The Anaesthesia Science Viva Book - part 6 pot

Alkalisation of local anaestheticsCommentary This technique is of clinical interest because it is used to shorten the latency of onset of effective anaesthesia, and is particularly usefu

Alkalisation of local anaesthetics

Commentary

This technique is of clinical interest because it is used to shorten the latency of onset

of effective anaesthesia, and is particularly useful in the context of extending anepidural block for urgent operative delivery It is of interest to FRCA examinersbecause it allows candidates to demonstrate their understanding of the basic mechan-isms of local anaesthetic action

The viva

You will be asked why it might be useful to add alkali to a local anaesthetic

comprise a lipophilic, aromatic portion, which is joined via an ester or amidelinkage to a hydrophilic, tertiary amine chain The presence of the amino groupmeans that they are weak bases, existing in solution partly as the free base, andpartly as the cation, as the conjugate acid When the acid HA dissociates to H⫹and A⫺the anion A⫺is a base because it serves as a proton receptor in thereverse reaction The special relationship of base A⫺to the acid HA is

acknowledged by calling it the conjugate base of the acid

ionised part of the local anaesthetic molecule, but a charged moiety will nottraverse the lipid and connective tissue membranes It is only when existing inthe uncharged form that the drug can gain access to the axoplasm

the ionised species (NH⫹) Both ionised and non-ionised drug forms can inhibit

Na⫹channels, but access to the axoplasm is via the uncharged species Oncewithin the axoplasm the local anaesthetic becomes protonated The ratio of thetwo forms is given by the Henderson–Hasselbalch equation, which in this

context can be written as pKa ⫽ pH ⫺ log[base]/[conjugate acid] The Ka is the

dissociation constant which governs the position of equilibrium between the

base and acid By analogy to pH, the pKa is the negative logarithm of that constant When pKa⫽ pH, the charged and uncharged forms are present in

equal concentrations Local anaesthetics have pKa values higher than body pH,

and the further away the dissociation constant is from body pH the moremolecules that exist in the ionised form The pH scale is logarithmic: hence if a

drug has a pKa of 8.4 it is 1 pH unit, that is a 10-fold H⫹concentration, awayfrom body pH, at which the drug will be 90% ionised and 10% non-ionised

are usually presented as aqueous solutions of the hydrochloride salts of thetertiary amine The tertiary amine is the base They are therefore prepared as thewater-soluble salt of an acid, usually the hydrochloride, which is stable insolution

solution nearer the pKa Addition of 1.0 ml NaHCO38.4% to 10.0 ml of lignocaine2%, will raise its pH from 6.5 to 7.2 This means that more drug will exist in thenon-ionised form so penetration will be more rapid

principle but with a different site of action Most local anaesthetics are marketed

as hydrochloride salts; it is, however, possible to combine the base form withcarbonic acid to form the carbonate salt rather than the hydrochloric acid The

H2CO3is in equilibrium with dissolved CO2 After infiltration of the drug, it isbelieved that the increased amount of CO2moves into the axoplasm, where itincreases the levels of the weak carbonic acid This lowers the intracellular pHand thereby favours cation production In clinical practice this theoreticalpromise has not been realised

● Clinical uses:Alkalisation is particularly useful in decreasing the onset time of a

block when speed may be of the essence The commonest example is when an

epidural block that has been used for labour analgesia needs to be extended for

surgical delivery

Direction the viva may take

If you have exhausted the core material above then you will have to be prepared for

the viva to take a potentially variable course Further aspects of local anaesthesia

about which you may be asked include:

G-coupled-receptor proteins Local anaesthetics have recently been shown to

interact with some of these proteins to modify the physiological response

fuller details see Mechanisms of action of general anaesthetics, page 287.)

intrinsic anaesthetic potency Lignocaine has low lipid solubility, whereas that of

bupivacaine is high For fuller details see Mechanisms of action of general

anaesthetics, page 287.

lipid emulsions (which increase the non-ionised proportion and release active

drug more slowly), suspensions, liposomes (which are amphipathic lipid

molecules encapsulating local anaesthetic) and polymer microspheres You will

not be expected to know about these in any detail

added to local anaesthetics in order to enhance their action See Spinal adjuncts to

local anaesthetics, page 199.

