A drug is broadly defined as any chemical agent that affects living protoplasm. About one-third of women in the UK take drugs at least once during pregnancy, but only 6% take a drug during the first trimester. In the puerperium, the use of drugs increases substantially with no difference in the pattern of prescribing between mothers who breastfeed and those who bottle-feed.
Possible effects of drugs in pregnancy include:
Teratogenicity (e.g. thalidomide)
Long-term latency (e.g. diethylstilbestrol (DES) – increased risk of vaginal adenocarcinoma after puberty, or abnormalities in testicular function and semen production)
Impaired intellectual or social development (e.g. phenobarbital or sodium valproate).
Language of Clinical Pharmacy
Prodrugs are pharmacologically inactive derivatives of active drugs. They are designed to maximise the amount of active drug that reaches its site of action through manipulation of the physicochemical, biopharmaceutical or pharmacokinetic properties of the drug. Prodrugs are converted into the active drug within the body through enzymatic or non-enzymatic reactions.
Distribution volume is a hypothetical concept that is defined as the volume that a drug would occupy if the concentration throughout the body were equal to that in plasma. The distribution volume depends on factors like lipid solubility and protein binding.
Clearance is the volume of plasma cleared of the drug in unit time. It determines what dose of drug is necessary to maintain a certain plasma concentration but does not indicate how rapidly the drug disappears when treatment is stopped. Patients with abnormal renal or liver function can have increased clearance times.
A receptor is any cellular molecule to which a drug binds to initiate its effects. Receptors can be proteins (hormones, growth factors and neurotransmitters) or nucleic acids (cancer chemotherapeutic agents). An agonist binds to a physiological receptor and often mimics the regulatory effects of endogenous signalling compounds. An antagonist binds to receptors without regulatory effects and blocks the endogenous agonist. Drugs that stabilise the receptor in its inactive form are called inverse antagonists. Receptors of relevance to clinical practice are summarised in Table 12.1 .
|Receptor||Subtype||Main Actions of Natural Agonist||Drug Agonist||Drug Antagonist|
|α 2||Hypotension, sedation||Clonidine|
|β 1||↑ Heart rate|
|Nicotinic||Contraction of striated muscle|
|Opioid||CNS neurotransmitter||Morphine, pethidine, etc.||Naloxone|
pKa is the pH at which half the drug is in its ionised form.
Henderson–Hasselbalch equation is used to calculate the ratio of ionised to non-ionised drug at each pH.
Absorption is the rate at which a drug leaves its site of administration and the extent to which this occurs.
Bioavailability is the term used to indicate the fractional extent to which a dose of drug reaches its site of action or a biological fluid from which the drug has access to its site of action.
Half-life (t ½ ) is the time taken for the plasma concentration, or the amount of the drug in the body, to be reduced by 50%. The half-life of a drug depends on its rate of clearance and volume of distribution. Highly lipophilic drugs may have an increased clearance but prolonged half-life.
Steady-state concentration is reached when drug elimination is equal to availability with repeated equal doses. It takes repeated dosing for about five half-lives to achieve steady state.
This is defined as structural or functional (e.g. renal failure) dysgenesis of the fetal organs. Typical manifestations of teratogenesis include congenital malformations with varying severity, fetal growth restriction (FGR), carcinogenesis and fetal demise. Lack of understanding of the mechanisms of teratogenicity makes it difficult to predict on pharmacological grounds that a particular drug will produce congenital malformations. The period of highest sensitivity to teratogens is early organogenesis. Later in fetal development, exposure to a teratogen is far less likely to be the cause of a structural defect, but can cause serious functional abnormalities, notably of the neuro behavioural type.
The major body structures are formed in the first 12 weeks after conception ( Fig. 12.1 ). Interference in this process causes a teratogenic effect. If a drug is given after this time, it will not produce a major anatomical defect, but possibly a functional one. The overall incidence of major congenital malformations is around 2% to 3% of all births, and of minor malformations, 9%. The part played by drugs is probably small. It has been estimated that 25% of congenital malformations are due to genetic or chromosomal abnormalities, 10% due to environmental causes including drugs and 65% are of unknown aetiology. Even known teratogens do not invariably cause anatomical defects and the mechanism of drug-induced teratogenicity remains unclear. The genetic composition of the fetus, the timing of the insult, maternal age, nutritional condition, disease status and the dose of the drug may play a role. The critical time for drug-induced congenital malformations is usually the period of organogenesis. This occurs approximately 20 to 55 days after conception, that is, 34 to 69 days (7 to 10 weeks) after the first day of the last menstrual period (see Fig. 12.1 ).
Pharmacokinetics is the mathematical description of the rate and extent of uptake, distribution and elimination of drugs in the body. It mainly concerns time. Pharmacok-inetics is important for drugs that are given for more than an isolated dose, and those whose margin of safety is narrow. The pharmacokinetics of a drug depends upon its concentration, structure, degree of ionisation, relative lipid solubility and binding to tissue proteins.
Oral absorption is unpredictable and is dependent on various factors such as gastric emptying time, surface area of absorption, blood flow, lipid solubility and physical state of the drug. Venous drainage from the oral mucosa is to the superior vena cava and hence bypasses first-pass metabolism. Rectal administration causes erratic absorption and irritation of the rectal mucosa but 50% of the dose will bypass the liver. Absorption after subcutaneous or intramuscular injection occurs by simple diffusion.
Distribution occurs in two phases: an initial rapid phase to the liver, kidney and brain followed by a slow phase to the muscles, viscera, skin and fat. The distribution of a drug is determined by its lipid solubility and the pH gradient between the intracellular and extracellular fluids.
Acidic drugs bind to albumin (e.g. salicylates, warfarin, anticonvulsants, non-steroidal anti-inflammatory drugs (NSAIDs))
Basic drugs bind to α 1 -acid glycoprotein (e.g. β-blockers, opioid analgesics, local anaesthetics)
Covalent bonding can occur with reactive drugs (e.g. alkylating agents).
Hypoalbuminaemia due to liver disease or nephrotic syndrome results in reduced binding and an increase in the unbound fraction of acidic drugs. An acute-phase response leads to an elevation of α 1 -acid glycoprotein levels and therefore to reduced availability of basic drugs. Fig. 12.2 summarises the different compartments in which drugs can be distributed in the materno-fetal unit.
