Ketamine is used:
1. for the induction of anaesthesia, especially in poor-risk patients with hypotension or asthma
2. as a sole agent for short procedures such as change of burns dressings
3. for pre-hospital care and mass casualties
4. for analgesia both post-operatively and in patients receiving intensive care
5. for pain relief in patients with chronic pain, and
6. for the reversal of severe unresponsive asthma.
Ketamine has a molecular weight of 238 and is presented as a colourless solution containing 10/50/100 mg/ml of racemic ketamine hydrochloride. It has a pH of between 3.5 and 5.5, with a pKa of 7.5. The racemic mixture contains in equal proportions two enantiomers due to its chiral centre of the cyclo-hexanone ring ([S-(+)-ketamine] and [R-(−)-ketamine]). All preparations now contain 0.1 mg/ml of benzethonium chloride as a preservative. S-(+)-ketamine is available in 5 and 25 mg/ml concentrations.
Mode of action
Ketamine is a non-competitive antagonist of the NMDA receptor Ca2+ channel pore and also inhibits NMDA receptor activity by interaction with the phencyclidine binding site. Inhibition of glutamate-gated NMDA receptors by ketamine provides a mechanism of a predominant analgesic profile. It reduces the pre-synaptic release of glutamate, in addition to complex interactions with opioid receptors. There is some evidence suggesting that ketamine acts as an antagonist at monoaminergic, muscarinic, and nicotinic receptors. Ketamine has local anaesthetic activity at high doses which may be the result of sodium channel inhibition.
S-(+)-ketamine has four times greater affinity for the NMDA receptor than R-(−)-ketamine. It is twice as potent as the racemic mixture and three times as potent as the R(−) form.
Routes of administration/doses
The intramuscular dose for induction of anaesthesia is 4–10 mg/kg; the onset of action is 2–8 minutes, and the duration of action is 10–20 minutes. The corresponding intravenous dose is 0.5–2 mg/kg, administered over a period of 60 seconds; the onset of action occurs within 30 seconds, and the duration of action is 5– 10 minutes. Ketamine may be used for the maintenance of anaesthesia, using an intravenous infusion at a rate of between 10 and 50 micrograms/kg/min. For sedation and analgesia, an intramuscular dose of 2–4 mg/kg or an intravenous dose of 0.2–0.75 mg/kg may be used, followed by an infusion of 5–20 micrograms/kg/min. Ketamine may also be administered orally, rectally, nasally, intrathecally, or extradurally. When used neuroaxially, the preservative-free solution must be used (not currently produced in the UK). Tolerance develops with repeated drug exposure.
Ketamine causes tachycardia, and an increase in the blood pressure, central venous pressure, and cardiac output, secondary to an increase in the sympathetic tone. These effects mask the mild direct myocardial depressant effect ketamine exerts (reduced effect with S-(+)-ketamine). Baroreceptor function is well maintained, and dysrhythmias are uncommon.
Ketamine causes mild stimulation of respiration, with relative preservation of airway reflexes. It acts as a bronchial smooth muscle relaxant and improves pulmonary compliance. The R-(−) isomer has greater activity against acetylcholine bronchial smooth muscle contraction, compared with the S-(+) form. Therefore, the racemic mixture may be a more suitable choice in patients with bronchospasm.
The dissociative state may be produced by separation functionally and electrophysiologically of the thalamo-neocortical and limbic systems. The eyes remain open; pupillary dilatation, nystagmus, and hypertonus occur. Cerebral blood flow, cerebral metabolic rate, and intracranial and intraocular pressures are all increased. Visceral pain is poorly obtunded by ketamine. The EEG demonstrates dominant theta activity with loss of the alpha rhythm. S-(+) ketamine has a faster recovery time.
PONV is common. Transient rashes occur in 15% of patients. Emergence delirium, unpleasant dreams, and hallucinations are common but may be alleviated by the use of a benzodiazepine premedication. Pain on injection (especially intramuscularly) can be reduced by combination with lidocaine. Bladder dysfunction is reported in chronic abusers.
The bioavailability of ketamine is: 20–25% (oral), 25–50% (nasal), and 93% (intramuscular).
Ketamine is 20–50% protein-bound in the plasma; the VD is 3 l/kg. The distribution half-life is 11 minutes. Recovery occurs due to redistribution across lipid membranes.
Ketamine is metabolized in the liver by N-demethylation and hydroxylation via the cytochrome P450 enzyme system of the cyclohexylamine ring. Norketamine, a metabolite, which is 30% as potent as ketamine, is metabolized to an inactive glucuronide.
Antisialogogue premedication is recommended prior to the use of ketamine. Emergence phenomena are less frequent in the young and elderly. Premedication can reduce the incidence of these reactions, as does leaving the patient in an undisturbed state during the recovery phase. Low-dose ketamine reduces tourniquet hypertension under general anaesthesia. Ketamine reduces inotropic requirements in septic patients. In animal models of endotoxic shock, ketamine reduces pulmonary drainage by enhancing haemodynamic stability and reducing pulmonary hypertension and extravasation. Ketamine may be harmful in patients with limited right ventricular reserve and increased PVR. Ketamine and thiopental are incompatible. Ketamine is a drug of misuse and is a Class C drug in the UK.
For the drug structure, please see Fig. 5.
Ketorolac trometamol is a dihydropyrrolizine carboxylic acid derivative. It is structurally related to indometacin.
As topical eye drops in a concentration of 5 mg/ml, and as a clear or pale yellow solution for injection in a concentration of 30 mg/ml.
Mode of action
Ketorolac is a non-specific inhibitor of COX which converts arachidonic acid to cyclic endoperoxidases, thus preventing the formation of prostaglandins, thromboxanes, and prostacyclin.
Routes of administration/doses
Ketorolac may be administered by intramuscular injection or by intravenous bolus administration at an initial dose of 10 mg. Subsequent doses of 10–30 mg may be administered every 4–6 hours for up to 2 days.
The topical ophthalmic dose is one drop to the affected eye three times a day.
Dyspepsia, nausea, bleeding from gastric and duodenal vessels, mucosal ulceration, perforation, and diarrhoea are expected COX-1 effects. Ketorolac may exacerbate gastrointestinal symptoms in patients with ulcerative colitis and Crohn’s disease.
Fluid retention may occur in some patients due to salt and water retention, and hence weight gain.
Gastrointestinal side effects are most commonly reported by patients. As with all NSAIDs, ketorolac use may lead to impaired renal function (especially in those patients who are dependent on renal prostaglandin production to maintain renal perfusion), and prolonged use may result in analgesic nephropathy.
All NSAIDs should be used with caution in patients with a history of, or risk factors for, cardiovascular disease, as there is an association between prolonged use of these drugs and arterial thrombotic events.
Following an intramuscular injection of ketorolac, the drug is rapidly absorbed. A mean peak plasma concentration of 2.2 micrograms/ml occurs 50 minutes after a 30 mg intramuscular injection. Intravenous administration of 30 mg of the drug results in a mean peak plasma concentration of 2.4 micrograms/ml 5.4 minutes after dosing.
91.4% of an administered dose is excreted renally; 6.1% of the dose is found in faeces. The total clearance of ketorolac in patients with normal renal function is 0.023 l/hour/kg, with a total half-life of 5.3 hours. In patients with impaired renal function, the half-life is prolonged to 10.3 hours.