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Bupivacaine and ropivacaine (compared)

Commentary

While a discussion about local anaesthetics logically would include all the agents thatcurrently are used, in practice it is quite difficult to focus such a viva effectively It ismuch easier to compare only two agents, which in turn is more interesting than con-centrating on only one You might conceivably be asked to talk solely about eitherbupivacaine or ropivacaine, but it is almost certain that some comparative infor-mation will still be required Make sure that your knowledge of bupivacaine isthorough, because this is a drug that you will have used frequently

The viva

You will be asked to compare bupivacaine and ropivacaine

reversible block of neuronal transmission, and which are synthetic derivatives ofcocaine Both possess the same three essential functional units, namely a

hydrophilic chain joined by an amide linkage to a lipophilic aromatic moiety

single methyl group attached to the tertiary amine Bupivacaine is identical apartfrom a butyl (C4H9) side chain The structure of ropivacaine (which is effectively

a derivative of bupivacaine, and which is prepared as the pure S-enantiomer ofpropivacaine) differs only in that there is a shorter propyl (C3H7) substituent onthe piperidine nitrogen atom

The affinity of local anaesthetics for the sodium channel is related to the length

of the aliphatic chains Affinity determines duration of action: hence ropivacaine,with its shorter propyl chain has a duration of action of 150 min as comparedwith 175 min for bupivacaine Both the drugs are around 96% protein bound

which is a determinant of potency Highly lipid-soluble agents such as

bupivacaine are highly concentrated in local tissue and dislodge slowly Asmeasured by partition coefficients bupivacaine is twice as soluble as ropivacaine,and is more potent

onset times are similar

myocardial and CNS toxicity has been quoted as being 25% less than racemicbupivacaine The cardiovascular and CNS toxicity of bupivacaine, however, is afunction of the R(⫹)-enantiomer The S(⫺)-enantiomer has less affinity for, anddissociates faster, from myocardial sodium channels Animal studies confirm afourfold decrease in the incidence of ventricular dysrhythmias and VF

Symptoms of CNS toxicity in human volunteers such as tinnitus, circumoralnumbness, apprehension, and agitation are also less with infusions of the S(⫺)-enantiomer This enantiomer is now available as L-bupivacaine (‘Chirocaine’),and would appear to be no more dangerous than ropivacaine

show biphasic activity, being vasodilators at high concentrations and

vasoconstrictors at low The vasoconstriction at low concentrations appears to beassociated particularly with the S-enantiomers Ropivacaine probably exertsgreater vasoconstrictor activity than bupivacaine, thereby reducing its potentialtoxicity and increasing the duration of action As already discussed, however, it

is no less toxic and has a shorter duration of action, so this vasoconstrictoractivity probably confers little benefit over laevobupivacaine

preferentially to block sensory nerves while sparing motor nerves It is of

particular advantage when the drugs are used in continuous epidurals for labour

and for surgical analgesia Selective block is a genuine phenomenon: etidocaine,

for example, demonstrates more potent motor than sensory block Etidocaine is

highly lipid soluble and penetrates better than bupivacaine into the large

myelinated A-␣-motor fibres It also penetrates into the cord itself to provide

long-tract anaesthesia But what of the claim that ropivacaine exhibits greater

sensory–motor dissociation than other local anaesthetics? This claim has been

based largely on studies that have used doses that are supramaximal for sensory

block, at which the greater motor-blocking effect of bupivacaine is obvious If the

doses are reduced, then little motor block will be evident with either drug, but

the differences in sensory block will be revealed It is well known that this group

of local anaesthetics demonstrates preferential sensory block: the purported

superiority of ropivacaine is in fact illusory, and is based on the fact that it is

simply a less potent drug

sensory–motor dissociation Drug entry into the sodium channels occurs when

the channel is open during the period of membrane depolarisation Nerves

conduct at different frequencies: pain and sensory fibres conduct at high

frequency whereas motor impulses are at a lower frequency This means that the

sodium channels are open more times per second Lignocaine, bupivacaine and

ropivacaine produce a more rapid and denser block in these sensory nerves of

higher frequency This is not true of drugs such as etidocaine, which is associated

with a much more profound motor block

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Induced hypotension

Commentary

This question has been around since before the current examiners were themselvesexamined, and it is seen as a predictable and standard topic You should be aware ofthe applied pharmacology, of the indications for the technique and of its potentialcomplications

