Page of

G 

G
Chapter:
G
Source:
Drugs in Anaesthesia and Intensive Care (5 ed.)
Author(s):

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0007

Gabapentin

Uses

Gabapentin is used in the treatment of:

  1. 1. post-herpetic neuralgia

  2. 2. painful diabetic neuropathy

  3. 3. partial seizures with or without secondary generalization, and

  4. 4. neuropathic pain.

Chemical

An acetic acid derivative which is a structural analogue of GABA.

Presentation

As 600/800 mg tablets and 100/300/400 mg capsules.

Main actions

Anticonvulsant and analgesic.

Mode of action

Gabapentin is structurally related to GABA but does not interact with GABA receptors. The binding site for the drug is the alpha-2-delta subunit of voltage-gated calcium channels. Gabapentin does not interact with sodium channels in vitro (cf. phenytoin, carbamazepine). It may also:

  1. 1. partially reduce the response to the glutamate agonist NMDA

  2. 2. reduce the release of monoamine neurotransmitters in vitro

  3. 3. stimulate glutamate decarboxylase (the enzyme which converts glutamate to GABA), and

  4. 4. increase the synaptic release of GABA.

Routes of administration/doses

The drug is administered orally and for all indications; a titration scheme can be employed during the initiation of therapy. Alternatively, an initially dose of 300 mg three times daily may be used. Dosage required for long-term epilepsy treatment is determined on an individual basis, although clinical trial data demonstrate the effective dosing range of between 900 and 3600 mg/day. Typically, dosage for treatment of neuropathic pain is up to 1800 mg/day, although a maximum dose of 3600 mg/day can be used. If discontinuation of gabapentin therapy is to be undertaken, this should be performed gradually over a minimum of 1 week, regardless of the indication. The total daily dose of the drug should be reduced in patients with renal impairment.

Effects

CNS

Gabapentin has analgesic and anticonvulsant properties and improves sleep in patients with neuropathic pain.

Toxicity/side effects

Dizziness, ataxia, nystagmus, somnolence, tremor, diplopia, nausea, and vomiting occur with a frequency >5%. Leucopenia, erectile dysfunction, and weight gain have all been reported, following use of the drug.

Kinetics

Absorption

Gabapentin is well absorbed orally and has a bioavailability of 60%. Peak plasma levels of the drug occur within 2–3 hours of administration.

Distribution

The drug is not bound to plasma proteins; the VD is 0.85 l/kg. In patients with epilepsy, gabapentin concentrations in the CSF are approximately 20% of the corresponding steady-state trough plasma concentrations. The drug is present in the breast milk of breastfeeding women.

Metabolism

Gabapentin is not metabolized in man and does not induce hepatic mixed function oxidase enzymes.

Excretion

The drug is excreted unchanged by renal excretion. The elimination half-life is 5–7 hours. The clearance is directly proportional to creatinine clearance.

Special points

Gabapentin enhances the analgesic effect of co-administered morphine. It is removed by haemodialysis. The bioavailability of the drug decreases with increasing dose which may minimize toxicity resulting from overdose. Co-administration of gabapentin with antacids containing aluminium and magnesium may reduce bioavailability of the drug by up to 24%.

Gelatins

Uses

Gelatins are used as plasma volume substitutes to expand and maintain circulating blood volume.

Chemical

Animal collagen derivatives. Two types of gelatin are available: succinylated gelatins (molecular weight: 30 000 daltons) and urea-linked gelatins (molecular weight: 35 000 daltons). They are produced by the thermal degradation of bovine gelatin.

Presentation

A number of agents are available in the UK for intravenous administration. Examples of commercially available products include:

  • Gelofusine® 4%, a succinylated gelatin

  • Volplex® 4%, a succinylated gelatin

  • Haemaccel® 3.5%, a urea-linked gelatin.

The above agents are presented in 0.9% sodium chloride for intravenous administration. Haemaccel® also contains the following electrolytes: K+ 5.1 mmol/l, Ca2+ 6.25 mmol/l.

Main action

Intravascular volume expansion.

Mode of action

Temporary increase in plasma oncotic pressure.

Routes of administration/doses

The specific dose of an agent administered is dependent on the clinical indication, the haemodynamic status of the patient, and the particular agent being used.

Effects

CVS

The haemodynamic effects of gelatins are proportional to the prevailing circulating volume. The duration of action of these agents depends on the specific agent in use.

Toxicity/side effects

The most important side effect is that of overtransfusion, leading to pulmonary oedema. Administration of gelatins dissolved in saline containing solvents may lead to a hypernatraemic, hyperchloraemic metabolic acidosis. Hyperkalaemia and hypercalcaemia may complicate the use of agents containing solvents that include the electrolytes potassium and calcium. Allergic reactions have been reported, following the use of these agents.

