A patient treated with anagrelide (Agrylin) has developed hypertension and treatment with thiazide

Fråga: A patient treated with anagrelide (Agrylin) has developed hypertension and treatment with thiazide diuretics or a beta-blocking agent eg atenolol is anticipated. What is the risk of an interaction? In case of such a risk, what alternative antihypertensive treatment could be recommended?

Sammanfattning: The combination of anagrelide with atenolol or thiazide diuretics has not been studied but, on a theoretical basis they are not expected to interact. Calcium channel blockers have a theoretical potential of metabolic interactions with anagrelide and are probably better avoided until studies of the safety of their combination have been carried out.

Svar: Anagrelide is an agent inhibiting formation of mature thrombocytes (1), hence it is used in thrombocytemia. Its mechanism of action is not known in molecular detail but its apparent effect is to inhibit polyploidization of the megacaryocyte and it reduces the cytoplasmic volume of these progenitors of thrombocytes (2). The drug inhibits thrombocyte aggregation, probably through inhibition of phosphodiesterase, but this effect is seen only at concentrations exceeding those attained in the treatment of thrombocytemia (2). There is some controversy as to the mediator of the effect on megacaryocytes, ie whether it is the parent compound or a metabolite, known as RL603, which is directly responsible (3,4). Regardless of this, the mechanism of action of anagrelide is apparently different from that of beta-blockers and thiazide diuretics and a pharmacodynamic interaction is therefore not expected.

The pharmacokinetics of anagrelide has been studied, only 5 healthy volunteers in a single dose study (5). The drug is almost completely metabolised with the previously mentioned RL603 as one, water-soluble product (4). No interactions between anagrelide and other drugs have been published. As neither thiazide diuretics nor the beta-blocker atenolol are metabolised to any appreciable extent, nor are they reported to metabolically interact with other drugs (6), does these appear to be an obvious risk of an interaction at the metabolic level. Other beta-blocking drugs are subject to extensive metabolism and, thus, have a possibillity to interact. The calcium channel blockers are in several instances well known for their metabolic interactions (6) and are better avoided. 1 Spencer CM, Brogden RN. Anagrelide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of thrombocythaemia. Drugs 1994;47:809-22. 2 Hong Y, Erusalimsky JD. Comparison of the pharmacological mechanisms involved in the platelet lowering actions of anagrelide and hydroxyurea: a review. Platelets 2002;13:381-6. 3 Erusalimsky JD, Hong Y, Franklin R. Is the platelet lowering activity of anagrelide mediated by its major metabolite 2-amino-5,6-dichloro-3,4-dihydroquinazoline (RL603). Exp Hematol 2002;30:625-7. 4 Lane WJ, Hattori K, Dias S, Peerschke EIB, Moore MAS, Blanset DL et al. Anagrelide metabolite induces thrombocytopenia in mice by inhibiting megakaryocyte maturation without inducing platelet aggregation. Exp Hematol 2001;29:1417-24. 5 Gaver RC, Deeb G, Pittman KA, Smyth RD. Disposition of anagrelide, an inhibitor of platelet aggregation. Clin Pharmacol Ther 1981;29:381-6. 6 FASS 2002 (The Swedish catalogue of approved medical products)