The viva

You will be asked about the intravenous drugs that can be used to induce hypotension

● The subject lends itself readily to a structured approach You can, for example,talk either about their physiological sites of action or organise your answeraccording to the groups of drugs that are available This is almost, but not quitethe same thing: labetalol, for instance, is a hypotensive drug with more than onesite of action

● The prime determinants of arterial BP are CO (HR and stroke volume) and SVR.Drugs used to induce hypotension can affect one or more of these variables

Drugs which affect SVR

a-adrenoceptor blockers

is 3 : 1), which also has weak␤-sympathomimetic action It decreases BP byreducing peripheral resistance due to its peripheral␣1-vasoconstrictor blockadeand mild␤-sympathomimetic vasodilatation The ␣2-blockade increases

noradrenaline (norepinephrine) release The dose is 1–5 mg, titrated againstresponse and repeated as necessary The drug has a rapid onset of 1–2 min, andhas an effective duration of action of around 15–20 min

Peripheral vasodilators

nitric oxide (NO) NO activates guanylate cyclase, which increases cyclic

guanosine triphosphate (cGMP) within cells This in turn decreases availableintracellular Ca2⫹ The drug causes venous vasodilatation more than arteriolar,and hence it decreases venous return and preload Myocardial oxygen demand isreduced because of the decrease in ventricular wall tension GTN has a rapidonset (1–2 min) and offset (3–5 min) which can allow precise control of BP Atypical infusion regimen would be to start at around 0.5␮g kg⫺1min⫺1, titratedagainst response There is no rebound hypertension when the infusion is

discontinued The drug increases CBF and ICP Tolerance to the effects of GTNmay develop, which may partially be prevented by intermittent dosing

hypotension via the action of NO In contrast to GTN it causes both arterial andvenous dilatation, leading to hypotension and a compensatory reflex

tachycardia The drug has a complex metabolism that results in the production

of free cyanide (CN⫺), which by binding irreversibly to cytochrome oxidase inmitochondria is potentially very toxic, causing tissue hypoxia and acidosis.Toxicity is manifest when blood levels exceed 8␮g ml⫺1 The maximum infusionrate is 1.5␮g kg⫺1min⫺1, and the total dose must not exceed 1.5 mg kg⫺1

Treatment of toxicity is with sodium thiosulphate 50% (20–25 ml intravenouslyover 5 min) and/or cobalt edetate 1.5% (20 ml rapidly) SNP also increases CBFand ICP Coronary blood flow is also increased The rapid onset (1–2 min) andoffset (3–5 min) of effect allows good control of BP, although patients maydemonstrate rebound hypertension when the infusion is stopped Tachyphylaxis

may be seen in some patients, the mechanism underlying which is uncertain.

The solution is unstable and so the giving set must be protected from light

Ganglion blockers

sympathetic and parasympathetic autonomic ganglia, but it has no effect at the

nicotinic receptors of neuromuscular junction It has some␣-blocking actions

and is a direct vasodilator of peripheral vessels It is a potent histamine releaser,

which contributes to its hypotensive action Reflex tachycardia is common, and

this may present a problem during surgery which mandates a quiet circulation

Trimetaphan also antagonises hypoxic pulmonary vasoconstriction The drug is

given by infusion at a rate of 20–50␮g kg⫺1min⫺1

Direct vasodilators

weak␣-antagonist action This is mediated via an increase in cGMP and decrease

in available intracellular Ca2⫹ The tone of arterioles is affected more than

venules A reflex tachycardia is common It is less easy to titrate the dose against

