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

Edward Scarth

and Susan Smith

DOI:
10.1093/med/9780198768814.003.0015

Pancuronium

Uses

Pancuronium is used to facilitate intubation and controlled ventilation.

Chemical

A bis-quaternary aminosteroid.

Presentation

As a clear colourless solution for injection containing 2 mg/ml of pancuronium bromide. The solution has a pH of 4.

Main action

Pancuronium acts by competitive antagonism of acetylcholine at nicotinic (N2) receptors at the post-synaptic membrane of the neuromuscular junction. The drug also has some pre-junctional action.

Routes of administration/doses

The drug is administered intravenously. The ED95 of pancuronium is estimated to be 0.05 mg/kg. An initial dose of 0.05–0.1 mg/kg is recommended in adults, providing muscle relaxation for between 65 and 100 minutes. Endotracheal intubation can be achieved within 90–150 seconds of an intravenous dose, with maximal resultant neuromuscular blockade achieved within 4 minutes following administration. Maintenance of neuromuscular blockade may be achieved with bolus doses of 0.01–0.02 mg/kg. An initial dose of 0.06–0.1 mg/kg is recommended in children. If pancuronium is administered after suxamethonium, then the initial intravenous dose of the former should be reduced to 0.02–0.06 mg/kg in both adults and children. The initial recommended dose in neonates is 0.03–0.04 mg/kg. The drug should not be given by infusion.

Effects

CVS

Pancuronium causes an increase in the heart rate, blood pressure, and cardiac output, secondary to a vagolytic action. The systemic vascular resistance remains unchanged after the administration of the drug. A slight fall in central venous pressure may occur.

RS

Neuromuscular blockade results in apnoea. Pancuronium has a very low potential for histamine release; bronchospasm is extremely uncommon.

AS

Reports of salivation have been noted.

Metabolic/other

Pancuronium may decrease the partial thromboplastin time and prothrombin time.

Toxicity/side effects

There have been rare reports of fatal anaphylactoid reactions with the administration of pancuronium. Cross-sensitivity may exist with vecuronium and rocuronium. A transient rash may occur, following the administration of pancuronium.

Kinetics

Distribution

Pancuronium is 15–30% protein-bound in the plasma, predominantly to albumin and gamma globulin; the VD is 0.241–0.280 l/kg, which is increased by approximately 50% in patients with cirrhosis. The drug does not cross the blood–brain barrier. Pancuronium has been shown to cross the placenta in small doses.

Metabolism

30–45% of an administered dose undergoes hepatic metabolism by deacetylation to 3-hydroxy-, 17-hydroxy-, and 3,17-hydroxy derivatives, with subsequent biliary excretion. The 3-hydroxy derivative (up to 25% of an injected dose) has half the NMB activity of the parent drug, compared to the other metabolites (<5% of an injected dose) which have approximately 50 times less potency than pancuronium.

Excretion

Pancuronium drug levels appear to decrease in a triphasic manner. Forty to 50% of the dose is excreted in the urine (80% as unchanged drug), with 5–11% appearing in the bile. The clearance is 1.10–2.22 ml/kg/min, and the elimination half-life is 69–161 minutes (decreased by 22% and doubled, respectively, in patients with cirrhosis).

Special points

The duration of action of pancuronium, in common with other non-depolarizing relaxants, is prolonged by hypokalaemia, hypocalcaemia, hypermagnesaemia, hypoproteinaemia, dehydration, acidosis, and hypercapnia. The following drugs, when co-administered with pancuronium, increase the effect of the latter: volatile anaesthetic agents, induction agents, fentanyl, suxamethonium, diuretics, calcium channel blockers, alpha- and beta-adrenergic antagonists, protamine, lidocaine, metronidazole, and the aminoglycoside antibiotics. Pancuronium appears to decrease the MAC of halothane; it also tends to counteract the depressant effect of halothane on the blood pressure.

Due to the increased VD seen in patients with cirrhosis, the initial dose to achieve adequate muscle relaxation may be higher. However, the duration of action of the drug may be prolonged in patients with cirrhosis, biliary dysfunction, and renal impairment. The dose should be reduced in the presence of renal impairment.

The use of pancuronium appears to be safe in patients susceptible to malignant hyperpyrexia.

Paracetamol

Uses

Paracetamol is used:

  1. 1. as an analgesic for the relief of pain of mild to moderate severity and

  2. 2. as an antipyretic agent.

Chemical

As acetanilide derivative.

Presentation

As tablets and suppositories containing 60/125/250/ 500 mg of paracetamol and a syrup containing 24/50 mg/ml. A number of fixed-dose combinations with codeine, dihydrocodeine, pentazocine, and metoclopramide are also available. The drug is often a component of proprietary cold cures. A dispersible tablet form is available but has a high sodium content due to the presence of sodium bicarbonate. An intravenous preparation for infusion containing 10 mg/ml of paracetamol is available in 50 ml and 100 ml vials. The intravenous preparation also contains cysteine hydrochloride monohydrate, disodium phosphate dihydrate, sodium hydroxide, and mannitol. The sodium content is <23 mg per 100 ml. The preparation is sealed in a glass vial also containing argon, as the drug is unstable in an oxygen-rich environment. The drug should be infused over a 15-minute period. An intravenous preparation containing the pro-drug propacetamol, 1 g of which is equivalent to 500 mg of paracetamol, is also available.

Main action

Analgesic and antipyretic.

Mode of action

The mode of action of paracetamol is poorly understood, although there is evidence of activity involving prostaglandin synthesis inhibition, and serotonergic and cannabinoid pathways. The drug inhibits COX isoenzymes COX-1 and COX-2, particularly in areas of low inflammation (cf. non-steroidal anti-inflammatory drugs). Prostaglandin synthesis within the CNS is inhibited which accounts for the antipyretic effect of the drug; specifically, it inhibits the synthesis of the E series of prostaglandins that are normally produced in the anterior hypothalamus in response to pyrogens. There is evidence that paracetamol enhances inhibitory serotonergic pain pathways, as well as inhibits the uptake of anandamide, an endocannabinoid, involved in nociception. The drug also acts peripherally by blocking impulse generation within the bradykinin-sensitive chemoreceptors responsible for the generation of afferent nociceptive impulses.

Routes of administration/doses

The dose for adolescents and adults weighing >50 kg is 500 mg to 1 g 4- to 6-hourly (maximum daily dose 4 g) for the oral, rectal, and intravenous routes. Analgesic doses in children range from 60 to 90 mg/kg/day in divided doses, depending on the age and route of administration. Analgesic doses in neonates range from 30 to 60 mg/kg/day in divided doses, depending on the post-conceptual age and route of administration. A loading dose may be given.

Effects

CNS

The maximum analgesic effect of paracetamol appears to be greater than that of any other non-opioid analgesic.

AS

Paracetamol is occasionally used as a model for drug absorption, as its rate of absorption is proportional to the gastric emptying rate. Drugs which alter gastric emptying alter the rate of paracetamol absorption. The drug has no effect on the liver, unless taken in overdose, and does not cause gastric ulceration.

Metabolic/other

The drug potentiates the effect of ADH. It has a dose-dependent effect on platelets, causing reduced aggregation via platelet COX-1 inhibition and a subsequent decrease in thromboxane A2 synthesis. This degree of inhibition is unlikely to cause clinically significant bleeding.

Toxicity/side effects

Gastrointestinal disturbances, skin reactions, and idiosyncratic haemopoietic disorders (thrombocytopenia, neutropenia) may occur with therapeutic doses. Approximately 5% of patients who are allergic to aspirin show cross-sensitivity to paracetamol.

Kinetics

Absorption

The drug is rapidly absorbed from the upper gastrointestinal tract; the bioavailability when administered by the oral route is 63–89% due to first-pass metabolism. Absorption is variable when administered rectally, and the bioavailability by this route is 24–98% of that observed after oral administration.

Distribution

At therapeutic levels, paracetamol is 0–5% protein-bound in the plasma; the VD is 0.7–1 l/kg. Being a non-ionized, lipid-soluble substance, paracetamol penetrates tissues and the blood–brain barrier well. The drug crosses the placenta.

