4. Induced Hypotension, Clonidine + Dexdor

Question 1

Indications:

Answer 1

should be used only to make the impossible possible, and not the possible easy

largely oblivious to that injunction and requested hypotension for any
procedure that involved blood loss

one example of which is the removal of choroidal tumours of the eye.
Moderate hypotension (as defined by a reduction in mean arterial pressure [MAP]
by up to 30%) is used for various operations,

including endoscopic sinus surgery,
middle ear surgery and
maxillary and mandibular osteotomies.

Question 2

Intravenous Drugs That Can Be Used to Induce Hypotension

Ideal agent

Answer 2

would include pharmacological stability and ease of preparation and administration
very rapid onset and offset of action,

with no rebound hypertension;
rapid metabolism and excretion,
with no direct or indirect organ toxicity;

a linear and predictable dose-response relationship

Question 3

The prime determinants of arterial blood pressure (BP)

Answer 3

The prime determinants of arterial blood pressure (BP) are cardiac output (CO),
which is the product of heart rate (HR) and stroke volume (SV), and systemic
vascular resistance (SVR). Drugs used to induce hypotension can affect one or more
of these variables.

Question 4

Drugs Which Affect Systemic Vascular Resistance (SVR)

Answer 4

α-Adrenoceptor Blockers
Phentolamine: this is a non-selective α antagonist (the ratio of α1:α2 effects is 3:1),
which also has weak β-sympathomimetic action. It decreases BP by reducing
peripheral resistance owing to its peripheral α1-vasoconstrictor blockade and mild
β-sympathomimetic vasodilatation.

Question 5

Peripheral Vasodilators

GTN

Answer 5

Glyceryl trinitrate (GTN) nitroglycerine:

its hypotensive action is mediated via nitric oxide (NO).

NO activates guanylate cyclase,
which increases cyclic GMP
(from guanosine triphosphate) within cells.

This in turn decreases available intracellular Ca2+.

The drug causes more venous than arteriolar dilatation

Question 6

Sodium nitroprusside (SNP)

Answer 6

Sodium nitroprusside (SNP): SNP is another nitrovasodilator which mediates hypotension
via NO. In contrast to GTN, it causes both arterial and venous dilatation,
leading to hypotension and a compensatory reflex tachycardia

complex metabolism that results in the production of free cyanide (CN−), which, by
binding irreversibly to cytochrome oxidase in mitochondria, is highly toxic, causing
tissue hypoxia and acidosis

Treatment of toxicity is with sodium thiosulphate

Question 7

Ganglion Blockers

Answer 7

Ganglion Blockers
Trimetaphan (trimethaphan): this agent is no longer available in the UK, but it was
a popular hypotensive drug, particularly in neurosurgery

Question 8

Direct Vasodilators

Answer 8

Hydralazine: this produces hypotension by direct vasodilatation together with a
weak α-antagonist action. This is mediated via an increase in cyclic GMP and
decrease in available intracellular Ca2+.

Question 9

Drugs Which Affect Cardiac Output (CO)

Answer 9

β-adrenoceptor blockers: there are many examples – all are competitive antagonists,
but their selectivity for receptors is variable. Selective β1-antagonism is clearly a
useful characteristic. Their influence on BP is probably because of decreased CO via a
decreased HR,

Question 10

Atenolol

Answer 10

Atenolol: this is a selective β1-antagonist except in high doses. It is long acting, with a
t½ of around 7 hours. Its use as a bolus (150 μg kg−1 over 20 minutes) is usually to
treat cardiac arrhythmias rather than to induce hypotension.

Question 11

Esmolol

Answer 11

: this is a relatively selective β1-antagonist. It is ultra-short acting, with a t½
of around 9 minutes.

Question 12

Labetalol

Answer 12

Labetalol: this acts both as α- and β-antagonist

which mediates a decrease in SVR without reflex tachycardia. It is a
popular drug in anaesthetic, obstetric anaesthetic and intensive therapy use

Question 13

Propanolol

Answer 13

Propanolol: this is a non-selective β-antagonist which is usually given as a bolus of
1.0 mg, repeated to a maximum of 5.0 mg

Question 14

α2-Adrenoceptor Agonists

Answer 14

Clonidine: this is an α-agonist with affinity for α2-receptors some 200 times greater
than that for α1. Its hypotensive effects are mediated via a reduction in central sympathetic outflow and by stimulation of presynaptic α2-receptors which inhibit
noradrenaline release into the synaptic cleft.