effect and the drug finds its main use in the control of hypertension in

pregnancy The maximum infusion rate is 10 mg h⫺1

Drugs which affect CO

● ␤-adrenoceptor blockers: There are many examples; all are competitive

anatagonists, but their selectivity for receptors is variable Selective␤1

-antagonism clearly is a useful characteristic Their influence on BP is due

probably to decreased CO via a decreased HR, together with some inhibition of

the renin–angiotensin system Unopposed␣1-vasoconstriction may compromise

the peripheral circulation without causing hypertension

— Atenolol: This is a selective␤1-antagonist except in high doses It is long

acting with a t1/2of around 7 h It is given more commonly as a bolus (over

20 min) of 150␮g kg⫺1for cardiac dysrhythmias than to induce

hypotension

— Esmolol: This is a relatively selective␤1-antagonist It is ultra-short acting,

with a t1/2of around 9 min It is rapidly metabolised by non-specific ester

hydrolysis Its infusion dose is 50–200␮g kg⫺1min⫺1

— Labetalol: This acts both as␣- and ␤-antagonist (in a ratio of 1 : 7), which

mediates a decrease in SVR without reflex tachycardia It is a popular drug

in anaesthetic, obstetric anaesthetic and intensive therapy use Its

elimination t1/2is 4–6 h It can be given as a bolus of 50 mg intravenously, or

at a rate of 1–2 mg kg⫺1h⫺1

— Propanolol: This is a non-selective␤-antagonist which is usually given as a

bolus of 1 mg, repeated to a maximum of 5 mg (in a patient who is

anaesthetised)

a2-adrenoceptor agonists

greater than that for␣1 Its hypotensive effects are mediated via a reduction in

central sympathetic outflow and by stimulation of presynaptic␣2-receptors

which inhibit noradrenaline release into the synaptic cleft It also possesses

analgesic and sedative actions Its elimination t1/2is too long at around 14 h to

allow its use for fine control of acutely raised BP, but it can be a useful adjunct in

Direction the viva may take

You will probably be asked to discuss the indications for, and dangers of, inducedhypotension

to make the impossible possible, and not the possible easy There was a timewhen surgeons largely were oblivious to that injunction, and induced

hypotension had many indications, particularly for neurosurgical and procedures

in the head and neck The indications have now shrunk to the point at which thetechnique is confined to a very few, very specialised surgical procedures, oneexample of which is the removal of choroidal tumours of the eye

hypoperfusion in key parts of the circulation Precipitate falls in BP may lead tocerebrovascular accidents and to myocardial ischaemia Drug-induced

hypotension usually shifts the autoregulatory curve to the left, and confersthereby a degree of protection In patients who are previously hypertensive,however, the curve is shifted to the right, making them more vulnerable tocatastrophic drops in perfusion of essential areas You should be able to draw thecurve of cerebral autoregulation to demonstrate these shifts

by factors such as hypovolaemia, the use of other drugs with hypotensiveactions such as volatile anaesthetic agents, the reduction in venous returnassociated with intermittent positive-pressure ventilation, and drugs whichrelease histamine The head-up position may also further diminish effectivecerebral perfusion

Hypotension and its management

Commentary

This may end up largely as a viva about drugs to treat hypotension, but it will be

introduced from first principles Vasopressors are the logical treatment for falls in BP

that have been induced pharmacologically, but they also find deployment in a variety

of clinical scenarios in which patients are hypotensive You will be expected to know

about this class of drugs and to be able to demonstrate judgement in their use

The viva

You will be asked to describe the prime determinants of arterial BP

● Systemic BP is determined by cardiac output (CO), which is the product of heart

rate (HR) and stroke volume, multiplied by systemic vascular resistance (SVR)

(BP⫽ CO ⫻ SVR)

● Hypotension may result from an inadequately compensated decrease in any one

or more of these variables

Direction the viva may take

You may be asked to follow this logical beginning by detailing the causes and

management of acute hypotension You can preface your answer by explaining, for

example, that a fall in vascular resistance may be compensated by reflex tachycardia,

but that initially it is useful nonetheless to analyse them in isolation

Reduction in HR: causes and management (BP ⫽ HR ⫻ SV ⫻ SVR)

muscles, anal or cervical dilatation, visceral traction, and sometimes,

instrumentation of the airway

be responsible Anaesthetic drugs may also contribute Volatile agents in high

concentrations, or halothane in normal concentrations, suxamethonium, opioids,

and anticholinesterases can all be associated with bradycardia Low doses of

atropine may provoke a paradoxical bradycardia (the Bezold–Jarisch reflex)

conducting system

membrane with a resulting fall in HR

to T4should be associated with bradycardia In practice this is often not seen

Management

● First of all diagnose the cause, and if it is amenable to treatment then act

accordingly Is it hypoxia? Treat immediately Is it surgical stimulus? If so then

stop traction on the extraocular muscles or the mesentery If drug treatment is

required the most effective immediate first-line drug is an anticholinergic agent,

usually atropine or glycopyrrolate Neither is a treatment for hypoxia

Reduction in stroke volume (BP ⫽ HR ⫻ SV ⫻ SVR)