Metabolism

Occurs predominantly in the liver, 80–90% being metabolized to glucuronide (60–80%) and sulfate (20–30%) and 10% by cytochrome P450 (CYP2E1) to a highly reactive intermediate metabolite (N-acetyl- p-benzo-quinoneimine (NAPQI)) which, in turn, is inactivated by conjugation with glutathione. In the CNS, paracetamol is metabolized to P-aminophenol and then to N-arachidonoylphenolamine.

Excretion

1–5% is excreted unchanged in the urine; the glucuronide and sulfate metabolites are actively secreted in the renal tubules at low concentrations and actively reabsorbed at high concentrations. The clearance is 5 ml/kg/min, and the elimination half-life is 2–4 hours in normal adults, 4–5 hours in neonates, and 11 hours in premature neonates.

Special points

Paracetamol should be used with caution in patients with renal or hepatic impairment. The dose interval should be increased in patients with severe renal impairment. Paracetamol is removed by haemodialysis. The drug may lead to an increase in the INR of patients taking warfarin, possibly due to reduced synthesis of vitamin K-dependent clotting factors.

Hepatic damage occurs readily with doses exceeding 15 g of the drug; with toxic doses, the supply of glutathione becomes depleted, and the highly reactive intermediate metabolite (NAPQI) combines with hepatic cell membranes, leading eventually to centrilobular necrosis. N-acetylcysteine (NAC) and methionine act as alternative supplies of glutathione and can protect against paracetamol-induced liver damage if administered within 10–12 hours of ingestion of paracetamol. A treatment intervention graph is widely available. The major complication is fulminant hepatic failure (with or without acute renal failure), usually occurring at 2–7 days. Liver function tests are a poor prognostic indicator under these circumstances. Criteria for referral to a specialist liver centre are: encephalopathy, INR >3 on day 2 (>4.5 on day 3 or any increase thereafter), creatinine >200 micromoles/l or oliguria, arterial pH <7.3, hypoglycaemia. Patients may be considered for transplantation if arterial pH is <7.3 (or <7.25 if NAC administered) or the combination of prothrombin time >100 seconds, creatinine >300 micromoles/l, and grade III encephalopathy. The following are associated with a poor outcome: bilirubin levels >4 mg/100 ml, INR >2.2, lactate >3.5 mmol/l at 4 and 12 hours, low factor V levels.

Methionine has been added to paracetamol preparations to decrease the risk of hepatotoxicity in overdosage.

Penicillin

Uses

Penicillin is used in the treatment of infections of:

  1. 1. the respiratory tract

  2. 2. ear, nose, and throat

  3. 3. skin, bone, soft tissues, and wounds, and in the treatment of

  4. 4. gonorrhoea

  5. 5. meningitis and

  6. 6. subacute bacterial endocarditis.

Chemical

The prototype penicillin.

Presentation

The preparation for oral use is phenoxymethylpenicillin (penicillin V) which is presented as 125/250 mg tablets and in an elixir as the potassium salt. The parenteral preparation is benzylpenicillin (penicillin G) which is a white crystalline powder presented in vials containing 0.3/0.6/3/6 g of sodium benzylpenicillin.

Main actions

Penicillin is a bactericidal antibiotic with a narrow spectrum of activity, which includes Streptococcus, Neisseria, Haemophilus, Corynebacterium, Bacillus, Clostridium, Listeria, and Treponema spp., some sensitive staphylococcal strains, and oral anaerobes. Penicillin is destroyed by beta-lactamases produced by some strains of Pseudomonas, Enterobacteriaceae, and Bacteroides.

Mode of action

Penicillin binds specifically to PBPs (transpeptidases and carboxypeptidases) in the bacterial cell wall and prevents peptidoglycan cross-linking, thereby decreasing the mechanical stability of the bacterial cell wall.

Routes of administration/doses

The adult oral dose is 125–250 mg 4- to 6-hourly; the corresponding intravenous and intramuscular dose is 0.6–4.8 g/day in 2–4 divided doses. One mega unit is 600 mg. Penicillin may also be administered intrathecally.

Effects

Metabolic/other

High doses of benzylpenicillin may produce hypernatraemia and hypokalaemia.

Toxicity/side effects

Gastrointestinal disturbances, allergic phenomena (including anaphylaxis), rashes, and haemolytic anaemia may occur with the use of the drug. High parenteral doses of penicillin may cause neuropathy and nephropathy.

Kinetics

Absorption

15–30% of an oral dose of benzylpenicillin (the drug is unstable under acid conditions) and 60% of an oral dose of phenoxymethylpenicillin is absorbed. The pharmacokinetics after absorption is similar for both preparations.

Distribution

Penicillin is 59–67% protein-bound in the plasma, predominantly to albumin; the VD is 0.32–0.81 l/kg.

Metabolism

Penicillin is metabolized to penicilloic acid which is inactive with subsequent transformation to penamaldic and penicillenic acid.

Excretion

60–90% of a dose is excreted in the urine by active tubular secretion; up to 25% is excreted unchanged. The elimination half-life is 0.7 hours.

Special points

Penicillin is removed by haemodialysis.

Pethidine

Uses

Pethidine is used:

  1. 1. for premedication

  2. 2. as an analgesic in the management of moderate to severe pain and

  3. 3. as an antispasmodic agent in the treatment of renal and biliary colic.

Chemical

A synthetic phenylpiperidine derivative.

Presentation

As 50 mg tablets and a clear, colourless solution for injection containing 10/50 mg/ml of pethidine hydrochloride.

Main actions

Analgesia and respiratory depression.

Mode of action

Pethidine is an agonist at mu- and kappa-opioid receptors. Opioids appear to exert their effects by increasing intracellular calcium concentration which, in turn, increases potassium conductance and hyperpolarization of excitable cell membranes. The decrease in membrane excitability that results may decrease both pre- and post-synaptic responses.

Routes of administration/doses

The adult oral dose is 50–150 mg 4-hourly; the corresponding dose by the intramuscular route is 25–150 mg and by the intravenous route 25–100 mg. Pethidine may also be administered via the epidural route; a dose of 25 mg is usually employed. The drug acts within 15 minutes when administered orally and within 10 minutes when administered intramuscularly; the duration of action is 2–3 hours.

Effects

CVS

Pethidine causes orthostatic hypotension due to the combination of histamine release and alpha-adrenergic blockade that it produces. The drug also has a mild quinidine-like effect and anticholinergic properties, which may lead to the development of tachycardia.

RS

The drug is a potent respiratory depressant, having a greater effect on the tidal volume than on the respiratory rate. Pethidine obtunds the ventilatory response to both hypoxia and hypercapnia. Chest wall rigidity may occur with the use of the drug. It has little antitussive activity.

CNS

Pethidine is one-tenth as potent an analgesic as morphine. It appears to cause more euphoria and less nausea and vomiting than an equipotent dose of morphine. Miosis and corneal anaesthesia follow the use of the drug.

AS

In common with other opioids, pethidine decreases the rate of gastric emptying. The drug appears to cause a less marked increase in bile duct pressure and less depression of intestinal activity (and therefore constipation) than equipotent doses of morphine.

GU

The drug decreases the ureteric tone; it may increase the amplitude of contractions of the pregnant uterus.

Metabolic/other

Pethidine increases ADH secretion and decreases adrenal steroid secretion.

Toxicity/side effects

Respiratory depression, nausea and vomiting, hallucinations, and dependence may complicate the use of pethidine. The drug evokes less histamine release than morphine.

Kinetics

Absorption

The bioavailability, when administered orally, is 45–75% due to a significant first-pass effect. The drug has a bioavailability of 100% when administered intramuscularly (into the deltoid muscle).

Distribution

Pethidine is 49–67% protein-bound in the plasma; the VD is 3.5–5.3 l/kg. The drug crosses the placenta; the mean cord blood concentration at delivery is 75–90% of the maternal venous concentration.

Metabolism

Occurs in the liver by N-demethylation to norpethidine and by hydrolysis to pethidinic acid; norpethidine is further hydrolysed to norpethidinic acid. The acid metabolites are further conjugated prior to excretion. Norpethidine may accumulate in the presence of renal failure and has 50% the analgesic potency of the parent compound and marked convulsant properties.

Excretion

1–25% of the administered dose is excreted unchanged in the urine, dependent upon the urinary pH. Norpethidine is excreted in the urine; accumulation may occur in the presence of renal or hepatic impairment. The clearance is 12–22 ml/min/kg, and the elimination half-life is 2.4–7 hours. The clearance is reduced by the co-administration of halothane.