Question 15

Complications and Risks of Induced Hypotension

Answer 15

Dangers and complications: these relate predictably to the consequences of
hypoperfusion in key parts of the circulation. Precipitate falls in BP may lead to
cerebrovascular hypoperfusion and stroke, and to myocardial ischaemia

Druginduced
hypotension usually shifts the autoregulatory curve to the left, and thereby
confers a degree of protection

patients who are previously hypertensive, however,
the curve is shifted to the right, making them more vulnerable to catastrophic drops
in perfusion of essential areas

As a generalization, however, the accepted recommendation is to
keep the MAP above 50 mmHg in the young and above 80 mm in elderly subjects

Question 16

Exacerbating influences:

Answer 16

the effects of induced hypotension will be enhanced by
factors such as hypovolaemia, the use of other drugs with hypotensive actions such as
volatile anaesthetic agents, the reduction in venous return associated with IPPV and
drugs which release histamine. The head-up position may also further diminish
effective cerebral perfusion.

Question 17

Clonidine

Answer 17

Clonidine is an agonist at α2-adrenoceptors (the ratio of α1:α2 is 1:200)

imidazole receptors
located centrally and appear to mediate sedation and hypnosis

Question 18

Acts @

Answer 18

acts at presynaptic α2-receptors, both centrally and peripherally,
to inhibit the release of noradrenaline.

In the hypothalamus, α2-receptors are inhibitory to the vasomotor outflow.

Clonidine also acts post-synaptically in the adrenal medulla.

α2-agonists activate receptors in the substantia gelatinosa
in the dorsal horn of the spinal cord,

which inhibits transmission down nociceptive neurons
stimulated by Aδ and C fibres.

They also inhibit the release of the nociceptive neurotransmitter Substance P.

Question 19

Pharmacokinetics

Answer 19

: the oral bioavailability of clonidine is 70–80%, with peak levels
attained at between 1 and 3 hours.

Following intravenous administration, the distribution half-life is around 20 minutes and the elimination half-life quoted as between 12 and 16 hours.

It undergoes hepatic metabolism, although 20–40% of an
oral dose is excreted unchanged

Question 20

The anaesthetic and medical uses of clonidine are numerous

Answer 20

1. Stress and pressor responses
2. Adjunctive use in anaesthesia and analgesia:
   dose of 1–2 μg kg−1 intravenously
   reduces the MAC of inhaled volatile agents and decreases the requirement for
   systemic analgesics.
3. Hypotensive anaesthesia:
   1–2 μg kg− 1 intravenously can produce modest and
   sustained hypotension which may improve operating conditions during which
   bleeding would otherwise mask the surgical field
4. Antisialogogue effect:
   a side effect of clonidine administration is reduced salivary
   secretion; this property can be useful in the perioperative period.
5. Alcohol withdrawal:
   clonidine inhibits the exaggerated release of sympathomimetic
   neurotransmitters during acute alcohol withdrawal.
6. Sedation and anxiolyis:
   it has both sedative and anxiolytic actions.
   It finds use as pre-operative medication
   (up to 4 μg kg−1 in both adults and children
   although the
   onset of action is relatively slow
7. Neuropathic pain:
   clonidine can attenuate symptoms in some patients. It is particularly
   effective when given through an intrathecal drug delivery system.
   Shivering: a low dose (up to 0.5 μg kg−1) may ameliorate postanaesthetic shivering.
8. Adjuvant use in regional anaesthesia

Question 21

Dexmedetomidine

Answer 21

: this is the R isomer of medetomidine,
which has the advantage
of being a more selective α2-agonist than clonidine

with reported ratios of α2:α1
activity of 220:1 for clonidine and 1620:1 for dexmedetomidine);

Their highest densities are found in the
locus coeruleus which, amongst other functions, mediates alertness. It also contains a
descending noradrenergic pathway which modulates nociceptive transmission

effective anxiolytic, sedative and analgesic than clonidine. It otherwise has the same
overall spectrum of activity, and the dose ranges are similar

Question 22

Pharmacokinetics

Answer 22

Pharmacokinetics:

following intravenous administration,

dexmedetomidine has a rapid distribution half-life of 6 minutes
a terminal elimination half-life of around 2 hours.

Its steady state volume of distribution is 118 L.

It is highly protein-bound (94%),
mainly to albumin, and undergoes hepatic metabolism via cytochrome P450
and by the formation of glucuronides.

Elimination is predominantly renal (95%), with the remainder being excreted in faeces