Drugs Can Undergo Different Types of Transport
Transcapillary movement : this is transfer of the drug with bulk transfer of water due to hydrostatic or osmotic pressure differences and accounts for the majority of unbound drug transfer.
Paracellular transport : this occurs between cell junctions and is the principal mechanism of excretion of drugs by the kidney.
Passive transport : this is diffusion of the drug through the cell membrane along a concentration gradient by virtue of its lipid solubility.
Active transport : this is characterised by a requirement for energy and involves the movement of a drug against an electrochemical gradient.
Facilitated diffusion : this is a carrier-mediated transport process in which there is no input of energy. Enhanced movement is down an electrochemical gradient.
Drugs that are lipid soluble are less likely to be excreted and polar compounds are likely to be excreted more quickly. The kidneys excrete drugs by filtration, tubular secretion and tubular re-absorption. Changes in renal function affect all three functions and are impaired in the elderly, as adult renal function decreases by 1% per year. Unbound drugs are excreted by filtration. P glycoprotein and multidrug resistance associated protein type 2 secrete ions and conjugated metabolites, respectively, into the tubules. Some of the ways that pregnancy influences pharmacokinetics are summarised in Table 12.2 .
|Maternal Pharmacokinetics||Fetal Pharmacokinetics||Placental Pharmacokinetics|
Pharmacodynamics is the study of biochemical and physiological effects of drugs on the body and their mechanism of action. The majority of the drugs pass through cells rather than between them. Broadly speaking, drugs act on four different targets: receptors, enzymes, membrane ion channels and metabolic processes. Drugs commonly act on electrical or chemical signalling pathways and drug action commonly involves a signal transduction pathway, which consists of receptor, cellular target and intermediary molecules.
Factors that Influence Drug Action
Drug metabolism will influence the duration and potency of the effect of specific drugs. Drugs are commonly converted to more polar metabolites to facilitate their excretion. This is frequently catalysed by enzymic reactions. While the majority of drug metabolism results in less toxic metabolites, occasionally it can result in the formation of more toxic compounds. A large number of drugs are metabolised by hepatic phase I and II reactions.
Phase I metabolism occurs in the endoplasmic reticulum and involves the formation of more polar metabolites of the original compound. These reactions can involve oxidation (catalysed by cytochrome P450 enzymes), hydrolysis, reduction, cyclisation or decyclisation. The polar metabolites may be directly excreted, usually in the urine, or may be converted further by phase II reactions.
Phase II reactions occur in the cytoplasm and commonly involve conjugation with sulphates, glucuronides, glutathione or amino acids and result in the formation of metabolites that are usually less toxic and more easily excreted.
The metabolism of a drug can be affected by enzyme induction, protein binding and the liver extraction ratio. Table 12.3 summarises the common drugs that influence the activity of the liver microsomal enzymes.
|Microsomal Induction (Cytochrome P450)||Microsomal Inhibition|
|Griseofulvin||Grapefruit juice, metronidazole|
Drugs that are likely to precipitate drug interactions are those that are highly protein bound, alter metabolism of other drugs or alter renal or hepatic metabolism. Drugs that are affected by drug interactions are those that have a steep dose–response curve and those that have a low toxic : therapeutic ratio (e.g. aminoglycosides, anticoagulants, anticonvulsants, antihypertensives, cardiac glycosides, cytotoxic drugs, oral contraceptives).
Pharmacokinetic interactions can be related to:
Drugs that decrease gastric emptying (e.g. morphine, anticholinergics)
Chelation of calcium, aluminium, magnesium salts by tetracycline
Binding of warfarin and digoxin by cholestyramine
Protein-binding displacement interactions
For example, warfarin and phenytoin are displaced by sulphonamides, salicylates, phenylbutazone and valproate
Metabolism interactions with induction or inhibition of cytochrome P450 or phase I functionalisation reactions (e.g. oral contraceptives decrease anticoagulant effect of warfarin). Table 12.3 summarises drugs that commonly influence microsomal enzymes
Probenecid and penicillin at the renal tubules
Quinidine doubles digoxin levels
Diuretics causing lithium retention.
Pharmacodynamic interactions could be antagonism at same site (e.g. pethidine/naloxone), synergism at same site (e.g. verapamil/β-blockers increase arrhythmias) or indirect, for example when alterations in coagulation, fluid and electrolyte balance affect drug action.
Impaired Liver Function
Liver disease can lead to impaired drug metabolism. The severity of the liver damage reflects the extent of the reduced metabolism, but clinical liver enzymes are of little value in predicting this. Drugs with high hepatic first-pass metabolism are most severely affected.
Physiological Changes that Affect Drug Metabolism in Pregnancy
The distribution volume for all drugs increases
There is delayed gastric emptying, resulting in slow peak levels of readily absorbed drugs (e.g. paracetamol) and increased bioavailability of slowly absorbed drugs (e.g. digoxin)
Nausea and vomiting in early pregnancy increases the clearance time affecting the dosage of drugs (e.g. anti-epileptics)
Increased body fat increases clearance of lipophilic drugs (e.g. thiopental) even though the plasma half-life is prolonged
Decreased albumin and raised free fatty acids lead to increase in free levels of albumin-bound drugs. Therefore measurement of these drugs may not reflect the actual concentration and saliva monitoring may be needed
Increased alveolar ventilation and cardiac output seen in normal pregnancy may lead to enhanced alveolar and intramuscular drug absorption
Renal blood flow increases and glomerular filtration rate (GFR) increases by 50% leading to enhanced renal clearance of many medications
α 1 -Acid glycoprotein levels do not change, but there is a large transplacental concentration gradient that affects transfer of drugs
Maternal albumin concentrations progressively decrease during pregnancy and fetal albumin concentrations progressively increase. They achieve equivalence at around week 30 of gestation. Albumin-bound drugs may be transferred to the fetus in a higher concentration. The placenta has cytochrome P450 sulphating and acetylating enzymes that can metabolise drugs.
The Placental Barrier
Virtually all drugs cross the placenta and achieve equal concentrations on either side over repeated administration. Most drugs have a molecular weight below 1000 daltons (Da), and molecules of this size cross the placenta (<600 Da cross easily). Lipid-soluble drugs are readily transferred across the placenta. Diffusion is the most important mode of transfer of drugs through the placenta. Fetal plasma is more acidic and leads to ion trapping of basic drugs.
