Ropivacaine: A Review on the Pharmacological Features, Therapeutic Efficacy and Side-effects When used for Caudal Epidural Analgesia
Correspondence Address :
Shilpa Shankar,
Junior Resident, Department of Anaesthesiology Jawaharlal Nehru Medical College, Dmims, Sawangi Meghe, Wardha, Maharashtra, India.
E-mail: shilshank@gmail.com
Inadequate post operative pain treatment can lead to clinical and psychological changes, as well as increased morbidity, mortality, and financial burden, all of which can influence quality of life. A review of the pharmacological characteristics, therapeutic efficacy in delivering postoperative analgesia, and side-effects of Ropivacaine is presented in this article. Motor blockade is an unwanted effect during the post operative period. The fear of side-effects and hemodynamic instability caused by the most of the analgesic drugs are the challenges faced in providing effective post operative analgesia in children. Ropivacaine has lesser cardiotoxic effects, lesser motor blockade and minimal side-effects as compared to bupivacaine. These properties make it a promising drug for pediatric caudal analgesia and forms a cost-effective method by decreasing the requirement of systemic analgesics, morbidity and improving the life quality postoperatively.
Haemodynamic instability, Motor blockade, Postoperative pain
The definition of pain is that it is an unpleasant sensory and emotional subjective sensation associated with definite or possible tissue damage or characterised in terms of such damage that can only be felt, not expressed. Epidural analgesia using local anesthetic drugs provides post operative pain relief which is much superior in comparison with systemic drugs (1).
ROPIVACAINE
Pharmacological Features
Mode of action: The drug blocks generation of action potential by blocking the sodium and potassium ion channels in the dorsal horn of spinal cord. Calcium ion channel inhibition in the spinal cord causes electrical input from nociceptive afferent neurons to be blocked, resulting in the powerful analgesic activity seen with centrally given local anesthetics. Also, the drug blocks the release of substance P and other neurotransmitters such as glutamate, substance P, (Prostaglandins), Calcitonin Generated Peptide [CGRP], neurokinin-1 and -2 [NK1, NK2]) at the presynaptic level. The production and transmission of pain signals are thereby inhibited (2),(3),(4).
Chemical Properties: Ropivacaine is a pipecoloxylidide derivative and it belongs to amino amide type. It is a 99.5 percent chiral pure S enantiomer produced via alkylation of the S enantiomer of di-benzoyl-tartaric acid. There are 0.1 percent, 0.2 percent, 0.5 percent, and 0.75 percent preparations available (3),(4). S-1-propyl-2,6-pipecoloxylidide hydrochloride monohydrate is the chemical name. A propyl group replaces the butyl group on the aromatic ring of bupivacaine. Ropivacaine has a molecular weight of 274 kDa, a pka of 8.07, a pH of 7.4 .The plasma half-life is 111 minutes, and the clearance rate is 10.3 litres per minute (5) (Table/Fig 1).
Ropivacaine inhibits sodium channels and hence serves as a sedative. It blocks the transmission of sodium ions as well as potassium ions through the channel. As a result, it inhibits the creation and transmission of nerve impulses (6).
Pharmacokinetics
Absorption: The plasma concentration of ropivacaine is affected by a number of factors such as route, dose and concentration of drug, vascularity of the site and hemodynamic condition of the patient. It has biphasic elimination. The sluggish absorption of ropivacaine from the spinal area is the rate limiting factor. As a result of the epidural route, ropivacaine has a longer duration of effect (7).
Distribution: It binds mostly to alpha 1-acid glycoproteins. This glycoprotein is increased in conditions of stress, surgery causing increase in the bound form of drug (7).
Metabolism: Liver is the site of metabolism. Aromatic hydroxylation, which involves Cytochrome P4501A is used for aromatic hydroxylation of the drug and form the metabolites (hydroxy and de alkylated forms) which are excreted in urine. These are created in large quantities during continuous epidural infusion (7).
Elimination by urine: The kidneys eliminate approximately 86 percent of the whole medication. The 387 ml/min is the overall clearance rate. After an intravenous route, the half-life is roughly 1.8 hours, and after an epidural route, it's around 4.2 hours (7).
Pharmacodynamics
The characteristic of blockage generated by ropivacaine is determined on the drug's concentration. It inhibits both A and C fibers even at low concentrations. Because ropivacaine has a lower lipid solubility than bupivacaine, it penetrates the myelin layer less effectively. Hence, C fibers are blocked preferentially as compared to A? fibers. Toxicity is manifested by initial nervous system symptoms such as restlessness, tremor, seizure and later causes medullary depression and coma (8). Its effects on various body systems are:
Cardiovascular system (CVS) and central nervous system (CNS) effects: Because of its less lipophilic nature and being a pure S enantiomer, ropivacaine has higher threshold for CVS and CNS toxicity. Only at high plasma concentrations CVS and CNS toxic manifestations will appear. They are primarily caused by sympathetic fiber blockade. As a result, there is a decrease in venous return and a decrease in heart rate, resulting in hypotension (8).
Respiratory system effects: Normal doses have no impact, but greater amounts cause toxicity, which causes respiratory depression as well as a medullary depressive effect (8).
Other effects: At 0.375% and 0.188% concentrations, it hinders platelet aggregation. It has antibacterial growth inhibitory property against Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli (8).
Indications: Ropivacaine is utilized for subarachnoid, epidural, caudal, peripheral nerve blocks and for local infiltration in surgical procedures and in labor analgesia (9).
