Oxytocin •the oxytocin receptor is a G protein-coupled receptor that is primarily coupled via G(q) proteins to phospholipase C-β •increases intracellular Ca++ •by release of intracellular Ca++ by inositol1,4,5-triphosphate as well as direct or depolarization-induced activation of voltagesensitive Ca++ channels •pharmacokinetics •absorption •administered intravenously for stimulation of labour •administered as nasal spray to induce postpartum lactation •inactive via oral route as it is destroyed in the stomach and intestines •not bound to plasma proteins •metabolised in liver and kidney •t½β of 5 minutes •effects on the uterus •stimulates both the frequency and force of contraction •at higher concentrations, produces sustained uterine contraction •sensitivity of uterus to oxytocin increases during pregnancy •exogenous oxytocin can increase or enhance rhythmic contractions at any time, but in early pregnancy only very high doses elicit a response •other effects •causes contraction of myoepithelial cells surrounding mammary alveoli, leads to milk ejection •has weak antidiuretic and pressor activity •indications •induction of labour •Rh incompatability •maternal diabetes •preeclampsia •augmentation of dysfunction labour in the presence of uterine inertia •incomplete abortion •control of postpartum haemorrhage •augment postpartum lactation •oxytocin challenge test •provides information about placental circulatory reserve •adverse effects •maternal death due to hypertensive episodes •water retention •uterine rupture •foetal death •contraindications •foetal distress •prematurity •abnormal foetal presentation •cephalopelvic disproportion •predispositions for uterine rupture

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Ergotamine •a fungal by-product belonging to a family of lysergic acid derivatives •effects on the uterus •causes strong uterine contractions via partial agonist effect on •α adrenoceptor (also antagonist effect) •serotonin receptor •dose-dependent effects •small dosages, rhythmic contraction and relaxation of uterus •large dosages, powerful sustained uterine contraction •increasing dominance of α1 receptors as pregnancy progresses •increases the sensitivity of uterus to the stimulant effects of ergot •ergonovine is more selective in uterine actions •agent of choice for obstetric application •adverse effects •gastrointestinal disturbances •diarrhoea, nausea, vomiting •activation of medullary vomiting centre and of gastrointestinal serotonin receptors •prolonged vasospasm resulting in limb gangrene, bowel infarction •contraindications obstructive vascular diseases collagen diseases DRUGS THAT INHIBIT UTERINE CONTRACTION •indicated to delay or prevent premature parturition, and to delay delivery for brief periods in order to undertake other therapeutic measures •tocolytic agents currently in use include β2 adrenergic agonists (ritodrine, terbutaline, fenoterol, albuterol) •magnesium sulphate •Ca++ channel blockers •prostaglandin synthase inhibitors •nitroglycerin Ritodrine •administration •available for both oral and intravenous administration •initial rate of 0.1 mg/min, gradually increasing to 0.35 mg/min or until labour is controlled, infusion maintained for 12 hours •conversion to oral therapy maximum dose 120 mg per day •other effects •produces dose related tachycardia, increase in systolic pressure, pulse pressure, stroke volume, and cardiac output and decrease in diastolic pressure and peripheral vascular resistance •secretion of renin is enhanced, resulting in decreased renal excretion of Na+, K+ and water •over hydration during therapy may result in pulmonary oedema (5%)

Drugs Used In Pregnancy
•can cause marked hyperglycaemia •may result in reactive hypoglycaemia should parturition proceed •hypokalaemia occurs as a result of movement of K+ into the intracellular compartment •other maternal side effects include tremor and palpitations Magnesium sulphate •indications •control of eclamptic seizures •inhibition of uterine activity •effects •dose dependent effect of Mg++ •4 to 8 meq/l : effective inhibition of uterine contractions •10 meq/l : progressive inhibition of neuromuscular transmission and loss of deep tendon reflexes •higher concentrations produce progressive inhibition of cardiac conduction, and can lead to respiratory depression and cardiac arrest •adverse effects •nausea, vomiting, ileus, visual blurring, diplopia, headaches, weakness and lethargy •drug interactions •increased sensitivity to muscle relaxants, especially nondepolarising agents Prostaglandin synthase inhibitor •inhibit cyclooxygenase which converts arachidonic acid into prostaglandin G2 •prostaglandins •enhance the production of myometrial gap junctions •stimulate the influx of intracellular calcium and the release of calcium from the sarcoplasmic reticulum •leading to activation of myosin light chain kinase and subsequent uterine contraction •promotes cervical ripening and uterine contraction

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Indomethacin •maternal side effects are minimal •risks •possibility of premature closure of ductus arteriosus and production of pulmonary hypertension •development of oligohydramnios •monitor side effects with foetal echocardiography and ultrasound •Nitroglycerin •indications •provides uterine relaxation for the removal of retained placenta or for extraction of the second twin •relaxation of the uterus with bolus doses of nitroglycerin 50 μg •treat preterm labour after foetal surgery •mechanism of action •denitrated by glutathione S-transferase, releasing free nitrite ion in smooth muscle cell as it is in other tissues •a different enzymatic reaction releases nitric oxide NO· •nitric oxide or (S-nitrosothiol derivative) causes activation of guanylyl cyclase