Special points

Pethidine may precipitate a severe hypertensive episode in patients receiving MAOIs. The drug reduces the apparent MAC of co-administered volatile agents. By convention, pethidine is used in asthmatic patients, although there is no published evidence that the drug causes bronchospasm less frequently than morphine in this group of patients.

Pethidine effectively inhibits post-anaesthetic shivering.

Phenelzine

Uses

Phenelzine is used in the treatment of:

  1. 1. non-endogenous depression and

  2. 2. phobic disorders.

Chemical

A substituted hydrazine.

Presentation

As tablets containing 15 mg of phenelzine sulfate.

Main action

Antidepressant.

Mode of action

Phenelzine is an irreversible inhibitor of mitochondrial monoamine oxidase, an enzyme involved in the metabolism of catecholamines and 5HT. It is assumed that the antidepressant activity of the drug is related to the increased concentration of monoamines in the CNS that results from the use of the drug.

Routes of administration/doses

The adult oral dose is 15 mg 6- to 8-hourly; this is reduced once a satisfactory response has been obtained. The maximum inhibition of enzyme activity is achieved within a few days, but the antidepressant effect of the drug may take 3–4 weeks to become established.

Effects

CVS

The predominant effect of the drug is orthostatic hypotension; MAOIs were formerly used as antihypertensive agents.

CNS

Phenelzine is an effective antidepressant which may also produce stimulation of the CNS, resulting in tremor and insomnia. The MAOIs suppress REM sleep very effectively.

AS

Constipation occurs commonly with the use of the drug; the mechanism of this effect is unknown.

Metabolic/other

Inappropriate secretion of ADH has been reported in association with the use of phenelzine.

Toxicity/side effects

Disturbances of the CNS (including convulsions and peripheral neuropathy), anticholinergic side effects, and hepatotoxicity may complicate the use of the drug. More importantly, a host of serious and potentially fatal interactions may occur between MAOIs and tyramine-containing substances, sympathomimetic agents, and CNS depressants (v.i.).

Kinetics

Data are incomplete.

Absorption

Phenelzine is readily absorbed when administered orally.

Metabolism

80% of the dose is metabolized by oxidation and hydroxylation to phenylacetic acid and parahydroxyphenylacetic acid. The drug may inhibit its own metabolism.

Excretion

Occurs predominantly in the urine as free and unconjugated aromatic forms of the drug.

Special points

MAOIs demonstrate several important drug interactions:

  1. 1. drugs, such as pethidine, fentanyl, morphine, and barbiturates, whose action is terminated by oxidation, have a more profound and prolonged effect in the presence of MAOIs; this is particularly marked in the case of pethidine. Marked hyperpyrexia, possibly due to 5HT release, may also occur when pethidine is administered to a patient who is already receiving MAOIs

  2. 2. indirectly acting sympathomimetic agents (e.g. ephedrine) produce an exaggerated pressor response in the presence of co-administered MAOIs; severe hypertensive episodes (which are best treated with phentolamine) may result from this interaction

  3. 3. MAOIs markedly exaggerate the depressant effects of volatile anaesthetic agents on the blood pressure and CNS

  4. 4. MAOIs inhibit plasma cholinesterase and may therefore prolong the duration of action of co-administered suxamethonium

  5. 5. MAOIs may also potentiate the effects of antihypertensive and hypoglycaemic agents, anti-parkinsonian drugs, and local anaesthetics.

A period of 2 weeks is required to restore amine metabolism to normal after the cessation of administration of phenelzine. This is the recommended period that should elapse between discontinuation of MAOI therapy and elective surgery. Post-operative analgesia for patients who are still receiving MAOI therapy has been safely provided using chlorpromazine and codeine.

Phenoxybenzamine

Uses

Phenoxybenzamine is used in the treatment of:

  1. 1. hypertensive crises

  2. 2. Raynaud’s phenomenon and

  3. 3. in the preoperative preparation of patients due for the removal of a phaeochromocytoma.

Chemical

A tertiary amine which is a haloalkylamine.

Presentation

As 10 mg tablets and a clear, colourless solution for injection containing 50 mg/ml of phenoxybenzamine hydrochloride.

Main actions

Vasodilatation (predominantly arterial).

Mode of action

Phenoxybenzamine acts via a highly reactive carbonium ion derivative which binds covalently to alpha-adrenergic receptors to produce irreversible competitive alpha-blockade. The drug increases the rate of peripheral turnover of noradrenaline and the amount of noradrenaline released per impulse by blockade of pre-synaptic alpha-2 receptors. Haloalkylamines also inhibit the response to serotonergic, histaminergic, and cholinergic stimulation.

Routes of administration/doses

The adult dose by the oral route is 10–60 mg/day in divided doses. The corresponding dose by intravenous infusion (diluted in glucose or saline) over 1 hour is 10–40 mg. After intravenous administration, the drug acts in 1 hour and has a duration of action of 3–4 days.

Effects

CVS

Phenoxybenzamine produces a decrease in the peripheral vascular resistance, which leads to a decrease in the diastolic blood pressure and pronounced orthostatic hypotension. A reflex tachycardia and an increase in cardiac output follow the administration of the drug. Phenoxybenzamine inhibits catecholamine-induced cardiac dysrhythmias. The drug causes a shift of fluid from the interstitial to the vascular compartment due to vasodilatation of pre- and post-capillary resistance vessels.

CNS

The drug decreases cerebral blood flow only if marked hypotension occurs. Motor excitability may follow the administration of phenoxybenzamine; however, sedation is the usual effect observed. Miosis occurs commonly.

AS

Phenoxybenzamine produces little change in gastrointestinal tone or splanchnic blood flow.

GU

The drug causes little alteration of renal blood flow; it decreases the motility of the non-pregnant uterus.

Toxicity/side effects

Dizziness, sedation, a dry mouth, paralytic ileus, and impotence may result from the use of phenoxybenzamine. The drug is irritant if extravasation occurs.

Kinetics

Data are incomplete.

Absorption

Phenoxybenzamine is incompletely absorbed after oral administration; the bioavailability by this route is 20–30%.

Distribution

The drug is highly lipophilic.

Metabolism

Phenoxybenzamine is predominantly metabolized in the liver by deacetylation.

Excretion

Occurs via the urine and bile; the half-life is 24 hours.

Special points

Systemic administration of the drug may lead to an increase in the systemic absorption of co-administered local anaesthetic agents. Phenoxybenzamine causes marked congestion of the nasal mucosa, and this may make nasal instrumentation more traumatic if topical vasoconstrictors are not used.

Phentolamine

Uses

Phentolamine is used for:

  1. 1. the diagnosis and perioperative management of patients with phaeochromocytoma

  2. 2. the acute treatment of hypertension occurring during anaesthesia and

  3. 3. the treatment of left ventricular failure complicating myocardial infarction.

Chemical

An imidazoline.

Presentation

As a clear solution for injection containing 10 mg/ml of phentolamine mesilate.

Main actions

Hypotension, positive inotropism, and chronotropism.

Mode of action

Phentolamine acts by transient, competitive alpha-adrenergic blockade (it is 3–5 times as active at alpha-1 as at alpha-2 receptors); it also has some beta-adrenergic agonist and anti-serotonergic activity.

Routes of administration/doses

The adult intramuscular dose for the control of paroxysmal hypertension is 5–10 mg; the drug may also be administered by intravenous infusion (diluted in glucose or saline) at the rate of 0.1–0.2 mg/min.

Effects

CVS

Phentolamine causes a marked reduction in the systemic vascular resistance, producing a decrease in blood pressure and a reflex tachycardia. The drug has a positive inotropic action, which is probably an indirect effect due to alpha-2 blockade leading to noradrenaline release. The coronary blood flow increases; the drug also has class I antiarrhythmic effects. In patients with heart failure, phentolamine causes an increase in the heart rate and cardiac output, with a concomitant decrease in the pulmonary arterial pressure, systemic vascular resistance, and left ventricular end-diastolic pressure.

RS

The drug increases the vital capacity, FEV1, and maximum breathing capacity in normal subjects, and prevents histamine-induced bronchoconstriction. Respiratory tract secretions are increased by the drug. Phentolamine is a pulmonary arterial vasodilator.

AS

The drug increases salivation, gastric acid, pepsin secretion, and gastrointestinal motility.