● The commonest cause is reduced venous return This may be due to an actual

reduction in circulating volume because of blood loss or dehydration, or to an

effective reduction in circulating caused by sympathetic block

● SV may also be diminished because the ventricle is failing

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Is it a failing ventricle? Consider using inotropes to support ventricular function.

Reduction in SVR (BP ⫽ HR ⫻ SV ⫻ SVR)

● The commonest cause of inadvertent profound hypotension is probably thatwhich is induced by the sympathetic block associated with spinal or epiduralanaesthesia

● In the context of intensive care medicine the commonest cause is sepsis

Management

● The rational management of hypotension that has been induced

pharmacologically is to treat it pharmacologically The reduced SVR associatedwith sepsis is different, but it still is usually managed with a combination ofvasopressor, fluids and inotropes

Further direction the viva could take

You will be asked about the range of drugs that is available to treat hypotension

Ephedrine

Chinese plant Ma Huang), which is now synthesised for medical use It is a

sympathomimetic drug which acts both directly and indirectly, and which has both

␣- and ␤-effects It also inhibits the breakdown of noradrenaline (norepinephrine)

by monoamine oxidase This mixture of effects mean that its main influence on

BP is via an increase in CO Its␣1-effects mediate peripheral vasoconstriction,while the␤1-effects are positive inotropy and chronotropy, and the␤2-effects arebronchodilatation (and vasodilatation) The bolus dose is 3–5 mg titrated againstresponse and repeated as necessary The drug has a rapid onset of action with aduration of action that is said to be around 60 min, but in practice appears to be less.Noradrenaline depletion due to its indirect action leads to tachyphylaxis

— Clinical usage: It traditionally has been favoured in obstetric anaesthesia

because it does not cause␣1-mediated vasoconstriction in theuteroplacental circulation The fetal EEG, however, does show excitationfor about 6 h after administration Ephedrine increases myocardial oxygendemand and so should be used in caution in patients with a pre-existingtachycardia or with cardiac disease It is also dysrhythmogenic It is aneffective bronchodilator

Phenylephrine

also possesses some weak␤-activity Its primary influence on BP is via

␣1-vasoconstriction with an increase in peripheral resistance The dose is 50–100␮gtitrated against response and repeated as necessary Onset is rapid and itsduration of action is often shorter than the 60 min that is claimed

— Clinical usage: It is an effective vasopressor which is especially popular in

some cardiac units It may also be used in obstetric anaesthesia despitetraditional avoidance of all pressor drugs apart from ephedrine

Phenylephrine has no more deleterious effects on neonatal cord pH thanephedrine and it raises the BP more effectively It is not dysrhythmogenic,

but it can cause a reflex bradycardia, which may require treatment with

atropine or glycopyrrolate It can be useful in patients in whom a

tachycardia should be avoided

Methoxamine

● This vasopressor was primarily a direct-acting␣1-agonist, with some minor

indirect and␤-adrenoceptor-blocking actions It is no longer manufactured,

although there are a few residual supplies which shortly will be exhausted

Metaraminol

actions and␣- and ␤-effects (␣-effects predominate) Its influence on BP is via ␣1

-vasoconstriction and increase in CO with increased coronary blood flow The

dose is 1–2 mg titrated against response and repeated as necessary The onset of

action is rapid (1–3 min) and duration of action around 20–25 min

— Clinical usage: It is a potent and effective vasopressor, which is particularly

useful for the treatment of hypotension due to sympathetic blockade

Noradrenaline (norepinephrine)