Kinetics

Data are incomplete.

Distribution

Gelatin-containing solutions are initially distributed into the plasma but later equilibrate with the extracellular fluid compartment, following excretion of the gelatin component.

Metabolism

In vitro studies suggest that gelatins are degraded by proteolytic enzymes into smaller peptides and amino acids.

Excretion

Approximately 75% is excreted via the urine. Gelatins have a half-life of approximately 4 hours.

Special points

Following renal excretion, gelatins have an osmotic diuretic effect within the renal tubules. Agents containing calcium should not be administered immediately following a blood transfusion through the same intravenous line, without the giving-set being flushed with saline. The ionic calcium component may enhance digoxin toxicity if administered concurrently.

Glucagon

Uses

Glucagon is recommended for use:

  1. 1. in the treatment of hypoglycaemia and

  2. 2. to facilitate radiological investigation of the gastrointestinal tract and has been used in the management of

  3. 3. cardiogenic shock

  4. 4. renal colic

  5. 5. acute diverticulitis, and

  6. 6. propranolol overdose.

Chemical

A polypeptide hormone extracted from the alpha cells of the pancreatic islets of Langerhans.

Presentation

As vials containing 1/10 mg of lyophilized glucagon hydrochloride with lactose—this is reconstituted in glycerol and water prior to use and in prefilled syringes containing 1 mg glucagon.

Main action

Elevation of blood sugar concentration, positive inotropism and chronotropism, and relaxation of smooth muscle.

Mode of action

Glucagon acts via cell membrane receptors which stimulate adenylate cyclase activity, leading to an increase in the intracellular concentrations of cAMP. The final effects of the hormone are mediated via a cascade of protein kinases.

Routes of administration/doses

Glucagon may be administered intravenously, intramuscularly, or subcutaneously in a dose of 1–5 mg for an adult. The drug may also be infused intravenously (diluted in 5% glucose) at a rate of 1–20 mg/hour. Glucagon acts within 1 minute when administered intravenously and in 8–10 minutes when administered intramuscularly or subcutaneously—the ensuing increase in the blood sugar concentration lasts 10–30 minutes.

Effects

CVS

Glucagon has marked positive inotropic and somewhat less marked positive chronotropic effects, and acts synergistically with beta-adrenergic agonist drugs in this respect. The drug does not increase myocardial irritability.

AS

The drug reduces tone throughout the entire gastrointestinal tract, including the common bile duct; gastric and pancreatic secretions are simultaneously inhibited.

GU

Glucagon decreases the ureteric tone and has a small effect in improving the renal blood flow and urine output.

Metabolic/other

Glucagon increases gluconeogenesis, glycogenolysis, lipolysis, proteolysis, and ketogenesis, leading to an increase in the blood sugar concentration. It also stimulates the release of endogenous catecholamines and may cause hypokalaemia secondary to an increase in the rate of insulin secretion.

Toxicity/side effects

The drug is usually well tolerated; nausea and vomiting, hypo- or hyperglycaemia, diarrhoea, and allergic phenomena may complicate the use of glucagon.

Kinetics

Absorption

Glucagon is inactive when administered orally. The bioavailability appears to be similar when administered intramuscularly or subcutaneously.

Metabolism

The drug is degraded by proteolysis in approximately equal quantities by splanchnic, hepatic, and renal routes. The precise metabolic pathways are unknown.

Excretion

The clearance is 8–12 ml/min/kg, and the elimination half-life is 3–6 minutes.

Special points

The clearance of glucagon is halved in patients with renal failure; the drug is not removed by haemodialysis.

Glucagon potentiates the anticoagulant effect of warfarin, but not that of heparin.

Glucose

Uses

Glucose solutions are used:

  1. 1. to provide a source of water (5% solutions) and

  2. 2. calories (10/20/50% solutions) and

  3. 3. in the treatment of hypoglycaemia.

Chemical

Glucose is D-glucopyranose D-glucose monohydrate, a monosaccharide obtained by the hydrolysis of cornstarch.

Presentation

As a clear, colourless sterile solution containing 5/10/20/50% glucose in water in ampoules or bags containing 500/ 1000 ml. The preparations are sterile and contain no buffers or bacteriostatic agents. The pH varies from 3.5 to 6.5, according to concentration. The 5% solution contains 170 kcal/l and has an osmolarity of 250 mOsm/l; the 10/20/50% solutions are appropriate multiples of these figures.

Main action

An increase in the blood sugar concentration and glycogen deposition; ketosis and nitrogen loss are decreased.

Routes of administration/doses

Glucose solutions are administered intravenously; the 20% and 50% solutions should preferably be administered via a central vein. The dose depends upon the state of hydration, nutritional requirements, and blood sugar concentration of the individual patient.