Metabolic/other

The drug increases insulin secretion.

Toxicity/side effects

Phentolamine is generally well tolerated but may cause orthostatic hypotension, dizziness, abdominal discomfort, and diarrhoea. Cardiovascular collapse and death have followed the administration of phentolamine when it is used as a diagnostic test for phaeochromocytoma.

Kinetics

Data are incomplete.

Absorption

The bioavailability is 20% when administered orally.

Metabolism

The drug is extensively metabolized.

Excretion

10% of the dose is excreted in the urine unchanged. The plasma half-life is 10–15 minutes.

Special points

Phentolamine causes marked congestion of the nasal mucosa, and this may make nasal instrumentation more traumatic if topical vasoconstrictors are not used.

Phenylephrine

Uses

Phenylephrine is used as an adjunct in the treatment of:

  1. 1. hypotension occurring during general or spinal anaesthesia

  2. 2. as a nasal decongestant and

  3. 3. as a mydriatic agent.

Chemical

A synthetic sympathomimetic amine.

Presentation

As a clear solution containing 10 mg/ml of phenylephrine hydrochloride.

Main action

Peripheral vasoconstriction.

Mode of action

Phenylephrine is a direct-acting sympathomimetic agent that has agonist effects at alpha-1 adrenoceptors. The drug does not affect beta-adrenoceptors.

Routes of administration/doses

Phenylephrine may be administered subcutaneously or intramuscularly in a dosage of 2–5 mg, with further doses titrated to response. The drug may be administered intravenously, following dilution in 0.9% sodium chloride (e.g. 10 mg of phenylephrine diluted in 100 ml of 0.9% sodium chloride yields a 100 micrograms/ml solution which can be diluted further, producing a 25 micrograms/ml solution) in 50–100 micrograms boluses. When administered intravenously, it has a duration of action of 5–10 minutes. When administered intramuscularly or subcutaneously, it has a duration of action of up to 1 hour.

Effects

CVS

Phenylephrine causes a rapid increase in the systolic and diastolic blood pressures due to an increase in the systemic vascular resistance. A reflex bradycardia occurs, which may cause a decrease in cardiac output.

RS

The drug is not known to cause bronchodilatation or act as a respiratory stimulant.

CNS

Phenylephrine has no stimulatory effects on the CNS. Phenylephrine causes mydriasis.

GU

The drug reduces uterine artery blood flow via its effect at alpha-adrenoceptors. Renal blood flow is decreased.

Metabolic/other

The drug may cause alterations in glucose metabolism.

Toxicity/side effects

Headaches, sweating, hypersalivation, tremor, and urinary retention may complicate the use of the drug. Extravascular injection of the drug may lead to tissue necrosis at the injection site.

Kinetics

There are no quantitative data available.

Metabolism

The drug is metabolized in the gastrointestinal tract and liver by monoamine oxidase.

Special points

Excessive hypertension may occur when phenylephrine is administered to patients with hyperthyroidism or those receiving MAOIs. Patients receiving cardiac glycosides, tricyclic antidepressants, or quinidine are at an increased risk of developing dysrhythmias when phenylephrine is administered.

Phenytoin

Uses

Phenytoin is used:

  1. 1. in the prophylaxis and treatment of generalized tonic–clonic and partial epilepsies and in the treatment of

  2. 2. fast atrial and ventricular dysrhythmias resulting from digoxin toxicity and

  3. 3. trigeminal neuralgia.

Chemical

A hydantoin derivative.

Presentation

As 25/50/100/300 mg capsules, a syrup containing 6 mg/ml, and as a clear, colourless solution for injection containing 50 mg/ml of phenytoin sodium.

Main actions

Anticonvulsant and antiarrhythmic.

Mode of action

Phenytoin has membrane-stabilizing activity and slows inward Na+ and Ca2+ flux during depolarization in excitable tissue; it also delays outward K+ flux. There appears to be a high-affinity binding site within the CNS for phenytoin, which suggests the existence of an endogenous ligand.

Routes of administration/doses

The adult oral dose is 200– 600 mg/day; a small dose should be used initially and gradually increased thereafter. The corresponding intramuscular dose is 100–200 mg 4-hourly for 48–72 hours, decreasing to 300 mg daily. The intravenous loading dose for the management of epilepsy is 10–15 mg/kg (administered slowly), followed by a maintenance dose of 100 mg 6- to 8-hourly. When used in the treatment of cardiac dysrhythmias, the corresponding intravenous dose is 3.5 mg/kg. The therapeutic range is 10–20 mg/l.

Effects

CVS

Phenytoin exhibits class I antiarrhythmic properties and enhances AV nodal conduction. Hypotension may complicate rapid intravenous administration of the drug; complete heart block, ventricular fibrillation, and asystole have also been reported under these circumstances.

CNS

80% of newly diagnosed epileptics can be controlled with phenytoin monotherapy. The drug acts as an anticonvulsant by stabilizing, rather than raising, the seizure threshold and by preventing the spread of seizure activity, rather than by abolishing a primary discharging focus.

Metabolic/other

Hyperglycaemia, hypocalcaemia, and alterations in liver function tests have been described consequent to phenytoin therapy. The drug suppresses ADH secretion.

Toxicity/side effects

Phenytoin has both idiosyncratic and concentration-dependent side effects. The idiosyncratic side effects include acne, gingival hyperplasia, hirsutism, coarsened facies, folate-dependent megaloblastic anaemia and other blood dyscrasias, osteomalacia, erythroderma, lymphadenopathy, systemic lupus erythematosus, hepatotoxicity, and allergic phenomena. The concentration-dependent side effects include nausea and vomiting, drowsiness, behavioural disturbances, tremor, ataxia, nystagmus, paradoxical seizures, peripheral neuropathy, and cerebellar damage. The drug is irritant if extravasation occurs when given intravenously and may cause muscular damage when administered intramuscularly.

Kinetics

Absorption

Absorption is very slow by both the intramuscular and oral routes. The oral bioavailability is 85–95%.

Distribution

Phenytoin is 90–93% protein-bound in the plasma; the VD is 0.5–0.7 l/kg.

Metabolism

There is a large genetic variation in the rate of metabolism of phenytoin, which occurs in the liver predominantly to a hydroxylated derivative which is subsequently conjugated to glucuronide. Phenytoin exhibits zero-order elimination kinetics just above the therapeutic range; the implication of this is that the dose required to produce a plasma concentration within the therapeutic range is close to that which will produce toxicity.

Excretion

70–80% of the dose is excreted in the urine by active tubular secretion as the major metabolite; 5% is excreted unchanged. The clearance is 5.5–9.5 ml/kg/day, and the elimination half-life is 9–22 hours in the first-order kinetics range; the latter increases at higher dose ranges when the capacity of the hepatic mono-oxygenase system becomes saturated. The dose of phenytoin should be reduced in the presence of hepatic impairment, but renal impairment requires little alteration of dosage (despite the fact that the free fraction of the drug increases in the presence of uraemia, an increase in the clearance and VD tends to offset this).

Special points

Phenytoin is a potent enzyme inducer and demonstrates a plethora of drug interactions, among which the most important are the precipitation of phenytoin toxicity by metronidazole and isoniazid and a reduced effectiveness of benzodiazepines, pethidine, and warfarin caused by the co-administration of phenytoin. The drug may also decrease the MAC of volatile agents and enhance the CNS toxicity of local anaesthetics; it appears to increase the dose requirements of all the non-depolarizing relaxants (with the exception of atracurium) by 60–80%.

The parenteral preparation of phenytoin precipitates in the presence of most crystalloid solutions.

The drug is not removed by dialysis.

Piperacillin

Uses

Piperacillin is used in the treatment of:

  1. 1. urinary and respiratory tract infections

  2. 2. intra-abdominal and biliary tract sepsis

  3. 3. gynaecological and obstetric infections

  4. 4. infections of skin, soft tissue, bone, and joints

  5. 5. septicaemia

  6. 6. meningitis and for

  7. 7. perioperative prophylaxis.

Chemical

A semi-synthetic penicillin.

Presentation

In vials containing 1/2 g and infusion bottles containing 4 g of piperacillin sodium. A fixed-dose combination with tazobactam is also available.