It is a powerful␣1-agonist with weaker␤-effects Its vasopressor effect is

mediated via␣1-vasoconstriction and the increase in peripheral resistance It is

administered by intravenous infusion (0.05–0.2␮g kg⫺1min⫺1) and titrated

against the desired level of arterial pressure Its onset and offset of action are

rapid

— Clinical usage: Noradrenaline is used more commonly in intensive care

medicine than in anaesthesia, particularly to treat the low SVR associated

with sepsis Sudden discontinuation of an infusion may be accompanied by

rebound severe hypotension This explains the occasional requirement for

the drug following removal of a noradrenaline-secreting

phaeochromocytoma Reflex bradycardia is common

Adrenaline (epinephrine)

which acts both as an␣1- and␤-agonist In low doses ␤-mediated vasodilatation

predominates, but the BP rises because of the increase in CO In high doses

adrenaline causes␣1-vasoconstriction It is given either as a bolus (in the case of

circulatory arrest) or as an intravenous infusion in the same dose range as

noradrenaline (0.05–0.2␮g kg⫺1min⫺1)

— Clinical usage: The use of adrenaline as a vasopressor is effectively limited to

catastrophic circulatory collapse and cardiac arrest

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You will be asked to describe its basic pharmacology and physiology.

the production and functioning of ATP (to which it is chelated) and the

biosynthesis of DNA and RNA It has an essential role in the regulation of mostcellular functions

— It acts as a natural calcium (Ca2⫹) antagonist High extracellular Mg2⫹leads

to an increase in intracellular Mg2⫹, which in turn inhibits Ca2⫹influxthrough Ca2⫹channels It is this non-competitive inhibition that appears tomediate many of its effects It also competes with calcium for binding sites

on sarcoplasmic reticulum thereby inhibiting its release

— High concentrations inhibit both the pre-synaptic release of ACh and aswell as post-junctional potentials

— Mg2⫹also has an antiadrenergic action: release at all synaptic junctions isdecreased, and it inhibits the release of catecholamines

as being the second most important intracellular cation It activates at least 300enzyme systems It affects the activity of neurones, of myocardial and skeletalmuscle fibres, and of the myocardial conduction system It also influencesvasomotor tone and hormone receptor binding

Effects on systems

Central and peripheral nervous systems

● Magnesium penetrates the blood–brain barrier poorly, but it neverthelessdepresses the CNS and is sedating It acts as a cerebral vasodilator, and itinterferes with the release of neurotransmitters at all synaptic junctions Deeptendon reflexes are lost at a blood concentration of 10 mmol l⫺1 High Mg2⫹levels do not, as once was thought, potentiate the action of depolarising musclerelaxants Predictably, however, they do decrease the onset time and reduce thedose requirements of non-depolarising relaxants

Cardiovascular

● It mediates a reduction of vascular tone via direct vasodilatation It also causessympathetic block and the inhibition of catecholamine release Magnesiumdecreases cardiac conduction and diminishes myocardial contractile force Thisintrinsic slowing is opposed partly by vagolytic action

● Magnesium acts as a vasodilator and diuretic

Direction the viva may take

The viva is likely to move onto clinical indications for its use

Therapeutic uses

to reduce CNS excitability Its use in the UK to preempt eclamptic convulsions is

not yet as widespread as in the USA

particularly ventricular, and those induced by adrenaline, digitalis and

bupivacaine The ECG of hypermagnesaemia shows a widening QRS complex

with a prolonged P–Q interval

and endocrine causes It may also be caused by malabsorption and is associated

with critical illness

primary treatment for the muscle spasm and autonomic instability caused by

this condition

in severe refractory asthma

Further direction the viva could take

You may at some stage be asked about magnesium toxicity

● Many of these toxic effects are predictable from its known actions

— The normal blood level is 0.7–1.0 mmol l⫺1, the therapeutic level is

4.0–8.0 mmol l⫺1

— Respiratory paralysis supervenes at around 15.0 mmol l⫺1

— Cardiac dysrhythmias At blood levels of 15.0 mmol l⫺1SA and AV block is

complete, and cardiac arrest will supervene at 25.0 mmol l⫺1

— Magnesium crosses the placenta rapidly, and so it may exert similar effects

in the neonate, which may exhibit hypotonia and apnoea

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Drugs used to treat diabetes mellitus