Some Commonly Used Drugs
The adrenal cortex synthesises two classes of steroid: the corticosteroids (glucocorticoids and mineralocorticoids), which have 21 carbon atoms, and the androgens, which have 19. Cortisone is the main glucocorticoid and aldosterone is the main mineralocorticoid. Cortisol is produced at a rate of 10 mg/day.
Corticosteroids act with specific receptor proteins in target tissues to modulate proteins synthesised by various target tissues. Hence, most effects of corticosteroids are not immediate but become apparent after several hours. The receptors are members of the nuclear receptor family. The glucocorticoid receptor is predominantly in the cytoplasm in an inactive form until it binds to glucocorticoids. Steroid binding results in receptor activation and translocation to the nucleus. The activated receptor interacts with specific DNA sequences in the regulatory regions of genes called glucocorticoid response elements (GREs) and these provide specificity to the induction of gene transcription.
Mineralocorticoids act similarly though the exact mechanism is unclear.
Hydrocortisone and numerous congeners including the synthetic analogues are orally effective. They can be administered intravenously to achieve high concentrations. Absorption from the skin is low but, if they are applied to a large area or on an occlusive dressing, the absorption may be sufficient to cause systemic effects. After absorption, >90% of cortisol is reversibly bound to protein. Two plasma proteins account for almost all of the steroid-binding capacity: corticosteroid-binding globulin (CBG) and albumin. A state of physiological hypercortisolism occurs during pregnancy. The elevated circulating oestrogens induce CBG production, and CBG and total plasma cortisol increase several-fold.
Glucocorticoids are administered in multiple formulations for disorders that share an inflammatory or immunological basis. With the exception of patients receiving replacement therapy for adrenal insufficiency, glucocorticoids are neither specific nor curative, but rather are palliative because of their anti-inflammatory and immunosuppressive actions.
Prednisolone is the biologically active form of prednisone. The placenta can oxidise prednisolone to inactive prednisone or even less active cortisone. Only 10% of the maternal prednisolone dose crosses the placenta. Four large epidemiological studies including steroids that readily cross the placenta (betamethasone and dexamethasone) have looked at the use of corticosteroids in first trimester and found an association with non-syndromic orofacial clefts. However, the overall risk is low. The Michigan Medicaid surveillance study looked at 229,101 patients exposed to prednisolone, prednisone and methylprednisolone during the first trimester; the data did not support an association between these agents and congenital defects. There are isolated reports of cataracts in the newborn if prednisolone was used throughout the pregnancy. During lactation, the infant is exposed to minimal amounts of steroid through the breast milk. At higher doses (>20 mg), it is recommended to wait at least 4 hours after a dose before nursing the baby.
Betamethasone administration to women with threatened preterm labour is associated with a decrease in respiratory distress syndrome, periventricular leukomalacia and intraventricular haemorrhage in pre-term infants. It can induce hyperglycaemia and may rarely precipitate myasthenic crisis or hypertensive crisis in the mother. Approximately 80% of the maternal betamethasone dose crosses the placenta. Single courses of betamethasone have no effects on the fetus but multiple courses have been associated with lower birth weights and reduced head circumference at birth. Follow-up studies have not shown any differences in cognitive and psychosocial development when compared with controls.
Hydrocortisone and its inactive precursor, cortisone, appear to present a small risk to the human fetus. Approximately 50% of the maternal dose of hydrocortisone crosses the placenta. These corticosteroids produce dose-related teratogenic and toxic effects in genetically susceptible experimental animals consisting of cleft palate, cataracts, spontaneous abortion, IUGR and polycystic kidney disease. However, there are no data to support these effects in the great majority of human pregnancies, although the small increase in incidence of cleft lip with or without cleft palate is supported by large epidemiological studies.
It is important to remember that in some women the benefits of corticosteroids can far outweigh the fetal risks when used to treat maternal inflammatory and autoimmune disease, and these agents should not be withheld if the mother’s condition requires their use.
General anaesthetics act by increasing the sensitivity of the γ-aminobutyric acid (GABA) A receptor to GABA thus enhancing inhibitory neurotransmission and depressing nervous system activity. Glycine receptor-mediated activation of chloride channels is responsible for inhibition of neurotransmission in the spinal cord and brain stem. Ketamine, nitrous oxide and xenon act via N -methyl- d -aspartate (NMDA) receptors and cause long-term modulation of synaptic responses.
Intravenous (i.v.) anaesthetics are unique drugs that induce anaesthesia rapidly as they quickly achieve high concentrations in the central nervous system (CNS). Intravenous anaesthetics affect synaptic function by inhibiting excitatory synapses and enhancing inhibitory synapses their pharmacological effects are terminated by redistribution to tissues with low blood flow. Commonly used drugs are thiopental and propofol for induction of anaesthesia. Thiopental is an ultrashort-acting agent that has quick entry into the CNS followed by quick redistribution of the drug. After i.v. administration, it causes unconsciousness with amnesia without analgesia or muscle relaxation. It is used mainly as an induction agent and by infusion during short procedures. It is also used to control convulsions in status epilepticus and eclamptic convulsions not responding to magnesium sulphate.
Inhalational anaesthetics can hyperpolarise neurones and hence reduce both pacemaker neurone and post-synaptic neurone action potentials. Halothane is commonly used. Due to its high lipid solubility and increased clearance from lungs, induction is slow and speed of recovery is also lengthened. Some 80% is excreted unchanged and 20% is metabolised by cytochrome P450 enzymes to trifluoroacetylate, which can bind to several liver proteins. Hypersensitivity to these proteins leads to halothane-induced hepatotoxicity.
A side effect of the drug is uterine smooth muscle relaxation and this can be helpful for manipulation of fetus (version) and for manual removal of placenta. It can also lead to an increased risk of postpartum haemorrhage. It is a triggering agent for malignant hyperthermia.
Nitric oxide (NO) is very insoluble in blood and other tissues. Due to its high insolubility, rapid induction and rapid emergence occurs during anaesthesia. On discontinuation of nitrous oxide it can diffuse from blood to alveoli and decrease the concentration of oxygen in alveoli (diffusional hypoxia). Hence 100% oxygen should be administered during recovery from NO. NO is a weak anaesthetic and analgesic at 20%, and is a sedative. A 50% concentration is frequently used to provide analgesia in labour and outpatient dentistry.