Effects

CVS

The haemodynamic effects of glucose solutions are proportional to the prevailing volaemic status; infusion of the crystalloid will temporarily restore cardiovascular parameters towards normal.

GU

Renal perfusion is temporarily restored towards normal in hypovolaemic subjects transfused with the crystalloid.

Toxicity/side effects

Overhydration leading to water intoxication, hyponatraemia, mental confusion, and fits may occur with injudicious use of isotonic solutions (5%). This may produce central pontine myelinolysis. Hyperglycaemia and venous thrombosis may occur with the 10/20/50% solutions.

Kinetics

Data are incomplete.

Absorption

Glucose is rapidly and completely absorbed when administered orally.

Distribution

Glucose solutions are initially distributed within the intravascular compartment and rapidly equilibrate within the intra- and extravascular space.

Metabolism

Glucose is completely metabolized to CO2 and water.

Excretion

The metabolic products are excreted via the lungs and kidneys.

Special points

Use of excessive quantities of glucose solutions (especially in premenopausal women and prepubertal children) may result in cerebral oedema and respiratory arrest, a condition associated with poor neurological outcome.

Glyceryl trinitrate

Uses

Glyceryl trinitrate is used in the treatment of:

  1. 1. stable, unstable, and variant angina

  2. 2. left ventricular failure secondary to myocardial infarction and

  3. 3. in the perioperative control of blood pressure and

  4. 4. for the prophylaxis of phlebitis associated with venous cannulation and may be of use in

  5. 5. decreasing infarct size in patients with acute myocardial infarction and used

  6. 6. to promote venodilation when administering peripheral total parenteral nutrition (TPN).

Chemical

An organic nitrate which is an ester of nitric acid.

Presentation

As 300/500/600 micrograms tablets for sublingual administration, 1/2/3/5 mg tablets for buccal administration, an oral spray delivering 400 micrograms per metered dose, a slow-release transdermal patch delivering 5/10 mg per 24 hours, and as a clear solution for injection (which must be protected from light) containing 0.5/1/5 mg/ml of glyceryl trinitrate.

Main action

Vasodilation of both arteries and veins.

Mode of action

Glyceryl trinitrate is metabolized to nitric oxide (NO) which then stimulates guanylate cyclase in the vascular smooth muscle cells, resulting in the relaxation of smooth muscles.

Routes of administration/doses

The adult dose is 0.3 mg by the sublingual route, 0.4–0.8 mg when delivered by buccal spray, 1–5 mg when delivered by the buccal route in tablet form, 5–10 mg/24 hours when administered transdermally, and (diluted in glucose or saline) at the rate of 10–400 micrograms/min when administered intravenously. The maximum effect occurs in 15–30 minutes when administered buccally or sublingually, and 90–120 seconds after intravenous administration.

Effects

CVS

At low dose ranges, glyceryl trinitrate causes venodilation and, at higher concentrations, venous and arterial vasodilation. The systolic blood pressure decreases more than does the diastolic blood pressure; the central venous pressure, pulmonary artery pressure, left ventricular end-diastolic pressure, and myocardial oxygen consumption all decrease with the use of glyceryl trinitrate. The cardiac output is usually unaltered or decreased slightly by administration of the drug; it may increase in patients with heart failure who have a high systemic vascular resistance. The coronary blood flow may decrease or remain unchanged. A reflex tachycardia occurs in normal subjects; no effect is observed on the heart rate in patients with heart failure. Glyceryl trinitrate reduces venous return (preload) and facilitates subendocardial blood flow with redistribution into ischaemic areas. It relieves coronary vasospasm and dilates arterioles, reducing afterload, and is thought to relieve angina primarily by reducing myocardial oxygen demand (secondarily to a fall in left ventricular end-diastolic pressure and myocardial wall tension); myocardial oxygen supply is simultaneously increased by redistribution of the coronary blood flow to the subendocardium.

RS

The drug causes bronchodilatation; intrapulmonary shunting may increase, but the mechanism of hypoxic pulmonary vasoconstriction appears to be unaffected in man.

CNS

The intracranial pressure may increase due to cerebral vasodilation.

AS

Glyceryl trinitrate relaxes the smooth muscle of the gastrointestinal and biliary tracts.

GU

The renal blood flow may decrease in patients with congestive cardiac failure, secondary to a fall in blood pressure, with no accompanying change in renal vascular resistance.

Toxicity/side effects

Hypotension, sinus tachycardia, and occasionally bradycardia, nausea, and vomiting may result from administration of the drug. Headaches occur more commonly with oral or sublingual than with intravenous administration.

Kinetics

The data vary widely.

Absorption

Absorption is rapid and efficient after sublingual administration, but slow after oral or transdermal administration; the bioavailability is 3% after oral administration due to a significant first-pass effect.