Commentary

Diabetes is common and the main clinical interest for anaesthetists lies in the ance of effective glucose homoeostasis This is not, however, the focus of this ques-tion, which concentrates more on an understanding of intermediary metabolism Therange of drugs is expanding, but you will not be asked in any detail about neweragents such as the meglitinides and glitazones You will, on the other hand, beexpected to know about insulin and something about the well-established biguanidesand sulphonylureas

Insulin

● This is a major anabolic hormone, which controls intermediary and not solelycarbohydrate metabolism

— Carbohydrate: It stimulates glycogen synthesis and inhibits glycogenolysis in

the liver, while also increasing glucose uptake and utilisation in muscle

— Fat: It increases lipid synthesis (fatty acids and triglycerides) and inhibits

lipolysis

— Protein: It enhances protein synthesis (hence its abuse among

bodybuilders), by enhancing amino acid uptake by muscle It decreasesprotein catabolism

cell membrane This consists of a large transmembrane glycoprotein complex,comprising two␣-extracellular-binding sites and two ␤-intracellular and

transmembrane proteins

help diabetics maintain constant blood glucose levels throughout the day.Soluble insulin (such as human ‘Actrapid’) works rapidly but its action isevanescent Longer-acting preparations are made by precipitating insulin withsubstances such as zinc and protamine, to form an insoluble depot compoundfrom which insulin is more slowly absorbed Insulin glargine is a modifiedinsulin analogue which because of slow absorption, provides a basal insulinsupply to mirror the normal physiological state Other forms of insulin can then

be given according to the patient’s particular requirements

Oral hypoglycaemic agents

Biguanides

skeletal muscle while decreasing hepatic gluconeogenesis They also reduce theplasma concentrations of low-density and very-low-density lipoproteins (LDLand VLDL, respectively) They may, rarely, cause a severe lactic acidosis,

particularly in patients with impaired renal function The underlying mechanism

of action of these agents has not fully been elucidated, but they act only in thepresence of residual endogenous insulin

● Pharmacokinetics:Metformin has an elimination t1/2of 3 h It is excreted renally

and so will accumulate if renal function is compromised, as frequently is the case

in diabetics

Sulphonylureas

the second-generation sulphonylureas, glibenclamide and glipazide

— Mechanism of action: Sulphonylureas promote insulin secretion from␤-cells

after binding to high-affinity receptors on the cell membrane They block an

ATP-sensitive potassium channel thereby allowing membrane

depolarisation, calcium influx and insulin release They can cause

prolonged and severe hypoglycaemia, particularly in the presence of other

drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs) which can

compete for metabolising enzymes and alter plasma protein binding

— Pharmacokinetics: Tolbutamide has a shorter t1/2(6–12 h) and duration of

action (4 h) than glibenclamide (t1/218–24 h and duration 10 h) or glipazide

(t1/216–24 h and duration 7 h) Some of these drugs, such as glibenclamide,

have active metabolites, and these, like the parent compound, are excreted

by the kidney Renal impairment mandates caution with their use

a-glucosidase inhibitors

— Mechanism of action: Acarbose inhibits intestinal␣-glucosidase, which

delays the breakdown and absorption of carbohydrates (sugars and starch)

Its inhibitory action is maximal against sucrase

— Pharmacokinetics: Most of the drug remains within the gut, with only about

1–2% being absorbed systemically Duration of action, therefore, will vary

greatly according to intestinal transit times

Glitazones (thiazolidinediones)

— Mechanism of action: The drugs reduce peripheral insulin resistance,

enhance glucose uptake by muscle and decrease hepatic gluconeogenesis

Their mechanism of action is complex, but they are agonists at the nuclear

PPAR␥-receptor which mediates lipogenesis and uptake both of glucose

and of free-fatty acids The drugs were developed after a glitazone that was

being investigated as a lipid-lowering agent demonstrated a

hypoglycaemic effect These current drugs also lower LDL concentrations

They increase plasma volume and some weight gain is common Their

onset of action develops over weeks and they should not be used as single

component therapy

— Pharmacokinetics: Time-to-peak action is 2 h and the t1/2for both is around

7 h Both drugs have active metabolites: weakly active in the case

of rosiglitazone, but with a long t1/2of 150 h, more active in the

case of pioglitazone, but with a shorter t1/2of 24 h

Meglitinides

been developed are nateglinide (licensed only for use in combination with

metformin) and repaglinide

— Mechanism of action: These also promote insulin secretion from␤-cells by

blocking the ATP-sensitive potassium channel in the cell membrane The

drugs are less potent than the sulphonylureas

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— Pharmacokinetics: The time-to-peak effect is short at about 55 min and they also have a rapid t1/2of around 3 h Inadvertent hypoglycaemia is thereforeless likely with their use.