A collaborative perinatal project showed no embryonic or fetal effects of NO. Its use during delivery may lead to neonatal depression and fetal accumulation of nitrous oxide, which increases over time; hence, it is safer to keep the induction to delivery time as short as possible.
Neuromuscular Blocking Agents
These agents are used as an adjunct to anaesthetics to provide muscle relaxation. Based on their mechanism of action they are divided into depolarising (e.g. succinylcholine) and non-depolarising (e.g. pancuronium). The actions of neuromuscular blocking agents are reversed by acetylcholine esterase inhibitors (e.g. neostigmine) and muscarinic receptor antagonists (e.g. glycopyrrolate). The only depolarising agent in use is succinyl choline, which acts by depolarising the membrane by opening sodium channels. A series of repetitive excitation followed by block transmission and neuromuscular paralysis occurs. Competitive antagonists act by decreasing the frequency of channel opening events that result in an action potential. At increasing doses the drug binds to the channels in a non-competitive manner.
Depolarising muscle relaxants (e.g. suxamethonium and succinylcholine) can cause histamine release and hyperkalaemia (and therefore should be avoided in patients with heart disease, trauma and burns). Malignant hyperthermia occurs due to calcium release from the sarcoplasmic reticulum of the skeletal muscle. Clinical features include contracture, rigidity and heat production resulting in hyperthermia-accelerated muscle metabolism and acidosis. Malignant hyperthermia is treated with dantrolene which inhibits calcium release.
Local anaesthetics cause a reversible block in the action potential responsible for nerve conduction. They decrease the permeability of the nerve to sodium and block propagation of electrical impulses. Combination with adrenaline (epinephrine) doubles their duration of action. Excessive administration can cause cerebral irritation and convulsions.
Warfarin interferes with cyclic conversion of vitamin K to its active metabolite, which is essential in carboxylation of glutamic acid residues of vitamin K-dependent coagulation factors (II, VII, IX, X). Carboxylation is necessary for binding of these factors to calcium and phospholipids. As protein S levels are also dependent on vitamin K activity, warfarin administration causes a prothrombotic state prior to the onset of an anticoagulant effect. It causes embryopathy in 5% to 10% of pregnancies where there is first-trimester exposure. The clinical features are similar to those of chondromalacia punctata (stippled epiphysis, nasal and limb hypoplasia). The embryopathy is secondary to vitamin K involvement in the post-translational modification of proteins enabling them to bind calcium. The use of warfarin in the second and third trimester is associated with recurrent micro-haemorrhages in the brain leading to optic atrophy, dorsal midline dysplasia and mental retardation. It is avoided after 36 weeks to prevent maternal and neonatal complications related to delivery.
Heparin is the anticoagulant of choice from the fetal perspective as it does not cross the placenta. It is a glycosaminoglycan and acts through interaction with antithrombin III. Antithrombin III inactivates thrombin, factor Xa and factor IXa. Two major side effects that can occur with heparin treatment are heparin-induced thrombocytopenia and osteoporosis. There are two types of thrombocytopenia that occur in association with heparin treatment. Non-immune heparin-associated thrombocytopenia is associated with a mild reduction in platelet count and occurs 2 to 5 days after heparin injection. Immune thrombocytopenia occurs due to IgG antiplatelet antibodies, 3 to 4 weeks after therapy, and increases the risk of thrombus formation.
Direct Oral Anticoagulants
These are oral anticoagulants that specifically inhibit factors IIa or Xa. They are also known as new oral anticoagulants (NOACs). Factor Xa is a clotting factor in the coagulation pathway that leads to thrombin generation and clot formation. They act by inhibition of prothrombinase complex-bound and clot-associated factor Xa, resulting in a reduction of thrombin in the coagulation cascade. The main advantage of direct oral anticoagulants (DOACs) is the oral administration and that they do not need drug monitoring or dose adjustments. Examples are Rivaroxaban and Apixaban.
All DOACs can cross the placenta and although no specific embryopathy pattern has been established, they are contraindicated in pregnancy and breastfeeding.
The pharmacokinetics of all antiepileptics is altered in pregnancy and therapeutic drug monitoring can be of benefit. Phenytoin, primidone, phenobarbital, carbamazepine and sodium valproate all cross the placenta and are teratogenic. Major abnormalities produced by anticonvulsants are neural tube, orofacial and congenital heart defects. Fetal hydantoin syndrome includes prenatal and postnatal growth restriction, motor or mental deficiency, short nose with broad nasal bridge, microcephaly, hypertelorism, strabismus, low-set or abnormally formed ears, limb and positional deformities. Sodium valproate and carbamazepine mainly cause neural tube defects and spina bifida (always lumbar). Valproate is no longer prescribed to women of childbearing age due to its significant association with neural tube defects and neurodevelopmental delay. Phenobarbital appears to be safer than phenytoin. The risk of teratogenicity rises with the use of more than one drug. The newer anticonvulsants are often prescribed along with other drugs, and it is difficult to ascertain teratogenic risk of these drugs in isolation.
Altered pharmacokinetics in pregnancy may lead to changes in drug levels and for most drugs the concentration of the free drug falls. If a woman is fit free, there is usually no need to measure serial drug levels or adjust the dose for most anticonvulsants. An exception is lamotrigine as levels of this drug invariably fall in pregnancy. In women who have regular seizures, and who are dependent on critical drug levels, it is worth monitoring drug levels and increasing dosages of anticonvulsants should be guided by serum concentrations. Vitamin K is given in the last 4 weeks of pregnancy to prevent haemorrhagic disease of the newborn. Carbamazepine, phenytoin and valproic acid are safe in breastfeeding. Succinimides (e.g. ethosuximide) are commonly used to treat petit mal epilepsy and are thought to have a low or no teratogenic potential.
Antiemetics are classified according to the predominant receptor on which they act.
