The effect of intrinsic sympathomimetic activity on beta‐receptor responsiveness after beta‐adrenoceptor blockade withdrawal.

Abstract

1 Heart rate (HR) and blood pressure (BP) changes supine, at 600 tilt and in response to increasing exercise loads, and HR responses to Valsalva's manoeuvre and to isoprenaline bolus injections were studied in 19 healthy volunteers to assess the response to abrupt withdrawal of atenolol n = 6, propranolol n = 6 and pindolol n = 7. 2 The dosage of each drug administered double-blind was gradually increased over a period of 2 weeks and the dose to produce maximum inhibition of exercise-induced tachycardia was continued for one further week. 3 Plasma renin activity, plasma noradrenaline and serum free thyroid hormones were measured during control periods, maximum dosage and withdrawal periods. 4 An increased sensitivity to isoprenaline injections was seen on Day 5 after withdrawal in the atenolol treated group whereas the pindolol treated group showed decreasing hyposensitivity to isoprenaline for the 13 days of observation after drug withdrawal and propranolol showed an intermediate effect.5 There was no overshoot in HR or BP measurements at rest or in response to tilting, Valsalva's manoeuvre or exercise with atenolol or propranolol and with pindolol the HR response to tilt only was significantly higher on the third day post-drug. 6 Plasma noradrenaline and serum free T3 were reduced on drug treatment and further reduced in the early withdrawal period but there were no consistent changes in plasma renin activity.

The syndrome associated with the withdrawal of beta‐adrenergic receptor blocking drugs.

“…There was an increase in triiodothyronine and free triiodothyronine but not thyroxine or free thyroxine levels in hyperthyroid subjects when propranolol was withdrawn, but no overshoot. We found a fall in free triiodothyronine from 3-adrenoceptor blockade (atenolol n= 6, pindolol n= 7, propranolol n= 6) in normals which returned to pretreatment levels when the beta blocker was stopped (Walden et al, 1982). Lindenfield et al (1980) failed to observe any increase in triiodothyronine levels after 2 weeks of propranolol 160 mg daily was stopped, free triiodothyronine levels were not reported.…”

“…Studies with atenolol, pindolol and propranolol in normal volunteers indicate that the administration of pindolol is not associated with increased sensitivity to isoprenaline after pindolol is stopped, in contrast to the other P-adrenoceptor blocking drugs that do not possess partial agonist action (Walden et al, 1982).…”

“…In our investigations in normal volunteers using doses of j3-adrenoceptor blockers sufficient to give maximum inhibition of exercise tachycardia, post propranolol hypersensitivity to isoprenaline was seen in two of six subjects, but in all of six subjects after atenolol. In contrast post pindolol hyposensitivity was seen in the first 13 days after drug withdrawal (Walden et al, 1982). Lindenfield et al (1980) administered adrenaline to ten normal subjects and ten patients with angina, in neither group was there an increase in the heart rate and systolic blood pressure responses 4 days post 2 weeks of propranolol 160 mg/day, compared to control or at least 6 days in the angina group that was studied for the longer period.…”

Withdrawal syndrome following cessation of antihypertensive drug therapy

“…The signs include hypertension occasionally in excess of pre‐treatment levels and tachyarrhythmias, especially sinus tachycardia and premature contractions. The symptoms may include nervousness, anxiety, sweating, nausea, headache and exaggeration of angina and occasionally myocardial infraction, sudden death or hyperthyroidism (51–57).…”

“…On the contrary, Ross and co‐workers (55) found no change in thyroid hormones in euthyroid patients when propranolol was administered in a dose of 160 mg daily for 4–8 weeks or when the treatment with propranolol was stopped. Walden and co‐workers (56) found a fall in free triiodothyronine after the administration of various β‐blockers (propranolol‐6, pindolol‐7 and atenolol‐6) in normal persons which returned to pre‐treatment levels when the β‐blockers were discontinued.…”