Direction the viva may take

You may be asked about diabetic ketoacidosis

● See Diabetic ketoacidosis, page 318.

Drugs which relax the uterus

Commentary

Tocolysis is indicated either to inhibit premature labour in an attempt to save a

threatened fetus, or to attenuate uterine contractions which are compromising

fetal oxygenation There is no placental blood flow during a contraction, and in a case

of fetal distress in which the decision has been made to proceed to operative

deliv-ery; it is logical to try to relax the uterus Anaesthetists are involved frequently with

mothers in these situations and so you should know about the principles of

manage-ment There are a number of drugs which exert a tocolytic effect: ensure that you are

familiar with at least the one that you have seen used most frequently

The viva

You will be asked to describe the classes of drugs which relax the uterus

b2-adrenoceptor agonists

as a tocolytic is no longer recommended

numerous␤2-receptors.␤2-agonists bind to these specific adrenergic receptors

which lie on the outer membrane of myometrial cells This stimulation activates

adenyl cyclase with the formation of cyclic adenosine monophosphate (cAMP),

the second messenger which in smooth muscle mediates relaxation (The process

is complex, but there is always the risk that some examiners may ask for more

detail Smooth muscle contraction depends on the interaction of actin and

myosin, an energy-dependent process that is reliant on the hydrolysis of ATP

The interaction of the myofilaments is dependent also on the phosphorylation of

myosin by myosin light-chain kinase This enzyme is activated by calmodulin,

which requires intracellular calcium ions for its activation Increased cAMP

decreases intracellular calcium and thereby inhibits myosin light-chain kinase.)

␤2-activity Hypotension, tachycardia and chest pain can complicate their use, as

can tachydysrhythmias Pulmonary oedema has been reported, to which

associated high infusion rates may contribute Patients may become agitated and

tremulous.␤2-agonism stimulates glucagon release and hepatic glycogenolysis

which lead to hyperglycaemia Increased insulin secretion occurs both in

response to this rise in blood glucose as well as to direct␤2-stimulation While

this maintains glucose homoeostasis the net effect is to lower serum potassium,

which moves into cells.␤2-agonists cross the placenta, increase fetal HR and can

also cause hyperglycaemia and hyperinsulaemia followed by hypoglycaemia

Magnesium sulphate

● MgSO4is an effective tocolytic (see Magnesium sulphate, page 178).

Calcium channel blockers

and also antagonises the release of calcium from sarcoplasmic reticulum

Oxytocin antagonists

the pregnant uterus that is similar to ritodrine but with a better side effect

profile Atosiban inhibits the second-messenger release of free intracellular

calcium which mediates uterine contraction The drug can be used in

conjunction with other tocolytic agents

CHAPTER

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which relaxes smooth muscle It is synthesised in the uterus and helps to

maintain uteroplacental blood flow Exogenous GTN is effective transdermally,sublingually or by intravenous infusion The drug may cause hypotension aswell as pulmonary oedema consequent upon an increase in vascular

permeability It may be less effective after 34-week gestation

Miscellaneous

● Other tocolytics include ethanol (ethyl alcohol), which is effective, but whichmay cause maternal intoxication, hypotension and hyperglycaemia Significantside effects also limit the use of diazoxide, which otherwise is another effectiveagent Volatile anaesthetic agents cause a dose-dependent relaxation of uterinesmooth muscle

Direction the viva may take

You may be asked about the clinical situations in which you, as an anaesthetist ratherthan as an obstetrician, might use these drugs

● To stop uterine contractions in a situation in which fetal distress mandatesurgent operative delivery One dramatic example of this is cord prolapse, inwhich the pressure of the presenting part on the umbilical cord may cut off thefetal blood supply A less common, but potentially more calamitous

complication, is that of acute uterine inversion