Serotonin Receptor Antagonists
Serotonin (5-HT3) receptors are present in multiple places involved in emesis, such as the vagal nerve, the solitary tract nucleus and the area postrema (located at the bottom of the fourth ventricle and contains the chemoreceptor trigger zone). Serotonin is released by the entero-chromaffin cells of the small intestine and may stimulate vagal afferents to initiate the vomiting reflex. 5-HT3 agents (i.e. Ondansetron) are widely used and effective against chemotherapy-induced nausea and hyperemesis gravidarum. Common adverse effects of these drugs include constipation or diarrhoea, headache and light-headedness. Ondansetron can be safely used in pregnancy and lactation. Early concerns regarding teratogenicity of this drug have not been confirmed by recent trials.
Dopamine Receptor Antagonists
Phenothiazines (prochlorperazine, chlorpromazine) and Benzamides (metoclopramide, domperidone) antagonise dopamine receptor (D2) at the chemoreceptor trigger zone at the area postrema. In addition, these drugs also have antihistaminic and anticholinergic effects. Side effects include orthostatic hypotension, peripheral anticholinergic effects (i.e. dry mouth, blurred vision, constipation, urinary retention), central anticholinergic effects (i.e. agitation, delirium, hallucinations, seizures and coma) and extrapyramidal effects, such as oculogyric crisis and parkinsonism. Dopamine receptor antagonists are not teratogenic and can be used in pregnancy and breastfeeding.
Histamine H1 receptor antagonists (promethazine, cyclizine, cinnarizine, doxylamine and dimenhydrinate) act on the vestibular nucleus and within the brainstem. Some antihistamines such as cyclizine and doxylamine have anticholinergic properties that inhibit muscarinic receptors at the same sites. Adverse effects include dizziness, drowsiness, dry mouth and fatigue. Antihistamines are used as first-line treatment for nausea and vomiting of pregnancy. Xonvea is a delayed-release tablet containing doxylamine succinate (an antihistamine) and pyridoxine hydrochloride (vitamin B6) which is specifically licensed for the treatment of nausea and vomiting in pregnancy.
Non-Steroidal Anti-Inflammatory Drugs
Aspirin and NSAIDs do not produce structural defects. They readily cross the placenta and achieve higher concentrations in the fetus as they are albumin bound. Salicylates and NSAIDs may increase the risk of neonatal haemorrhage via inhibition of platelet function. NSAIDs may lead to oligohydramnios via effects on fetal kidney. If given in the third trimester, they can cause premature closure of ductus arteriosus and neonatal hypertension. Premature ductus closure and oligohydramnios are reversible. If used, they should be discontinued at 32 weeks. Low-dose aspirin is used in the prophylaxis of early-onset severe pre-eclampsia, migraine attacks and treatment of antiphospholipid syndrome. Aspirin in low doses inhibits thromboxane A 2 resulting in a decrease in vasoconstrictor prostaglandins.
Cyclooxygenase (COX) enzymes are responsible for production of the prostaglandin series of bioactive compounds. Specifically COX converts arachidonic acid to prostaglandin H 2 . There are three known COX isoforms, designated COX-1, COX-2 and COX-3. COX-1 and 2 are both expressed in tissues and have biological functions. COX-3 is a splice variant of COX-1. COX-1 is found in the gastric mucosa, kidney and platelets. COX-2 is an inducible form, although to some extent it is present constitutively in the CNS, juxtaglomerular apparatus of the kidney and placenta during late gestation. Recent development of selective COX-2 inhibitors is of major clinical interest as these have been related to lower incidence of gastrointestinal bleeding. Both COX-1 and -2 inhibitors can cause sodium retention and reduction of the GFR. Fetal COX-2 inhibition can be responsible for neonatal chronic renal failure and therefore maternal usage should be avoided until further studies confirm the safety of this group of drugs.
Colchicine reduces the inflammatory response to the deposition of monosodium urate crystals in joint tissue, in part by inhibiting neutrophil metabolism, mobility and chemotaxis. It also inhibits cell division in metaphase by binding tubulin and thereby interfering with mitosis. It is used to treat gouty arthritis and for prophylaxis of recurrent gout attacks. It is also used in familial Mediterranean fever, Behçet disease and amyloidosis. Colchicine given to either parent within 3 months of the time of conception may result in increased frequency of trisomy 21.
Penicillin crosses the placenta and attains fetal concentrations equal to those found in the maternal circulation. It is considered safe in pregnancy and lactation. It does have the potential to modify the normal bacterial flora of the mother’s genital and gastrointestinal tract.
Tetracyclines are derived from streptomyces species. They inhibit bacterial protein synthesis by binding to the bacterial ribosome and preventing access of transfer RNA (tRNA) to messenger RNA (mRNA) in ribosome complexes. It is a broad-spectrum antibiotic, crosses the placenta, chelates with calcium and is deposited in the developing teeth and bones of the fetus. The risk of tooth discoloration is highest from mid pregnancy up to 5 years postnatally. It also causes transient inhibition of bone growth if given in pregnancy. Maternal hepatoxicity can occur in the form of acute fatty liver. It is considered safe for breastfeeding by the American Academy of Pediatrics.
Quinolones act by targeting bacterial DNA gyrase and topoisomerase IV and inhibit DNA replication. In developing adolescents their use is associated with acute arthropathy of the weightbearing joints. Recent studies have shown no effect when used in the first trimester. They are not recommended when breastfeeding due to the risk of arthropathy and phototoxicity.
Aminoglycosides penetrate the cell wall and cytoplasmic membrane of susceptible microorganisms and act on the bacterial ribosome leading to cell death. Aminoglycosides are ototoxic in adults and streptomycin is definitely toxic to the fetal ear causing eighth nerve damage with auditory impairment. Gentamicin should not be withheld if indicated clinically. Single-dose gentamicin is safer for mother, but increased serum levels can cause renal and eighth nerve toxicity, hence divided doses are preferred. Gentamicin can interact with magnesium sulphate and cause rapid onset of respiratory arrest. Parenteral aminoglycosides carry a greater risk than oral aminoglycosides due to poor absorption of the latter into the systemic circulation. A small amount of the drug is excreted in the breast milk and therefore the risk to the neonate is low.