Distribution

Glyceryl trinitrate is 60% protein-bound in the plasma in animal models; the VD is 0.04–2.9 l/kg.

Metabolism

The drug is rapidly metabolized in the liver and red blood cells by reduction to dinitrates, mononitrates, and nitrites, all of which are less active than the parent compound.

Excretion

80% is excreted in the urine; trace amounts are exhaled as CO2. The clearance after intravenous administration is 0.3–1 l/min/kg, and the elimination half-life is 1–3 minutes.

Special points

40–80% of the dose of intravenous glyceryl trinitrate is adsorbed onto plastic giving-sets. The drug has been shown to increase the duration of pancuronium-induced neuromuscular blockade and may also slow the catabolism of opioids. Clinically important tolerance does not occur with continued intravenous administration of the drug.

The drug is not removed by dialysis.

Excess cardiovascular mortality has been noticed with the use of nitrates and sildenafil.

Glycopyrronium bromide

Uses

Glycopyrronium bromide is used:

  1. 1. in premedication where an antisialogogue action is desired

  2. 2. to protect against the peripheral muscarinic effects of anticholinesterases

  3. 3. for the treatment of bradycardias in anaesthetized patients

  4. 4. for the treatment of hyperhydrosis (via topical administration) and

  5. 5. for symptom control in palliative care.

Chemical

A quaternary ammonium compound.

Presentation

As a clear solution for injection containing 0.2 mg/ml of glycopyrronium bromide and as a powder for topical application. It is also supplied in a fixed-dose combination containing 0.5 mg of glycopyrronium bromide and 2.5 mg of neostigmine per ml.

Main action

Anticholinergic; glycopyrronium bromide has a particularly profound anti-secretory action.

Mode of action

Glycopyrronium bromide acts by competitive antagonism of acetylcholine at peripheral muscarinic receptors.

Routes of administration/doses

The adult intravenous and intramuscular dose is 0.2–0.4 mg; the paediatric dose is 4–10 micrograms/kg. The peak effect occurs 3 minutes after intravenous injection.

Effects

CVS

Glycopyrronium bromide has little effect on the blood pressure when used in normal doses and causes less dysrhythmias than atropine. Tachycardia occurs when the drug is administered intravenously in doses >0.2 mg to anaesthetized patients. Glycopyrronium bromide is protective against bradycardias due to the oculocardiac reflex or suxamethonium when administered intravenously. The vagolytic effects of the drug last approximately 2–3 hours.

RS

The drug has a significant and long-lasting bronchodilator effect and causes an increase in the physiological dead space.

CNS

Glycopyrronium bromide is unable to cross the blood–brain barrier and is theoretically devoid of any central effects; however, headache and drowsiness are well-recognized sequelae of the drug. Post-anaesthetic recovery appears to be significantly more rapid with glycopyrronium bromide than with atropine. Glycopyrronium bromide has no effect on pupil size or accommodation.

AS

The drug has a powerful antisialogogue effect that lasts approximately 8 hours after intravenous or intramuscular injection—the drug is five times as potent as atropine in this respect. Glycopyrronium bromide reduces gastric volume by 90% for 4 hours after administration and reduces antral motility. The drug reduces lower oesophageal sphincter tone.

Metabolic/other

The drug inhibits sweat gland activity, but little effect is produced on body temperature. Glycopyrronium bromide has a weak local anaesthetic action.

Toxicity/side effects

Typical anticholinergic side effects are produced by the drug: dry mouth, difficulty in micturition, and inhibition of sweating.

Kinetics

Absorption

Oral absorption is poor and erratic; bioavailability by this route is 5%. The drug seems to be absorbed in comparable amounts when administered by either the intramuscular or intravenous route.

Distribution

Redistribution of the drug occurs rapidly—90% disappears from the plasma in 5 minutes. The drug crosses the placenta and may cause fetal tachycardia. The VD is 0.2–0.64 l/kg.

Metabolism

In animals, glycopyrronium bromide occurs by hydroxylation and oxidation in the liver; very little biotransformation of the drug occurs in man.

Excretion

Excretion occurs in the urine (85%) and bile (15%), and 80% unchanged. The clearance of glycopyrronium bromide is 0.89 l/min, and the elimination half-life is 0.6–1.1 hours.

Special points

When used in combination with neostigmine to reverse non-depolarizing neuromuscular blockade, glycopyrronium bromide causes less initial tachycardia and less anticholinesterase-induced late bradycardia than atropine (and control of secretions is superior) due to the fact that the time courses of action of neostigmine and glycopyrronium bromide are better matched.

The drug is physically incompatible with thiopental, methohexital, and diazepam.

Copyright © 2021. All rights reserved.