Clonidine is a direct-acting α2 adrenergic agonist available as tablets for oral administration in three dosage strengths: 0.1 mg, 0.2 mg and 0.3 mg. Clonidine is available as tablets, as a transdermal patch, or as an injectable form.
Pharmacokinetics and Metabolism
Clonidine is well absorbed orally, and is nearly 100% bioavailable. It is highly lipid soluble and easily penetrates the CNS. The plasma level of Clonidine peaks in approximately 3 to 5 hours. The mean half life of the drug in plasma is about 12 hours. Following oral administration about 40-60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver.
Clonidine is thought to exert its hypotensive effect within the CNS by virtue of its conversion to α methyl norepinephrine, a potent α2 adrenergic agonist. It results in reduced sympathetic outflow from the central nervous system and in decreases in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. The patient’s blood pressure declines within 30 to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4 hours. Clonidine hydrochloride leads to a moderate reduction (15% to 20%) of cardiac output with no change in the peripheral resistance. Slowing of the pulse rate has been observed in most patients given Clonidine, but the drug does not alter normal haemodynamic response to exercise.
Clonidine has been found to be useful in the treatment of hypertension, alcohol, opiate, and nicotine withdrawal syndromes, attention-deficit/hyperactivity disorder (ADHD), and Tourette’s syndrome. In addition, Clonidine has also been used for migraine headaches and hot flashes associated with menopause.
Uses in Anaesthesia Practice
1) Anaesthetic Sparing Action
Per oral Clonidine has been shown to be an effective preanaesthetic medication to reduce anaesthetic requirement. Per oral Clonidine has been shown to reduce the sleep dose of several I.V. inducing agents. The amount of opoids required for postoperative analgesia is reduced.
2) Adrenergic and Haemodynamic Stability
Improved haemodynamic and adrenergic stability during surgery have been among the major advantages ascribed to Clonidine premedication. α2 agonist drugs are felt to act by reducing the overall tonic sympathetic action, while relatively preserving phasic sympathetic responses. This suggests that in situations where acute sympathetic responses are necessary, such as during sudden hypovolemia, appropriate compensatory mechanisms will be preserved. Similarly, sensitivity to boluses of vasodilator drugs is unchanged. On the other hand, Clonidine treated patients show exaggerated responses to vasopressors such as phenylephrine and ephedrine.
3) Analgesic Action
I.V. Clonidine has been shown to significantly reduce morphine requirements in relieving postoperative pain in placebo controlled double blind experiments.
4) Clonidine has been effective in decreasing secretions due to its antisialagogue effects.
5) Clonidine has been effective in attenuating the rise in intraocular pressure associated with laryngoscopy and tracheal intubation.
6) Other Effects in Anaesthesia
Clonidine 3-5µg/kg did not markedly depress the ventilator response to CO2 and did not potentiate morphine or Fentanyl induced respiratory depression. Clonidine 150 µg has also been found to effectively diminish postoperative shivering and oxygen consumption. α2 adrenergic agonists have also been used to block the occurrence of muscle rigidity after rapid administration of large doses of narcotics.
Side Effects as Premedication
The important perioperative side effects are bradycardia, hypotension and peri operative sedation. Clonidine should not be abruptly withdrawn but rather, slowly decreased over several days to avoid withdrawal symptoms. Treatment includes atropine sulfate for bradycardia, intravenous fluids and/or vasopressor agents for hypotension and vasodilators for hypertension.
β-blockers are drugs that competitively and selectively block the action of catecholamines mediated via the β-receptors. Atenolol is a synthetic, β1-selective blocking agent. Atenolol is available as 25, 50 and 100 mg tablets for oral administration.
Pharmacokinetics and Metabolism
In man, absorption of an oral dose is rapid and consistent but incomplete. Approximately 50% of an oral dose is absorbed from the gastrointestinal tract, the remainder being excreted unchanged in the feces. Peak blood levels are reached between 2-4 hours after ingestion. Atenolol undergoes little or no metabolism by the liver, and the absorbed portion is eliminated primarily by renal excretion. Over 85% of an intravenous dose is excreted in urine within 24 hours compared with approximately 50% for an oral dose.
The elimination half-life of oral Atenolol is approximately 6 to 7 hours. A significant beta blocking effect of Atenolol, as measured by reduction of exercise tachycardia, is apparent within one hour following oral administration of a single dose. This effect is maximal at about 2 to 4 hours and persists for at least 24 hours. Following oral doses of 50 mg or 100 mg, both β-blocking and antihypertensive effects persist for at least 24 hours.
a) Effect on Cardiovascular system: Atenolol has negative chronotopic and negative ionotropic effects which prevents the increase in heart rate, cardiac output and stroke volume along with a reduction in myocardial contractility. Atenolol, given as a single daily oral dose, is an effective antihypertensive agent providing 24-hour reduction of blood pressure.
b) Effect on Respiratory System: Blockade of β2 receptor site in the bronchi and bronchioles can lead to the development of increased airway resistance and bronchospasm. This action is very much decreased with a cardioselective β-blocker.
c) Effect on Metabolism: Atenolol can lead to an increase of plasma triglycerides and total cholesterol as well as to reduced high-density lipoprotein cholesterol values.
d) Anaesthesia and Major Surgery: It is not advisable to withdraw β-adrenoreceptor blocking drugs prior to surgery. However, care should be taken when using anaesthetic agents such as those which may depress the myocardium. Vagal dominance, if it occurs, may be corrected with atropine. Atenolol, like other β blockers, is a competitive inhibitor of β-receptor agonists and its effects on the heart can be reversed by administration of such agents like dobutamine or isoproterenol with caution.
Atenolol is used in the management of hypertension, angina pectoris, acute myocardial infarction and for the therapy of supraventricular and selected cases of ventricular arrythmias.
Side effect as premedication
a) Cardiovascular side effects: Atenolol can lead to bradycardia and hypotension. Abrupt cessation of chronic β-blocker therapy can lead to exacerbation of angina and in some cases sudden withdrawal may even cause myocardial infarction and death.
b) Respiratory side effects: Non-selective β-blockers like Propanolol block β2-Adrenergic receptors on the lungs and result in bronchospasm. This is less with β1-selective and those with intrinsic sympathomimetic activity.
c) Diabetes and Hypoglycemia: β blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. At recommended doses Atenolol does not potentiate insulin-induced hypoglycemia and does not delay recovery of blood glucose to normal levels.