Chloramphenicol inhibits protein synthesis in bacteria and rickettsiae by preventing peptide bond synthesis in ribosomes. It also inhibits mitochondrial protein synthesis in mitochondrial ribosomes but not in cytoplasmic ribosomes in mammalian cells. Mammalian erythropoietic cells seem to be particularly sensitive and chloramphenicol can cause aplastic anaemia which limits its use to severe life-threatening conditions. It should be avoided in late pregnancy and during labour because of potential risk of grey baby syndrome which starts 2 to 9 days after the start of treatment. In the first 24 hours there can be vomiting, refusal to suck, irregular and rapid respiration, abdominal distension, periods of cyanosis and passage of loose, green stools. The baby then becomes flaccid, turns an ashen-grey colour and becomes hypothermic after the first 24 hours. This occurs due to a failure of the drug to be conjugated with glucuronic acid owing to inadequate enzyme in the liver or to inadequate renal excretion of the unconjugated drug. In a nursing infant it can also cause idiosyncratic bone marrow suppression.
Bacteriostatic antibiotics act at the same site as chloramphenicol. Erythromycin is safest. Erythromycin estolate can cause cholestatic hepatitis as a hypersensitivity reaction to the estolate ester. It has no adverse side effects in the nursing infant. It causes inhibition of cytochrome P450 and therefore can potentiate the actions of warfarin, anticonvulsants, digoxin and corticosteroids.
Clindamycin is a derivative of an amino acid. It binds to bacterial ribosomes and suppresses protein synthesis and is used in labour for patients who are sensitive to penicillin.
Sulphonamides are structural analogues and competitive antagonists of para-aminobenzoic acid and prevent utilisation of PABA (para-aminobenzoic acid) for synthesis of folic acid. They readily pass through the placenta and are sufficient to cause therapeutic and toxic effects. Sulphonamides should be avoided in the first trimester and during the latter part of pregnancy. If given to the mother near delivery they can cause haemolytic anaemia, hyperbilirubinaemia and kernicterus. They compete with bilirubin to bind with plasma albumin. Sulphonamides are excreted in low concentrations in breast milk and pose no risk for healthy, full-term infants. They are contraindicated if the infant is stressed, ill or premature, and in those with glucose-6-phosphate dehydrogenase (G6PD) deficiency or hyperbilirubinaemia.
Trimethoprim inhibits reduction of dihydrofolate to tetrahydrofolate and readily crosses the placenta. It is a highly selective inhibitor of the dihydrofolate reductase of unicellular organisms, and it has sufficient effect on human folate metabolism to cause megaloblastic anaemia and increase serum homocysteine concentrations. It causes neural tube defects if given in the first trimester.
Metronidazole is a prodrug that requires activation by susceptible organisms. Anaerobic bacteria contain ferredoxins that can donate electrons to metronidazole, unlike aerobic bacteria. This forms a highly reactive nitro radical anion that targets DNA and other vital biomolecules. Metronidazole is catalytically recycled and increasing levels of oxygen inhibit metronidazole-induced cytotoxicity. There is a possible association with oral clefts when it is used in early pregnancy, but a large meta-analysis (from Drug-Free America) has shown no effect. Its use in breastfeeding is controversial and lactation is withheld for 12 to 24 hours following a 2 g dose. It can cause diarrhoea and secondary lactose intolerance in breastfed infants.
Nitrofurantoin is reduced by bacteria into an active metabolite that causes DNA damage and is bacteriostatic at low concentrations and bactericidal at high concentrations. It is used for treatment and prophylaxis of urinary tract infection and is more potent in acidic urine. It can cause haemolytic anaemia in the newborn if given late in pregnancy. Nitrofurantoin is actively transported into human milk, achieving concentrations in milk greatly exceeding those in serum with an observed milk to serum ratio of 6.2 ± 2.7, and causes haemolytic anaemia in G6PD-deficient children.
Acyclovir inhibits viral DNA synthesis. It is phosphorylated to acyclovir triphosphate by herpes simplex virus (HSV) thymidine kinase, which competes for endogenous deoxyguanosine triphosphate and acts as a chain terminator in the synthesis of viral DNA. Resistance to the drug is due to a mutation in the thymidine kinase enzyme. Acyclovir has poor oral bioavailability and the absorbed drug is reached in good concentrations in breast milk, amniotic fluid and the placenta. It is used in the treatment of HSV and varicella-zoster infection. It has been used in pregnancy and is believed to be safe. Common side effects include nausea, vomiting and headache and it occasionally causes renal insufficiency and neurotoxicity.
Interferons (INF) are potent cytokines secreted by virtually all cells in the body in response to viral infection. They possess antiviral, immunomodulatory and antiproliferative actions. Three major classes are recognised: α, β and γ. Clinically used INF-α are used in the treatment of chronic hepatitis B and C virus infections and in refractory condylomata acuminata (genital warts). Dose-limiting side effects are myelosuppression with granulocytopenia and thrombocytopenia. Febrile illness is more common after INF administration to which tolerance gradually develops.
Triazole antifungal drugs (e.g. fluconazole and itraconazole) inhibit sterol demethylase and thus impair the biosynthesis of ergosterol in the cytoplasmic membrane. Ketoconazole inhibits steroid biosynthesis by inhibition of cytochrome P450 and can cause menstrual irregularities, gynaecomastia and in high doses azoospermia. Itraconazole is less likely to cause hepatotoxicity and corticosteroid suppression. Triazole antifungals can cause anomalies similar to Antley–Bixler syndrome (an autosomal recessive disorder characterised by craniofacial and other skeletal abnormalities) if given in doses exceeding 400 mg in the first trimester. They are safe in breastfeeding.
Thioamides (propylthiouracil, thiamazole and carbimazole) act principally by blocking the synthesis of T 4 by preventing iodination of tyrosine residues. Propylthiouracil also inhibits peripheral conversion of T 4 to T 3 . Carbimazole is rapidly converted to thiamazole, the active metabolite. Thioamides cross the placenta, propylthiouracil less than carbimazole. Carbimazole exposure particularly in the first trimester is associated with birth defects such as aplasia cutis choanal atresia and tracheo-oesophageal fistula, therefore its use is not recommended in women of childbearing age unless they are using effective contraception. In high doses thioamides may cause fetal hypothyroidism and goitre. Thioamides can also cause agranulocytosis as a rare complication. The lowest possible dose to maintain the free thyroxine level within the normal range should be used. Block and replace regimens should not be used as thyroxine does not cross the placenta sufficiently to protect the fetus from hypothyroidism. Patients who are on maintenance carbimazole need to be switched to propylthiouracil prior to pregnancy. They are safe in breastfeeding, although neonatal thyroid function tests should be checked if high doses are used. Less propylthiouracil is excreted into breast milk as it is more protein bound.