Main actions

Piperacillin is a bactericidal broad-spectrum antibiotic that is effective against many beta-lactamase-producing organisms. In vitro, it shows activity against the Gram-negative organisms Escherichia coli, Haemophilus influenzae, and Klebsiella, Neisseria, Proteus, Shigella, and Serratia spp.; anaerobes, including Bacteroides and Clostridium spp.; and the Gram-positive enterococci Staphylococcus, and Streptococcus spp. It is particularly effective against Pseudomonas, indole-positive Proteus, Streptococcus faecalis, and Serratia marcescens.

Mode of action

Piperacillin binds to cell wall PBPs and inhibits their activity; specifically, it affects PBP 1A/B which are involved in the cross-linking of cell wall peptidoglycans, PBP 2 which is involved in the maintenance of the rod shape, and PBP 3 which is involved in septal synthesis.

Routes of administration/doses

The adult intravenous dose is 4 g 6 to 8 hourly (each gram should be infused over 3–5 minutes), and the intramuscular dose 2 g 6 to 8 hourly.

Effects

Metabolic/other

Piperacillin has a lower sodium content than other disodium penicillins and causes less fluid and electrolyte derangements; serum potassium levels may decrease after the administration of the drug.

Toxicity/side effects

Gastrointestinal upsets, abnormalities of liver function tests, allergic reactions, and transient leucopenia and neutropenia may complicate the use of the drug. Deterioration in renal function has been reported in patients with pre-existent severe renal impairment treated with piperacillin.

Kinetics

Absorption

Piperacillin is poorly absorbed when administered orally and is hydrolysed by gastric acids.

Distribution

The drug is 16% protein-bound in the plasma; the VD is 0.32 l/kg. High concentrations are found in most tissues and body fluids.

Metabolism

Piperacillin is not metabolized in man.

Excretion

20% is excreted in the bile; the remainder is excreted in the urine by glomerular filtration and tubular secretion. The elimination half-life is 36–72 minutes.

Special points

The dose of piperacillin should be reduced in the presence of renal impairment; the drug is 30–50% removed by haemodialysis.

Prednisolone

Uses

Prednisolone is used:

  1. 1. as replacement therapy in adrenocortical deficiency states and in the treatment of

  2. 2. allergy and anaphylaxis

  3. 3. hypercalcaemia

  4. 4. asthma

  5. 5. panoply of autoimmune disorders

  6. 6. some forms of red eye and

  7. 7. in leukaemia chemotherapy regimes and

  8. 8. for immunosuppression after organ transplantation.

Chemical

A synthetic glucocorticosteroid.

Presentation

As 1/2.5/5/20 mg tablets of prednisolone, a solution for injection containing 25 mg/ml of prednisolone acetate, and as eye/ear drops and retention enemas.

Main actions

Anti-inflammatory.

Mode of action

Corticosteroids act by controlling the rate of protein synthesis; they react with cytoplasmic receptors to form a complex which directly influences the rate of RNA transcription. This directs the synthesis of lipocortins.

Routes of administration/doses

The adult oral dose is 5–60 mg/day in divided doses, using the lowest dose that is effective and on alternate days, if possible, to limit the development of side effects. The intramuscular or intra-articular dose is 25–100 mg once or twice weekly.

Effects

CVS

In the absence of corticosteroids, vascular permeability increases; small blood vessels demonstrate an inadequate motor response, and the cardiac output decreases. Steroids have a positive effect on myocardial contractility and cause vasoconstriction by increasing the number of alpha-1 adrenoreceptors and beta-adrenoreceptors and stimulating their function.

CNS

Corticosteroids increase the excitability of the CNS; the absence of glucocorticoid leads to apathy, depression, and irritability.

AS

Prednisolone increases the likelihood of peptic ulcer disease. It decreases the gastrointestinal absorption of calcium.

GU

Prednisolone has weak mineralocorticoid effects and produces sodium retention and increased potassium excretion; the urinary excretion of calcium is also increased by the drug. The drug increases the glomerular filtration rate and stimulates tubular secretory activity.

Metabolic/other

Prednisolone exerts profound effects on carbohydrate, protein, and lipid metabolism. Glucocorticoids stimulate gluconeogenesis and inhibit the peripheral utilization of glucose; they cause a redistribution of body fat, enhance lipolysis, and also reduce the conversion of amino acids to protein. Prednisolone is a potent anti-inflammatory agent which inhibits all stages of the inflammatory process by inhibiting neutrophil and macrophage recruitment, blocking the effect of lymphokines, and inhibiting the formation of plasminogen activator. Corticosteroids increase red blood cell, neutrophil, and haemoglobin concentrations, whilst depressing other white cell lines and the activity of lymphoid tissue.

Toxicity/side effects

Consist of an acute withdrawal syndrome and a syndrome (Cushing’s) produced by prolonged use of excessive quantities of the drug. Cushing’s syndrome is characterized by growth arrest, a characteristic appearance consisting of central obesity, a moon face, and buffalo hump, striae, acne, hirsutism, skin and capillary fragility, together with the following metabolic derangements—altered glucose tolerance, fluid retention, a hypokalaemic alkalosis, and osteoporosis. A proximal myopathy, cataracts, mania, and an increased susceptibility to peptic ulcer disease may also complicate the use of the drug.

Kinetics

Absorption

Prednisolone is rapidly and completely absorbed when administered orally or rectally; the bioavailability by either route is 80–100%.

Distribution

The drug is reversibly bound in the plasma to albumin and a specific corticosteroid-binding globulin; the drug is 80–90% protein-bound at low concentrations, but only 60–70% protein-bound at higher concentrations. The VD is 0.35–0.7 l/kg, according to the dose.

Metabolism

Occurs in the liver by hydroxylation with subsequent conjugation.

Excretion

11–14% of the dose is excreted unchanged in the urine. The clearance is dose-dependent and ranges from 170 to 200 ml/min; the elimination half-life is 2.6–5 hours.

Special points

Prednisone and prednisolone are metabolically interchangeable; only the latter is active. The conversion of prednisone to prednisolone is rapid and extensive and occurs as a first-pass effect in the liver. Prednisolone is four times as potent as hydrocortisone and six times less potent than dexamethasone. It has been recommended that perioperative steroid cover be given:

  1. 1. to patients who have received steroid replacement therapy for 2 weeks prior to surgery or for 1 month in the year prior to surgery and

  2. 2. to patients undergoing pituitary or adrenal surgery.

Glucocorticoids antagonize the effects of anticholinesterase drugs.

Pregabalin

Uses

Pregabalin is used in the treatment of:

  1. 1. peripheral and central neuropathic pain

  2. 2. partial seizures with or without secondary generalization and

  3. 3. generalized anxiety disorder.

Chemical

The drug is a GABA analogue ((S)-3-(aminomethyl)- 5-methylhexanoic acid).

Presentation

As 25/50/75/100/150/200/225/300 mg capsules. Each capsule contains 35/70/8.25/11/16.5/22/24.75/33 mg of lactose monohydrate, respectively.

Main actions

Anticonvulsant, analgesic, and anxiolytic.

Mode of action

Pregabalin 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.

Routes of administration/doses

The dose range is 150–600 mg/day in two or three divided doses. The initial dose is 150 mg/day, increased to 300 mg/day after 1 week, with subsequent increases achieved on a weekly basis, based on individual response and tolerability. Discontinuation of treatment should be performed over at least a week. The dose needs to be reduced in patients with renal impairment.

Effects

CNS

Pregabalin has analgesic, anticonvulsant, and anxiolytic properties.

Toxicity/side effects

Weight gain may occur in diabetic patients during treatment with pregabalin, requiring dose modification of hypoglycaemic therapies. Pregabalin treatment has been associated with dizziness and somnolence. Data from controlled studies demonstrate an increased incidence of blurred vision, reduced visual acuity, and diplopia.

Kinetics

Absorption

Pregabalin is rapidly absorbed orally in the fasted state, has a bioavailability of >90%, and is independent of the dose administered. The rate of absorption is decreased when the drug is given with food.

Distribution

The drug is not bound to plasma proteins; the VD is 0.56 l/kg. Animal studies demonstrate that pregabalin crosses the placenta and is present in breast milk.

Metabolism

Pregabalin undergoes minimal metabolism in man; 0.9% of an administered dose is excreted as the major metabolite N-methylated pregabalin.

Excretion

Approximately 98% of an administered dose is excreted unchanged in the urine. The elimination half-life is 6.3 hours. Pregabalin plasma and renal clearances are directly proportional to creatinine clearance.