•acute adverse effects •vasodilatation, hypotension, tachycardia and throbbing headache

Drugs Used In Pregnancy
PROPHYLAXIS OF GASTRIC ACID ASPIRATION •particulate acids •concerns include inadequate mixing and aspiration of particulate matter •non-particulate acids •sodium citrate produces a gastric fluid pH of above 2.5 in 64-84% of patients, for 30 to 45 minutes •H2 receptor antagonists •ranitidine is highly ionised, unlikely to cross the placenta •cimetidine inhibits microsomal mixed function oxidase system of the liver, prolonging the elimination of several drugs used in anaesthesia e.g. amide local anaesthetics ANAESTHETIC AGENTS Thiopentone •crosses placenta rapidly and can be detected in the umbilical venous blood with 30 seconds, affecting APGAR scoring •induction-delivery (ID) time not an issue provided cardiac output in mother, oxygenation are maintained Ketamine •rapidly crosses the placenta •as ketamine raises arterial blood pressure by 15-25%, should avoid in the hypertensive patient •increases uterine tone Muscle Relaxants •highly ionised at physiologic pH, low lipid solubility •placental transfer is limited •plasma cholinesterase activity in foetal or premature infant blood is approximately half that of the adult •plasma cholinesterase fall by 20-30% in the mother during pregnancy •as ID time progressively lengthens, ratio of umbilical venous concentration to maternal venous concentration (UV/MV) increases Local Anaesthetic Agents •most are weak bases, foetal acidosis may lead to “iontrapping” within the foetal circulation •neonate capable of biotransformation of local anaesthetics, but the rate of metabolism and excretion is slower than that of the adult •dealkylation of bupivacaine to active metabolite, pipecolylxylidide (PPX) •elimination of metabolites of lignocaine •terminal elimination half-lives of local anaesthetic agents in neonate may also be prolonged due to increased Vd Narcotics •lipid-soluble unionised fraction rapidly crosses the placenta to reach the foetus •neonate cannot n-methylate pethidine to norpethidine as effectively as the adult •increased sensitivity of newborn to morphine due to an immature blood-brain barrier which permits a large amount of morphine to gain access to receptor sites

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•intrathecal opioids for labour analgesia •modes of action •segmental analgesia •binding to opioid receptors at dorsal horn, interfering with both pre- and postsynaptic substance P release •with more lipid-soluble opioids, segmental block predominates, and duration of action is shorter •supraspinal actions from cephalic spread •hydrophilic opioids result in greater rostral spread •transplacental transfer •significantly reduced by enhanced maternal protein binding •increased by acidaemic foetus •opioids used for regional analgesia during labour and caesarean section •fentanyl (ED95 25μg), clinical use 25μg during first stage of labour, 10μg during caesarean section •sufentanyl (ED50 2.6μg, ED95 8.9μg), clinical use 10μg during first stage of labour or 7.5μg with local anaesthetic (2.5mg bupivacaine) •pethidine, for the opioid and local anaesthetic effects •morphine, clinical use 100μg, for caesarean section •side effects •pruritus •pregnant patients are susceptible because of an interaction between oestrogen and opioid receptors Inhalational agents •pregnancy reduces anaesthetic requirement •MAC is reduced by up to 40% for isoflurane during pregnancy •inhalational agents diffuse rapidly across the placenta because they are highly lipid soluble, unionised compounds •halothane, enflurane, isoflurane and diethyl ether cause uterine relaxation in a dose-related manner •nitrous oxide and cyclopropane have little or no effect upon uterine activity VASOCONSTRICTORS Phenylephrine •relatively pure α agonist •acts directly on receptors •noncatecholamine, therefore not metabolised by COMT •longer duration of action than catecholamines •applications •mydriasis •nasal decongestant •pressor agent •side effects •rebound hyperaemia •mucosal ischaemia

Drugs Used In Pregnancy
Ephidrine •noncatecholamine phenylisopropylamine •mixed-action mechanism of action •stimulates both alpha and beta receptors and its peripheral actions are due partly to release of stored noradrenaline and partly to direct effect on receptors •has α1, α2, β1, β2 adrenergic receptor-agonist properties. •40% of the thermogenic activity of ephedrine is reported to be due to the activation of the β3 adrenoreceptors in the adipose tissues •also stimulates thyroid function •duration of action •long •pressor and cardiac responses to ephedrine persist for one hour following intramuscular or subcutaneous administration of 25 to 50 mg •may deplete norepinephrine stores in sympathetic nerve endings, so that tachyphylaxis to cardiac and pressor effects of the drug may develop

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•metabolism •small amounts of ephedrine are slowly metabolized in the liver •p-hydroxyephedrine, p-hydroxynorephedrine, norephedrine, and conjugates of these compounds •elimination •the drug and its metabolites are excreted in the urine, mostly as unchanged ephedrine •rate of urinary excretion is dependent on urinary pH •as a weak base, excretion is accelerated by acidification of urine •elimination half-life of the drug has been reported to be about 3 hours when the urine is acidified to pH 5 and about 6 hours when urinary pH is 6.3 •comparison between ephedrine and phenylephrine •phenylephrine shorter duration than ephedrine •ephedrine has greater cardiac and central nervous system effects

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