Biologic Agents and Kinase Inhibitors
Biologic drugs are commonly used to treat a large number of immune-mediated conditions, such as rheumatic and inflammatory bowel diseases, idiopathic thrombocytopenic purpura, psoriasis and asthma.
Pharmacological agents act by inhibiting cytokines (tumour necrosis factor (TNF) or interleukin (IL)), inhibiting T-cell activation or depleting B cells.
Three approaches are used in order to downregulate or inhibit the functions of cytokines:
soluble receptor antagonists: bind to the cytokine in serum and inhibit its interaction with cell receptors.
monoclonal antibodies (mAb): homogenous preparations of antibodies (or fragments of antibodies) which binds to plasma protein (i.e. TNFα) and stops it from interacting with their normal targets.
cell surface receptor antagonist: compete with cytokines for binding in membrane receptor.
Tumour Necrosis Factor Inhibitors
Etanercept is a soluble receptor antagonist that consists in two TNF receptors bound to the Fc portion of immunoglobulin G. The medication is bivalent, which means that one etanercept molecule binds two TNF molecules.
Infliximab is a chimeric (human and murine) mAb directed against TNF.
Adalimumab is a recombinant human mAb and due to its humanised construction, it is associated with a lower risk of anti-drug antibody formation.
Certolizumab pegol is a humanised anti-TNF-α antibody Fab’ fragment linked to polyethylene glycol (PEG). It lacks Fc portion and can’t be actively transported by the placenta.
TNF inhibitors are not teratogenic but are actively transported through the placenta reaching a peak transfer after 28 weeks. Hence it is recommended that treatment is stopped, if possible, by the third trimester (Infliximab at 16 weeks due to its long half-life). If continued beyond the recommended gestational age, the neonate should not have any live vaccinations for the first 6 months of life due to the possibility of neonatal immunosuppression. The exception is Certolizumab which has a molecular structure that only allows slow diffusion across the placenta, therefore it can be safely used throughout pregnancy. All TNF inhibitors can be used during breastfeeding.
Anakinra is a IL-1 receptor antagonist. It should not be used in combination with other biologic agents due to increased risk of serious adverse events. Other examples of IL-1 inhibitors include canakinumab and rilonacept.
Tocilizumab and Sarilumab act by inhibiting IL-6, while Secukinumab and Ixekizumab inhibit IL-17.
Ustekinumab is a human monoclonal antibody that binds to the p40 subunit shared by IL-12 and IL-23, blocking those inflammatory cytokines.
There is insufficient evidence to support the use of IL inhibitors in pregnancy and breastfeeding, therefore they should be avoided.
T-Cell Activation Inhibitors
Abatacept prevents the suppression of T reg activity and prevents increased T effector cell activity. In view of insufficient evidence, its use should be avoided in pregnancy and breastfeeding.
Rituximab, a mAb, eliminates CD20-positive B cells, induces complement mediated cytotoxicity and stimulates apoptosis.
Belimumab is an anti-B lymphocyte stimulator (BLyS) mAb. It prevents stimulation of B cells.
There is insufficient evidence to support the use of B-cell depleting agents in pregnancy and breastfeeding, therefore they should be avoided.
These agents are not biologics, but target pathways that mediate cell signalling, growth and division. Janus kinases (JAK) are cytoplasmic protein tyrosine kinases that are critical for signalling transduction to the nucleus from ILs 2, 4, 7, 9, 15 and 21. Tofacitinib and Baricitinib are examples of JAK inhibitors. An advantage of these agents is that they can be orally administered but should not be used in pregnancy or breastfeeding.
All biologic drugs supress the immune system and increase the risk of infection and reactivation of latent infections (i.e. tuberculosis). Once biologics are started, live vaccine is contraindicated, and chemoprophylaxis is required if latent tuberculosis is identified. Side effects include gastrointestinal (nausea, vomiting, diarrhoea, constipation), respiratory (coughing, dyspnoea), haematological (anaemia, leucopoenia, thrombocytopenia), neurological (musculoskeletal pain) and altered mood
These drugs affect rapidly dividing cells. Methotrexate, chlorambucil and cyclophosphamide are all contraindicated in pregnancy. Cyclophosphamide may be used in life-threatening conditions like progressive proliferative glomerulonephritis because of its immunosuppressant actions.
Azathioprine is used commonly for conditions like systemic lupus erythematosus, inflammatory bowel disease and in transplant patients. It is a 6-mercaptopurine derivative which interferes with antibody production and halts proliferation of T cells. There is extensive experience of its use in pregnancy and current evidence suggests an increased risk of impaired fetal immunity, but that this is not sustained in the neonate. FGR has been reported, but it is hard to separate the effect of chronic maternal disease on fetal growth from the potential effect of azathioprine. Only a small proportion of azathioprine is transferred into breast milk.
Mycophenolate mofetil is a prodrug that is rapidly hydrolysed to mycophenolic acid (MPA), a selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase. Since T and B lymphocytes are dependent on this pathway, it causes selective inhibition of antibody formation, cellular adhesion and migration. It is used primarily in prophylaxis of transplant rejection and is used in combination with glucocorticoids and a calcineurin inhibitor but not with azathioprine. Toxicity is mainly gastrointestinal and haematological. Its use is associated with an increased incidence of infections, especially sepsis associated with cytomegalovirus. It is excreted mainly by the kidney as an inactive phenolic glucuronide.
Alkylating agents are derived from nitrogen mustard. They become strong electrophiles through formation of carbonium ion intermediates that react with various nucleophilic moieties, such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl and imidazole groups forming covalent linkages and alkylating them.