Special points

Due to the lactose content of pregabalin preparations, the drug should be avoided in patients with galactose intolerance, lactase deficiency, or glucose–galactose malabsorption.

The drug is removed by haemodialysis, with plasma pregabalin concentrations reduced by approximately 50% following 4 hours of haemodialysis.

Prilocaine

Uses

Prilocaine is used as a local anaesthetic.

Chemical

A secondary amide which is an amide derivative of toluidine.

Presentation

As a clear, colourless solution containing racemic prilocaine hydrochloride (S- and R-enantiomers) in concentrations of 0.5/1/2/4%. A 3% solution with 0.03 IU of felypressin per ml is also available. The pKa of prilocaine is 7.7–7.9 and is 33% unionized at a pH of 7.4. The heptane:buffer partition coefficient is 0.9.

Main action

Local anaesthetic.

Mode of action

Local anaesthetics diffuse in their uncharged base form through neural sheaths and the axonal membrane to the internal surface of cell membrane Na+ channels; here they combine with hydrogen ions to form a cationic species which enters the internal opening of the Na+ channel and combines with a receptor. This produces blockade of the Na+ channel, thereby decreasing Na+ conductance and preventing depolarization of the cell membrane.

Routes of administration/doses

Prilocaine may be administered topically, by infiltration, or epidurally; the toxic dose of prilocaine is 6 mg/kg (8 mg/kg with felypressin). The maximum dose is 400 mg. The drug has a rapid onset of action and has a duration of action 1.5 times that of lidocaine.

Effects

CVS

Prilocaine has few haemodynamic effects when used in low doses, except to cause a slight increase in the systemic vascular resistance, leading to a mild increase in the blood pressure. In toxic concentrations, the drug decreases the peripheral vascular resistance and myocardial contractility, producing hypotension and possibly cardiovascular collapse.

RS

The drug causes bronchodilatation at subtoxic concentrations. Respiratory depression occurs in the toxic dose range.

CNS

The principal effect of prilocaine is reversible neural blockade; this leads to a characteristically biphasic effect in the CNS. Initially, excitation (light-headedness, dizziness, visual and auditory disturbances, and seizure activity) occurs due to inhibition of inhibitory interneurone pathways in the cortex. With increasing doses, depression of both facilitatory and inhibitory pathways occurs, leading to CNS depression (drowsiness, disorientation, and coma). Local anaesthetic agents block neuromuscular transmission when administered intraneurally; it is thought that a complex of neurotransmitter, receptor, and local anaesthetic is formed, which has negligible conductance.

AS

Local anaesthetics depress contraction of the intact bowel.

Toxicity/side effects

Prilocaine is intrinsically less toxic than lidocaine. Allergic reactions to the amide-type local anaesthetic agents are extremely rare. The side effects are predominantly correlated with excessive plasma concentrations of the drug, as described above. Methaemoglobinaemia may occur if doses in excess of 600 mg are used and is caused by the metabolite O-toluidine, although this condition may occur at lower doses in patients suffering from anaemia or a haemoglobinopathy, or in patients receiving therapy known to also precipitate methaemoglobinaemia (sulfonamides). Use of prilocaine for paracervical block or pudendal nerve block in obstetric patients is not recommended, as this may give rise to methaemoglobinaemia in the neonate, as the erythrocytes are deficient in methaemoglobin reductase.

Kinetics

Data are incomplete.

Absorption

The absorption of local anaesthetic agents is related to:

  1. 1. the site of injection (intercostal > caudal > epidural > brachial plexus > subcutaneous)

  2. 2. the dose—a linear relationship exists between the total dose and the peak blood concentrations achieved and

  3. 3. the presence of vasoconstrictors which delay absorption.

The addition of adrenaline to prilocaine solutions does not influence the rate of systemic absorption, as:

  1. 1. the drug is highly lipid-soluble, and therefore uptake into fat is rapid and

  2. 2. the drug has a direct vasodilatory effect.

Distribution

Prilocaine is 55% protein-bound in the plasma, predominantly to alpha-1 acid glycoprotein; the VD is 190–260 l.

Metabolism

Prilocaine is rapidly metabolized in the liver by amide hydrolysis, initially to O-toluidine which is, in turn, metabolized by hydroxylation to 4- and 6-hydroxytoludine. Some metabolism also occurs in the lungs and kidneys. Excessive plasma concentrations of O-toluidine may lead to the development of methaemoglobinaemia, which responds to the administration of 1–2 mg/kg of methylene blue.

Excretion

<5% of the dose is excreted unchanged in the urine. The terminal elimination half-life is 1.6 hours.

Special points

The onset and duration of conduction blockade is related to the pKa, lipid solubility, and the extent of protein binding. A low pKa and high lipid solubility are associated with a rapid onset time; a high degree of protein binding is associated with a long duration of action. Local anaesthetic agents significantly increase the duration of action of both depolarizing and non-depolarizing relaxants.

EMLA® is a white cream used to provide topical anaesthesia prior to venepuncture and has also been used to provide anaesthesia for split skin grafting. It contains 2.5% lidocaine and 2.5% prilocaine in an oil–water emulsion. When applied topically under an occlusive dressing, local anaesthesia is achieved after 1–2 hours and lasts for up to 5 hours. The preparation causes temporary blanching and oedema of the skin; detectable methaemoglobinaemia may also occur.

Prochlorperazine

Uses

Prochlorperazine is used in the treatment of:

  1. 1. nausea and vomiting

  2. 2. vertigo

  3. 3. psychotic states, including mania and schizophrenia, and

  4. 4. in premedication.

Chemical

A phenothiazine of the piperazine subclass.

Presentation

As tablets containing 3/5/25 mg, suppositories containing 5/25 mg, as a clear, colourless solution for injection containing 12.5 mg/ml of prochlorperazine maleate, and as a syrup containing 1 mg/ml of prochlorperazine mesilate.

Main actions

Antiemetic.

Mode of action

The antiemetic and neuroleptic effects of the drug appear to be mediated by central dopaminergic (D2) blockade, leading to an increased threshold for vomiting at the chemoreceptor trigger zone; in higher doses, prochlorperazine appears to have an inhibitory effect at the vomiting centre.

Routes of administration/doses

The adult dose is 5–20 mg 8 to 12 hourly, and the corresponding intramuscular dose is 12.5 mg 6-hourly.

Effects

CVS

Prochlorperazine may cause orthostatic hypotension secondary to alpha-adrenergic blockade. ECG changes, including an increased QT interval, ST depression, and T and U wave changes, may also occur.

RS

The drug may cause mild respiratory depression.

CNS

Prochlorperazine has neuroleptic properties but appears to be less soporific than perphenazine.

AS

Lower oesophageal tone is increased by the drug.

Metabolic/other

In common with other phenothiazines, prochlorperazine has anti-adrenergic, anti-inflammatory, antipruritic, anticholinergic, and antihistaminergic effects. The drug may also cause hyperprolactinaemia.

Toxicity/side effects

Prochlorperazine may cause extrapyramidal reactions, jaundice, leucopenia, and rashes. The neuroleptic malignant syndrome (a complex of symptoms that include catatonia, cardiovascular lability, hyperthermia, and myoglobinaemia), which has a mortality in excess of 10%, has been reported in association with the use of the drug.

Kinetics

Data are incomplete.

Absorption

The drug is slowly absorbed when administered orally; the bioavailability is 0–16% by this route.

Distribution

The drug is highly protein-bound (91–99%); the VD is 20–22 l/kg.

Metabolism

Prochlorperazine undergoes significant first-pass metabolism in the liver; its metabolic pathways include CYP3A4 and CYP2D6. Metabolism may occur by S-oxidation to a sulfoxide.

Excretion

The half-life of prochlorperazine is 6–8 hours.

Special points

Prochlorperazine is not removed by haemodialysis.

Promethazine

Uses

Promethazine is used in the treatment of:

  1. 1. nausea and vomiting (including motion sickness)

  2. 2. allergic reactions

  3. 3. pruritus and for

  4. 4. sedation in children.

Chemical

A phenothiazine.

Presentation

As 10/25 mg tablets, an elixir containing 1 mg/ml, and a clear, colourless solution for injection containing 25 mg/ml of promethazine hydrochloride.

Main actions

Antihistaminergic, sedative, and antiemetic.

