The adrenoceptors of sympathetic nervous system are of two maintypes, namely alpha and beta. Drugs that block beta adrenoceptors(better known as beta blockers) are therapeutically exploited to reduce,for example, normal sympathetic stimulation of heart. The activityof heart in response to stress and exercise is reduced, its consumptionof oxygen is diminished, and in this way exercise-induced angina can bemanaged. Beta blockers given orally can also be used in managementof cardiac arrhythmias, hypertension, myocardial infarction, and heartfailure. They may also be used for some symptoms of anxiety and for migraine prophylaxis. Some beta blockers are used in form of eye dropsfor glaucoma and ocular hypertension.
Not all beta receptors are identical but can be further subdivided into twogroups,beta1 and beta2. The former are found in heart and latter in bronchi. Since one of unwanted adverse effects of generalised betablockade can be loss of normal noradrenaline-stimulated bronchodilation (leading to bronchospasm), cardioselective beta1-blockingdrugs (e.g. atenolol,metoprolol) were developed, which have less effecton beta2 receptors. However, it should be emphasised that selectivityis not absolute because bronchospasm can still occur with these drugs, particularly at high doses. table 1 below,(below) includes an indication of thecardioselectivity of commonly used systemic beta blockers. Some betablockers also have alpha1-blocking activity,which causes vasodilatation, and this is also indicated in table 1 below,(below). Some beta blockers,such as celiprolol and nebivolol,also have vasodilator activity but producethis by mechanisms other than blocking alpha1 receptors. Other betablockers also possess intrinsic sympathomimetic activity in that they canactivate beta receptors and are therefore partial agonists. Sotalol has additional class III antiarrhythmic activity,and therefore it has a range of interactions not shared by most other beta blockers.
Beta blockers may be lipophilic drugs (such as metoprolol) or hydrophilic (such as atenolol). The lipophilic beta blockers are more likelyto be involved in pharmacokinetic interactions than hydrophilic drugs.Many of lipophilic beta blockers are principally metabolised by cytochrome P450 isoenzyme CYP2D6 (see table 1 below’,(below)), anddrugs that are inhibitors or inducers of this isoenzyme (see table 4 below,) increase or decrease their levels. Propranolol is also metabolised inpart by CYP1A2 (see ‘Beta blockers + SSRIs).
This section is generally concerned with those drugs that affect activity of beta blockers. Where beta blocker is affecting drug, theinteraction is dealt with elsewhere.
Rapidly metabolised to an active metabolite after which about 50 % is excreted by liver and 50 % excreted in urine
Largely excreted unchanged in urine
50% hepatic metabolism and 50 % excreted unchanged in urine
Primarily metabolised by CYP2D6,although other isoenzymes do contribute.
Mostly excreted unchanged (only 1-3% metabolised) with 50 % excreted in bile and 50 % excreted in urine
Conjugated in liver
Largely excreted unchanged in urine
Extensively metabolised by liver
30 to 40 % excreted unchanged in urine, rest excreted by liver and kidney as inactive metabolites.
Largely excreted unchanged in urine
Mostly metabolised by liver, with some involvement from CYP2D6. 20 % excreted unchanged. Timolol and metabolites renally excreted.
| Table 4 Drugs affecting or metabcytochrome P450 isoenzymes | olised by the CY | P2 family of | |
|---|---|---|---|
| Isoenzyme | Inhibitors | Inducers | Substrates |
| CYP2B6 | Thiotepa | Phenobarbital Phenytoin | Cyclophosphamide Ifosfamide |
| CYP2C8 | Gemfibrozil Rifampicin Trimethoprim | Pioglitazone Repaglinide Rosiglitazone | |
| CYP2C9 | Amiodarone Azoles Fluconazole Miconazole Voriconazole Fluvastatin SSRIs Fluoxetine Fluvoxamine Sulfinpyrazone Ticlopidine Zafirlukast | Aprepitant Rifampicin | Irbesartan Losartan Nateglinide NSAIDs Celecoxib Diclofenac Etoricoxib Valdecoxib Phenytoin Statins Fluvastatin Rosuvastatin Sulphonylureas Glibenclamide Gliclazide Glimepiride Glipizide Tolbutamide* S-Warfarin* |