Cyclophosphamide must be activated metabolically by microsomal enzymes of the cytochrome P450 system. The metabolites phosphoramide mustard and acrolein are thought to be the ultimate active cytotoxic moieties. Cyclophosphamide can be given either orally, intramuscularly or intravenously. It has a half-life of 4 to 8 hours in patients receiving it intravenously. It does not cross the blood–brain barrier and is eliminated primarily by the kidney. It is used to treat lymphoma, myeloma, chronic leukaemia, breast cancer, small cell lung cancer and ovarian cancer, and may be used as an alternative to azathioprine in Wegener granulomatosis, childhood nephrosis and severe rheumatoid arthritis. Side effects include bone marrow suppression (affecting white cells more than platelets), alopecia, impaired function of both humoral and cellular immunity. Cystitis is relatively common due to renal excretion of the metabolite acrolein and this disappears after discontinuation of treatment.
Melphalan is an amino acid derivative of mechlorethamine, an alkylating agent. It is used for the treatment of multiple myeloma and cancer of the breast and ovary. It can cause relatively prolonged bone marrow suppression and affects both white cells and platelets but does not cause alopecia.
Ifosfamide is an analogue of cyclophosphamide. Its use is associated with relatively low levels of bone marrow suppression, but more bladder toxicity, and hence it is administered with mesna.
Chlorambucil is an aromatic nitrogen mustard and with an anti-tumour activity similar to melphalan. It is well absorbed orally and is used for palliative treatment of lymphomas, chronic lymphocytic leukaemia and myeloma. Bone marrow toxicity is relatively common.
Dacarbazine: the triazeno group of this alkylating agent causes methylation of DNA and RNA and inhibition of nucleic acid and protein synthesis. It is the most active agent in metastatic melanoma and is combined with doxorubicin for treatment of sarcomas and Hodgkin disease. Side effects include bone marrow depression, a flu-like syndrome and alopecia.
Methotrexate is an antimetabolite which competes for binding sites on dihydrofolate reductase and inhibits the binding of folic acid. Hence, the essential co-factor tetrahydrofolate for synthesis of thymidylate, purines, methionine and glycine is inhibited. Cells in the S phase of the cell cycle are very sensitive. Resistance can occur due to increase in intracellular dihydrofolate reductase levels or appearance of altered forms of dihydrofolate reductase. It is well absorbed orally and mainly excreted through the kidneys. Methotrexate is used in combination chemotherapy for acute lymphoblastic leukaemia, Burkitt lymphoma and trophoblastic choriocarcinoma and is used in low doses to cause immune suppression in non-malignant conditions like rheumatoid arthritis and psoriasis. The major dose-limiting toxic side effect is myelosuppression, and occasionally hepatitis and lung toxicity can occur due to a hypersensitivity reaction. High doses of methotrexate can also cause renal failure.
Purine analogues include thioguanine and mercaptopurine (which is converted to thioguanine). This is incorporated into DNA and prevents cell multiplication by inhibition of purine synthesis. These drugs are used in the treatment of leukaemia. Leukopenia and thrombocytopenia are common adverse effects.
5-Fluorouracil is a pyrimidine analogue that kills cells in the S phase of the cell cycle by competitively inhibiting DNA synthesis. It is metabolised largely in the liver and excreted in urine. Side effects include myelosuppression, skin rashes, nail discoloration and photosensitivity. 5-Fluorouracil is used in the treatment of breast cancer, gastrointestinal adenocarcinomas and carcinomas of the ovary, cervix and bladder. Topical treatment has been useful in superficial basal cell carcinoma and treatment of premalignant keratoses of the skin.
Doxorubicin and daunorubicin are anthracycline antibiotics that have the ability to intercalate between base pairs and hinder DNA synthesis. Cells in the S phase are more sensitive. Drug resistance occurs due to enhanced active efflux of the drug. These drugs are not absorbed orally and cause necrosis if given intramuscularly or subcutaneously. Doxorubicin is used in the treatment of breast, ovary, endometrial, bladder and thyroid cancers. It can cause transient cardiac arrhythmias and depression of myocardial function. Myelosuppression occurs to a lesser extent and the drug may cause radiation recall reactions.
Bleomycin is a glycopeptide that binds to DNA and produces single- and double-strand scission and fragmentation of DNA. It is poorly absorbed orally and excreted mainly from the kidneys. Fatal lung toxicity can occur in 10% to 20% of cases. Skin toxicity may manifest as hyperpigmentation and erythematous rashes, and low-grade, transient fever is common. It is used in combination with platinum-based drugs to treat advanced testicular carcinomas and ovarian germ cell tumours.
α-Cisplatin is a platinum coordination complex used in the treatment of epithelial malignancies. α-Cisplatin enters the cell by diffusion and reacts with water to yield a positively charged molecule. Platinum compounds react with DNA to form intrastrand and interstrand cross-links. The cross-linking is most pronounced during the S phase of the cell cycle. α-Cisplatin is used in the treatment of cancers of bladder, head and neck, endometrium and ovary. It is nephrotoxic and ototoxic. Nephrotoxicity can be abrogated by hydration and diuresis. Repeated cycles can cause neuropathy.
Carboplatin has a similar mechanism of action and clinical spectrum to cisplatin. Carboplatin is relatively well tolerated and there is less nausea, neurotoxicity, ototoxicity and nephrotoxicity than with cisplatin. A dose-limiting toxic side effect is myelosuppression, evident as thrombocytopenia. It is an alternative in patients with responsive tumours who cannot tolerate cisplatin clinically due to impaired renal function, refractory nausea, significant hearing impairment or neuropathy.
Vincristine and vinblastine are plant alkaloids that bind avidly to tubulin and cause arrest in metaphase of cells. They act in the M phase of the cell cycle. Vinca alkaloids are used in the treatment of methotrexate-resistant choriocarcinoma, myelomas, Hodgkin and non-Hodgkin lymphomas, Ewing sarcoma and neuroblastoma. Vinblastine is more toxic to the bone marrow and vincristine is more neurotoxic.
Paclitaxel is a plant compound which binds to tubulin dimers and microtubulin filaments and prevents their depolymerisation. This causes disruption of mitosis and cytotoxicity. Major side effects include myelosuppression and peripheral neuropathy. It is used in treatment of breast, ovary, lung and head and neck carcinomas.
Diuretics may cause a reduction in the intravascular volume and decrease placental perfusion. However, reviews of the use of diuretics in pregnancy have not shown any adverse fetal effects, although some diuretics can cause maternal electrolyte imbalances. Table 12.4 summarises the site and mode of action and the maternal and fetal side effects of commonly used diuretics.