Mode of action

Promethazine acts primarily as a reversible competitive antagonist at H1 histaminergic receptors; it also has some anticholinergic, anti-serotonergic, and anti-dopaminergic activity.

Routes of administration/doses

The adult oral dose is 20–75 mg daily in divided doses; the corresponding intramuscular and intravenous dose is 25–50 mg. The drug acts within 15 minutes and has a duration of action of 8–20 hours.

Effects

CVS

When normal therapeutic doses are used, promethazine has no significant cardiovascular effects. Rapid intravenous administration may cause transient hypotension.

RS

The drug causes bronchodilatation and a reduction in respiratory tract secretions, and has antitussive properties.

CNS

Promethazine is a potent sedative and anxiolytic; it also has a slight antanalgesic effect. It reduces motion sickness by suppression of vestibular end-organ receptors and by an inhibitory action at the chemoreceptor trigger zone. The drug has local anaesthetic properties.

AS

Promethazine decreases the tone of the lower oesophageal sphincter.

Toxicity/side effects

The drug exhibits predictable anticholinergic side effects and may produce extrapyramidal reactions when used in high doses. Jaundice, photosensitivity, excitatory phenomena, and gastrointestinal and haemopoietic disturbances may complicate the use of promethazine.

Kinetics

Absorption

Promethazine is well absorbed when administered orally but undergoes an extensive first-pass metabolism.

Distribution

The drug is 93% protein-bound in the plasma; the VD is 2.5 l/kg.

Metabolism

Promethazine is metabolized in the liver by sulfoxidation and N-dealkylation.

Excretion

Occurs predominantly in the urine, 2% unchanged. The clearance is 1.41 l/min, and the elimination half-life is 7.5–10 hours.

Special points

The depressant effects of the drug on the CNS are additive with those produced by anaesthetic agents.

Promethazine is not removed by haemodialysis.

Propofol

Uses

Propofol is used:

  1. 1. for the induction and maintenance of general anaesthesia

  2. 2. for sedation during intensive care and regional anaesthesia, and has been used

  3. 3. in the treatment of refractory nausea and vomiting in patients receiving chemotherapy and

  4. 4. in the treatment of status epilepticus.

Chemical

Propofol is 2,6-diisopropylphenol; a phenol derivative. The molecular weight is 178.27. It is a weak organic acid with a pKa of 11.

Presentation

Being highly lipid-soluble, as a white oil-in-water emulsion containing 1% or 2% w/v of propofol in soybean oil (100 mg/ml), egg lecithin (purified egg phosphatide) (12 mg/ml), benzyl alcohol (1 mg/ml) (to retard the growth of accidental microorganism inoculation), glycerol (22.5 mg/ml), and sodium hydroxide to adjust pH (7–8.5). The drug is also available combined with Lipofundin® containing medium-chain triglycerides.

Main action

Hypnotic

Mode of action

The mode of action is unclear. It potentiates the inhibitory transmitters glycine and GABA (via different mechanisms to those of thiobarbiturates and benzodiazepines) and may reduce Na+ channel opening times.

Routes of administration/doses

Propofol is administered intravenously in a bolus dose of 1.5–2.5 mg/kg for induction and as an infusion of 4–12 mg/kg/hour for maintenance of anaesthesia in adults. Children require a bolus dose increase of 50% and an increase of maintenance infusion by 25–50%. Patients who are elderly or unstable require dose reductions accordingly (induction 1–1.5 mg/kg, maintenance 3–6 mg/kg/hour). Co-induction of an opioid and/or benzodiazepine, or administration as premedication, will lower the required dose of propofol further. Consciousness is lost in about 30–40 seconds, with emergence occurring approximately after 10 minutes from a single dose. Plasma concentrations of 2–6 micrograms/ml and 0.5–1.5 micrograms/ml are associated with hypnosis and sedation, respectively.

Effects

CVS

Propofol produces a 15–25% decrease in the blood pressure and systemic vascular resistance, without a compensatory increase in the heart rate; the cardiac output decreases by 20%. In fit patients, the haemodynamic response to laryngoscopy is attenuated. Vasodilation occurs secondary to propofol-stimulated production and release of NO. Profound bradycardia, possibly through resetting of the baroreceptor reflex, and asystole may complicate the use of the drug.

RS

Bolus administration of propofol produces apnoea of variable duration (30 to ≥60 seconds) and suppression of laryngeal reflexes. Infusion of the drug produces a decrease in the tidal volume, tachypnoea, and a depressed ventilatory response to hypercarbia and hypoxia. Propofol causes bronchodilation, possibly via a direct effect on bronchial smooth muscle. The drug does not increase intrapulmonary shunting and may preserve the mechanism of hypoxic pulmonary vasoconstriction.

CNS

Propofol produces a smooth, rapid induction, with rapid and clear-headed recovery. Intracranial pressure, cerebral perfusion pressure, and cerebral oxygen consumption all decrease, following drug administration. Up to 10% of patients may manifest excitatory effects in the form of dystonic movements. These may be due to an imbalance between subcortical excitatory and inhibitory centres. Such movements are not accompanied by seizure activity on EEG recordings, and propofol has been used in the treatment of status epilepticus. Animal modules demonstrate that propofol has anticonvulsant properties. There are case reports of vivid dreams, some of a sexual nature, following propofol maintenance.

Intraocular pressure is decreased, following administration of propofol in normal subjects.

AS

Propofol appears to possess intrinsic antiemetic properties which may be mediated by antagonism of dopamine D2 receptors.

GU

In animals, propofol causes a reduction in the excretion of Na+.

Metabolic/other

Special care should be applied in patients with disorders of fat metabolism or patients receiving total parenteral nutrition as 1 ml of 1%. Propofol contains 0.1 g of fat (medium-chain triglycerides), with a calorific value of 1 cal/ml. Clinically significant impairment of adrenal steroidogenesis does not occur. Propofol is a free-radical scavenger.

Toxicity/side effects

Pain on injection occurs in up to 28% of subjects. The incidence may be reduced by the addition of lidocaine (1 ml of 1%), cooling the drug, and the use of large veins. Addition of lidocaine in quantities >20 mg lidocaine per 200 mg propofol results in emulsion instability and increases in globule size, which have been associated with reduced anaesthetic potency in animals. There are case reports of epileptiform movements, facial paraesthesiae, and bradycardia, following the administration of propofol, although the incidence of allergic phenomena is low. The use of propofol appears to be safe in patients susceptible to porphyria (although urinary porphyrin concentrations may increase) and malignant hyperpyrexia. There are reports of neurological sequelae and increased mortality complicating long-term use.

Propofol infusion syndrome has been seen in both children and adults receiving prolonged propofol administration and is characterized by metabolic acidosis, rhabdomyolysis, and multi-organ failure. It is not licensed for sedation on the intensive treatment unit (ITU) for children <16 years of age. The quinol metabolites may occasionally cause green discoloration of the urine and hair. Propofol should not be used in patients allergic to soya or peanuts.

Kinetics

Distribution

Propofol is 98% protein-bound in the plasma; the VD is 4 l/kg. The distribution half-life is 1.3–4.1 minutes, resulting in a brief duration of action following bolus administration of the drug, as it distributes into different compartments (alpha phase). The distribution of propofol is based on a three-compartment pharmacokinetic model which is employed in target-controlled infusion (TCI) programmes.

Metabolism

Propofol is rapidly metabolized in the liver, undergoing conjugation to an inactive glucuronide (49–73%), or metabolized to a quinol, which is excreted as sulfate and glucuronide conjugates of the hydroxylated metabolite via cytochrome P450. Inter-patient variability determines the ratio between the glucuronide and hydroxylated pathways. Extrahepatic metabolism probably contributes, since drug clearance exceeds hepatic blood flow. Renal and hepatic disease has no clinically significant effect on the metabolism of propofol.

Excretion

The metabolites are excreted in the urine; 0.3% is excreted unchanged. The clearance is 18.8–40.3 ml/kg/min, and the elimination half-life is 9.3–69.3 minutes. The clearance is higher in children and decreased in the presence of renal failure. Following extended administration, its terminal elimination half-life may be prolonged, together with an increasing context-sensitive half-time, although, under normal conditions, propofol is non-cumulative.

