TOCOLYSIS IN VETERINARY OBSTETRICS
Tocolysis is an obstetrical procedure to prolong gestation in patients, some of which are experiencing preterm labor. This is achieved through various medications that work to inhibit contractions of uterine smooth muscle. The main medications used are beta-adrenergic agonist receptors, calcium channel blockers, cyclooxygenase inhibitors, and magnesium sulfate.
Tocolysis, a Greek derivative (tokos = childbirth or labor; lysis = dissolution), refers to reduced myometrial contractions following administration of variety of agents designated astocolytic drugs (Norwitz et al., 1999). Chemically, these drugs are categorized to β-sympathomimetics, calcium antagonistics, oxytocin antagonistics, and prostaglandin antagonistics which are popular in human obstetrics in comparison to veterinary practice, where the use is restricted to only β-sympathomimetics like isoxsuprine, ritodrine, terbutaline and clenbuterol (Menard, 1994 and Garg et al., 2004). The mode of administration is easy and desired action is exerted through activation of adenylecyclase followed by increased cAMP, protein phosphorylation and intracellular calcium sequesterization leading to diminished activity of contractile proteins culminating to muscle relaxation. These drugs act on β-receptors: β-1 and β-2 (Innes and Nicherson, 1975) in general, thus, might have side effects of cardiovascular origin besides maternal haemodynamics and fetal asphyxia (Matsuda et al., 2002). Smooth muscles are innervated by the sympathetic nervous system having α and β receptors; α receptors are responsible for the muscular contractions whereas β receptors are responsible for the muscular relaxation. β1 receptors are confined to heart and small intestine and β2 receptors are confined to the vascular smooth muscle, myometrium, bronchial tree (Putnam et al.,1985). Stimulation of β2 receptor causes bronchodilation, relaxation of the uterus and vasodilation in most species. So, drugs that produce this effect are termed uterine myorelaxants, tocolytic drugs or simply tocolytics. Isoxsuprine lactate was used first in cattle (Ahlers and Anderson, 1967) with an introduction of other drugs, the detailed pharmacokinetics ofClenbuterol and Terbutaline has been studied in cattle (Dave et al., 1998 and Melanie et al., 2007). However, clinical applications especially obstetrical problems including Preterm labor (Perez et al., 1997), nocturnal delivery (Hirst et al., 2005), dystocia (Erkert andMacallister, 2002), caesarean section (DeNooij, 1984), fetotomy (Menard and Diaz, 1987) and uterine prolapse (Zennetti, 1983) have been managed successfully apart from increased rate of pregnancies in recipients following surgical embryo transfer (Gregory and Rodrigues, 1986). Experimental studies conducted in sheep with KUR-1246, new derivative of β-sympathomimetic group (Kiguchi et al., 2002) and Meluadrine Tartrate; a plant extract (Matsuda et al., 2002) in goats have shown many fold greater potency of these products as smooth muscle relaxants with less side effects on cardiovascular system, general metabolism of dam and fetus. Effect of Oxytocin on uterine involution, cervical dilation and resumption of ovarian activity post-lambing in ewes and other farm animals is well known (Mohamed et al 2021) hence axytocin antagonists are used as tocolytics.
Drugs used as Tocolytics
β-sympathomimetics – Isoxsuprine, Ritodrine, Terbutaline, salbutamol, Orciprenaline, Fenoterol,Clenbuterol, Meluadrine Tartrate, KUR-1246. Calcium antagonists– Nifedipine, Verapamil, Nicardipine, Nitrendipine. Oxytocin antagonists – Atosiban and all Beta-sympathomimetics. Prostaglandin antagonists – Indomethacin Other agents –glyceryltrinitrate, Extracts of Bryophyllumpinnatum, omega-3 long chain Polyunsaturates, NSAIDs and Magnesium sulfate (Norwitz et al, 1999). Isoxsuprine lactate was the first agents to be used for treatment of preterm labor. Subsequently new agents invented that stimulate β2 receptors andused as tocolytics without side effects, for examples-ritodrine, salbutamol, terbutaline, clenbuterol, orciprenaline .
Clinical use of tocolytic drugs
Preterm labor/ threatened abortion
In spite of a tremendous efforts the incidence of premature labor in animals is around 5–7 % worldwide. Statistics indicate that preterm birth is the leading factorcausing neonatal morbidity and mortality in animals. In the routine practice progesterone therapy is generally advocated for the treatmentof premature labor, but it has some adverse effects like when labor pain has reached to its maximum amplitudes, the drug does not work or become ineffective. And the another side effect is, It prolongs gestation length, when administered during advanced stages of pregnancy, as a result, chances of dystocia increases due to additional weight gain of the fetus. In a clinical trial when 300 μg, Clenbuterol, i/m, injected in a cow for the treatment of premature labor, the treatment induced inhibition of uterine contractions without any side effects. Kiguchi et al (2002) found that a newly synthesized B-sympathomimetic agent KUR-1246 is a very potent tocolyticagent. The tocolytic effects of KUR-1246 was compared with Ritodrine hydrochloride on oxytocin-induced uterine contraction in pregnant sheep and the efficacy was judged on the basis of cardiovascular parameters of dam and general metabolism of dam and fetus.
Compiled & Shared by- Team, LITD (Livestock Institute of Training & Development)
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