Contraindications: The drug is contraindicated in those with allergic to local anesthetic agents, sepsis, regional infections, unstable hemodynamics. Also, it should not be used for Bier’s block and paracervical block (9).
Side-effects (9)
Excessive plasma levels caused by overdosing, unintentional intravascular injection, or sluggish metabolic breakdown are all causes of ropivacaine side-effects. The mean dosages of total and free plasma concentrations at which deleterious effects manifest are about 4.3 and 0.6 microgram/ mL, respectively. The organ wise details of side-effects are discussed below.
Cardiovascular side-effects: bradycardia, hypotension, vasovagal response, syncope, and arrhythmias.
Neurological effects: involuntary motor activities, slow movements, neuropathy, vertigo, tremors and coma.
Digestive System: emesis, incontinence, and tenesmus
Hearing and Vestibular: tinnitus, deafness
Liver: jaundice
Musculoskeletal system: muscle cramps
Psychiatric effects: confusion, anxiousness, amnesia, delusions, hallucination, decreased sleep and nightmares
Skin: urticaria
Genito urinary effects: incontinence of urine.
Blood vessels and hematological effects: Deep vein thrombosis, phlebitis, and pulmonary embolism.
The side-effects caused as a result of drug interactions are mentioned as follows:
• Used with caution in combination with other structurally similar amide type Local Anaesthetic (LA) drugs as it can cause additive toxic effects.
• Usage of fluvoxamine like cytochrome P4501A2 inhibitor drug in combination with ropivacaine, can lead to increased plasma concentration of ropivacaine.
• Interaction and competitive inhibition of drugs like theophylline and imipramine metabolized by CYP1A2 is also seen (10).
Therapeutic Efficacy: Administration, Route and Dosages
Ropivacaine is available in concentrations of 0.2 percent, 0.5 percent, 0.75 percent, and 1 percent in ampules of isobaric solution (Table/Fig 2) (11),(12),(13),(14).
Literature Search and Review
This review article was prepared after a thorough study of the literature from 1990 to 2021 using data search engines such as ‘Scopus’,’ PubMed’, ‘Web of Science’, and ‘Google Scholar’. Focus was made on the articles using ropivacaine for caudal epidural in the pediatric age group. The articles using ropivacaine as the study drug but not for caudal epidural and study population other than pediatric group were not included in the review. Preference was given to the articles comparing ropivacaine with another local anesthetic drug or studies using different concentrations of ropivacaine (Table/Fig 3) [15-37].
Ropivacaine is Food and Drug Administration (FDA) approved drug for surgical anesthesia and acute pain management. It can be used in surgeries for epidural block, major nerve blocks and local infiltration, for caudal or epidural (continuous infusion or intermittent bolus) post operative analgesia and for labour pain control, a concentration of 0.05 to 0.1% ropivacine provides only sensory block, 0.3% can be used for profound sensory and slight motor block and 1% for both profound sensory and motor block. Ropiovacaine has better safety profile than bupivacaine. Its lesser motor blockade and lesser potency as compared to bupivacaine limits its use in spinal anesthesia (38). Li K et al., reported the use of ropivacaine as an adjuvant to patient controlled analgesia for wound infiltration in transforaminal lumbar interbody fusion. It was concluded that wound infiltration with ropivacaine effectively reduced opioid consumption and the side-effects of opioids (39). Pere PJ et al., reported that pharmacokinetics of ropivacaine is not altered by impaired renal function/ renal failure (40). Van de Vossenberg G et al., reported a pediatric case in which long term high dose ropivacaine was used for continuous epidural administration without any severe side-effects or complications (41). However, further studies need to be conducted in larger populations to evaluate its safety profile in immunocopromised and in paediatric continuous epidural administraion.
Ropivacaine selectively blocks A delta and C fibers involved in pain transmission to a great extent than A beta fibers involved in the motor function. Ropivacaine is also less lipophilic. Therefore, it is less likely to penetrate large myelinated motor fibers resulting in lesser amount of motor blockade and longer post operative analgesia. Motor blockade in children during the post operative period is one among the reason for undue anxiety in the parents. This greater degree of motor sensory differentiation makes utilising a preferred drug when motor blockade is undesired such as in providing post operative analgesia. This can be used as a cost-effective method of post operative analgesia by decreasing the requirement of systemic analgesics, associated side-effects of systemic drugs like opioids, duration of hospital stay, morbidity and improving the quality of life postoperatively (42).
Ropivacaine is an excellent drug for providing intra and post operative analgesia using caudal epidural technique. Epidural block via caudal route is used as a complement to general anesthesia in pediatric population. This technique utilising a good effective local anesthetic agent with the preferred characteristics of lesser motor blockade and prolonged analgesia with minimal side-effects, not only gives good post operative analgesia but also helps in reducing the requirement of polypharmacy using inhalational and intravenous agents, decrease the stress response during surgery and helps in speedy recovery. This review article suggests that the duration of analgesia is prolonged when ropivacaine is used along with adjuvant drugs. Also, the drug maintains hemodynamic stability with minimal side-effects and has the added advantage of lesser cardiotoxicity.
DOI: 10.7860/JCDR/2022/56478.16687
Date of Submission: Mar 19, 2022
Date of Peer Review: Apr 26, 2022
Date of Acceptance: May 13, 2022
Date of Publishing: Aug 01, 2022
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? NA
• Was informed consent obtained from the subjects involved in the study? NA
• For any images presented appropriate consent has been obtained from the subjects. NA
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