Special points

Propofol may increase the energy required for successful cardioversion. The drug causes a shortened duration of seizure activity during electroconvulsive therapy, although it does not decrease the efficacy of the treatment. Propofol is physically incompatible with atracurium. Aqueous emulsions of the drug support both bacterial and fungal growth, leading to the development of a formulation of propofol in 0.005% disodium edetate (EDTA) which provides less support for bacterial growth. TCI models can be used for propofol maintenance, such as ‘Marsh’ or ‘Schnider’, which use patient covariates to maintain a predetermined plasma or ‘effector site’ concentration.

There is evidence that preparations containing Lipofundin® produce less discomfort on injection and a shortened ventilation period for patients sedated on the ITU, when compared with other propofol preparations.

In morbidly obese patients, the lean body weight should be used for TCI induction of anaesthesia. The total body weight should be used to calculate TCI maintenance.

Drug structure

For the drug structure, please see Fig. 6.


Fig. 6 Drug structure of propofol.

Fig. 6 Drug structure of propofol.

Propranolol

Uses

Propranolol is used in the treatment of:

  1. 1. hypertension

  2. 2. angina

  3. 3. variety of cardiac tachydysrhythmias

  4. 4. essential tremor and in the adjunctive management of

  5. 5. anxiety

  6. 6. thyrotoxicosis

  7. 7. hypertrophic obstructive cardiomyopathy

  8. 8. phaeochromocytoma and in the prophylaxis of

  9. 9. recurrence of myocardial infarction

  10. 10. migraine and

  11. 11. oesophageal varices.

Chemical

An aromatic amine.

Presentation

As tablets containing 10/40/80/160 mg and as a clear solution for injection containing 1 mg/ml of propranolol hydrochloride.

Main actions

Negative inotropism and chronotropism.

Mode of action

Propranolol acts by competitive antagonism of beta-1 and beta-2 adrenoceptors; it has no intrinsic sympathomimetic activity. It also exerts a membrane-stabilizing effect when used in very high doses by the inhibition of Na+ currents.

Routes of administration/doses

The adult oral dose is 30–320 mg/day in 2–3 divided doses, according to the condition requiring treatment. The corresponding dose by the intravenous route is 1–10 mg, titrated according to response.

Effects

CVS

Propranolol is negatively inotropic and chronotropic, and leads to a decrease in myocardial oxygen consumption; the mechanism of the antihypertensive action of the drug remains poorly defined. Blockade of beta-2 adrenoceptors produces an increase in the peripheral vascular resistance.

RS

Propranolol causes a decrease in FEV1 by increasing airways resistance; it also attenuates the ventilatory response to hypercapnia.

CNS

The drug crosses the blood–brain barrier; its central effects may be involved in the mechanism of the antihypertensive action of the drug. Propranolol diminishes physiological tremor and decreases intraocular pressure.

GU

Propranolol decreases uterine tone, especially during pregnancy.

Metabolic/other

The drug decreases plasma renin activity and suppresses aldosterone release. Propranolol causes a decrease in the plasma free fatty acid concentration and may also cause hypoglycaemia due to blockade of gluconeogenesis. The drug increases total body sodium concentration and thus the extracellular fluid volume. Propranolol prevents the peripheral conversion of levothyroxine to triiodothyronine.

Toxicity/side effects

The side effects of propranolol are predictable manifestations of non-specific beta-adrenergic blockade. The drug may thus precipitate heart failure or heart block; exacerbate peripheral vascular disease; lead to bronchospasm, sleep disturbances, and nightmares; mask the symptoms of hypoglycaemia; and cause impaired exercise tolerance.

Kinetics

Absorption

90% of an oral dose of propranolol is absorbed; the bioavailability is 30–35% due to an extensive first-pass metabolism.

Distribution

The drug is 90–96% protein-bound in the plasma, predominantly to alpha-1 acid glycoprotein; the VD is 3.6 l/kg.

Metabolism

Propranolol undergoes extensive hepatic metabolism by oxidative deamination and dealkylation, with subsequent glucuronidation; the 4-hydroxy metabolite is active.

Excretion

Occurs via the urine; <1% of the dose is excreted unchanged. The clearance is 0.5–1.2 l/min, and the elimination half-life is 2–4 hours. The dose should be reduced in the presence of hepatic failure; no alteration in dose is necessary in the presence of renal impairment.

Special points

Beta-adrenergic blockade should be continued throughout the perioperative period; abrupt withdrawal of propranolol may precipitate angina, ventricular dysrhythmias, myocardial infarction, and sudden death. The co-administration of propranolol and non-depolarizing relaxants may lead to a slight potentiation of the latter.

The drug is not removed by dialysis.

Protamine

Uses

Protamine is used:

  1. 1. to neutralize the anticoagulant effects of heparin and

  2. 2. to prolong the effects of insulin.

Chemical

A purified mixture of low-molecular-weight cationic proteins prepared from fish sperm.

Presentation

As a clear, colourless solution for injection containing 10 mg/ml protamine sulfate.

Main actions

Neutralization of the anticoagulant effect of heparin; in high doses, protamine has a weak intrinsic anticoagulant effect.

Mode of action

Both in vitro and in vivo, the strongly basic compound protamine complexes with the strongly acidic compound heparin to form a stable salt—this complex is inactive. The intrinsic anticoagulant effect of the drug appears to be due to the inhibition of the formation and activity of thromboplastin.

Routes of administration/doses

Protamine is administered by slow intravenous injection; the dose should be adjusted, according to the amount of heparin that is to be neutralized, the time that has elapsed since the administration of heparin, and the activated coagulation time (ACT). One mg of protamine will neutralize 100 units of heparin. A maximum adult dose of 50 mg of the drug should be administered in any 10-minute period.

Effects

CVS

Protamine is a myocardial depressant and may cause bradycardia and hypotension, secondary to complement activation and leukotriene release. The pulmonary artery pressure may increase, leading to an impairment of right ventricular output.

Toxicity/side effects

Rapid intravenous administration of protamine may be complicated by acute hypotension, bradycardia, dyspnoea, and flushing. Anaphylactoid reactions may also occur; antibodies to human protamine often develop in vasectomized males and may predispose to hypersensitivity phenomena.

Kinetics

Data are incomplete.

Metabolism

The metabolic fate of the protamine–heparin complex has not been well elucidated; it may undergo partial degradation, thereby freeing heparin.

Prothrombin complex

Uses

Prothrombin complex is used in the treatment and prophylaxis of bleeding resulting from congenital or acquired deficiencies of prothrombin complex coagulation factors.

Chemical

Human plasma-derived prothrombin complex coagulation factors (II, VII, IX, and X), together with proteins C and S.

Presentation

As a powder in vials containing 250 or 500 IU, together with a solvent for intravenous injection. Following reconstitution, the following approximate concentration of each component is present:

  • factor II—20–48 IU/ml

  • factor VII—10–25 IU/ml

  • factor IX—30–31 IU/ml

  • factor X—22–60 IU/ml

  • protein C—15–45 IU/ml

  • protein S—12–38 IU/ml.

The total protein content following reconstitution is 6–15 mg/ml. The following substances are also present: heparin, human antithrombin III, human albumin, sodium chloride, sodium citrate, and hydrochloric acid or sodium hydroxide for pH adjustment. The sodium content of reconstituted prothrombin complex is up to 343 mg per 100 ml.

Main actions

Neutralization of the anticoagulant effect resulting from deficiency in factors II, VII, IX, and X.

Mode of action

Increased plasma levels of factors II, VII, IX, and X.

Routes of administration/doses

Prothrombin complex is administered intravenously. Advice regarding the dose and administration frequency should be sought from a haematologist prior to administration.

Toxicity/side effects

There is a risk of subsequent thrombosis and/or DIC with repeated dosing. There are very rare reports of allergic reactions during or following administration. Development of antibodies to any of the coagulation factors may occur very rarely.

Kinetics

Data are incomplete.

Distribution

Distribution of prothrombin complex is identical to endogenous coagulation factors.

Metabolism

The plasma half-life of each component of prothrombin complex is as follows:

  • factor II—60 hours

  • factor VII—4 hours

  • factor IX—17 hours

  • factor X—31 hours

  • protein C—47 hours

  • protein S—49 hours.

Factors IX and X and proteins C and S exhibit two-compartment model pharmacokinetics. Metabolic pathways involved in prothrombin complex metabolism are identical to those involved in endogenous factor/protein breakdown.

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