P1: PSB Printer: Yet To Come
9780521704632c16 CUFX213A/Peck 9780521618168 December 28, 2007 13:34
Section IIICardiovascular drugs
Renal – urine may become darker in colour when exposed to air, due to the break-
down of methyldopa or its metabolites.
Hepatic – liver function may deteriorate during long-term treatment and fatal
hepatic necrosis has been reported.
Miscellaneous – it fluoresces at the same wavelengths as catecholamines so that
assays of urinary catecholamines may be falsely high. Assays of VMA are not
affected. It may cause constipation and gynaecomastia (due to suppressed pro-
lactin release).Kinetics
Methyldopa is erratically absorbed from the gut and has a very variable oral bioavail-
ability and a slow onset of action. It is subject to hepatic first-pass metabolism, being
converted to the O-sulphate. Less than 20% is bound to plasma proteins. Approxi-
mately 50% is excreted unchanged in the urine.Clonidine
Clonidine is anα-agonist with an affinity forα 2 -receptors 200 times that forα 1 -
receptors. Some studies identify it as a partial agonist.Presentation and uses
Clonidine is available as 25–300μgtablets and as a colourless solution for injection
containing 150μg.ml−^1 .Atransdermal patch is available but this takes 48 hours to
achieve therapeutic levels. It is used in the treatment of hypertension, acute and
chronic pain, the suppression of symptoms of opioid withdrawal and to augment
sedation during ventilation of the critically ill patient.Mechanism of action
The useful effects of clonidine rest on its ability to stimulateα 2 -receptors in the lateral
reticular nucleus resulting in reduced central sympathetic outflow, and in the spinal
cord where they augment endogenous opiate release and modulate the descending
noradrenergic pathways involved in spinal nociceptive processing. MAC appears to
be reduced by stimulation of central postsynapticα 2 -receptors.
Transmembrane signalling ofα 2 -receptors is coupled to Gi,leading to reduced
intracellular cAMP. K+channels are also activated.Effects
Cardiovascular – following intravenous administration the blood pressure may
rise due to peripheralα 1 stimulation, but this is followed by a more prolonged
fall in blood pressure. Cardiac output is well maintained despite a bradycardia.
The PR interval is lengthened, atrioventricular nodal conduction depressed and
the baroreceptor reflexes are sensitized by clonidine resulting in a lower heart
rate for a given increase in blood pressure. Its effects on the coronary circulation