Potassium channel openers
The opening of potassium channels induces the efflux of potassium, which increases cellular polarization when the cell is already in a polarized state, and accelerates its repolarization following a depolarization, reducing the duration of the action potential and the influx of calcium in the cell by the voltage-dependant calcium channels. The decrease of the calcium influx induces in its turn smooth muscle relaxation and decrease of insulin secretion.
The therapeutic uses of potassium channel openers result from these two properties, smooth muscle relaxation and decrease of insulin secretion. Drugs acting only on one of these targets have been sought but their effects on other targets can appear in particular circumstances.
Possible consequences of the opening of potassium channels
K+ -channel openers with vasodilator effect
Potassium channel openers with vasodilator effect are minoxidil, nicorandil and diazoxide. They decrease the vascular peripheral resistance and have therapeutic uses for arterial hypertension, angina pectoris, cerebral vasospasm and arteritis.
- Minoxidil
Minoxidil is an effective antihypertensive drug when it is given by general route but, because of its almost constant adverse effects, tachycardia and fluid retention, it is seldom used for the treatment of hypertension. Minoxidil, inactive by itself, acts through its sulphated metabolite which could transmit its sulfate group to proteins controlling the opening of potassium channels.
Fortuitous observations of hypertrichosis and hair regrowth in patients treated by oral minoxidil, led to a new therapeutic use: hair regrowth and prevention of hair loss, by twice-daily topical application. There are several preparations of minoxidil for topical use, one of the first to being marketed was REGAINE*.
- Nicorandil
Nicorandil, Ikorel*, is an opener of potassium channels which has in addition a NO-mimetic effect: it is a nitrated derivative releasing nitric oxide which increases the concentration of intracellular cyclic GMP. It induces a vasodilation and is used for the prophylactic treatment of angina pectoris attacks. Its adverse effects are headache by vasodilation.
- Diazoxide
Diazoxide has a chemical structure which resembles that of thiazide diuretics but its pharmacological properties are different: it induces the opening of potassium channels, increases the polarization of the vascular cells which are relaxed, leading to hypotension and increases the polarization of the pancreatic beta-cells which releases less insulin, leading to hyperglycemia. It has antidiuretic effect and induces salt and water retention.
Diazoxide, Hyperstat*, is used in injectable preparation for the treatment of hypertensive emergency, except those resulting from an excessive catecholamine release in patients with pheochromocytoma, which are treated by an adrenergic alpha-blocker. The hypotensive action of diazoxide appears very quickly after its intravenous administration.
The openers of potassium channels could also be used for relaxation of smooth muscles other than vascular ones, bronchial muscles for example. But at present, there is no bronchodilator drug of this type.
K+-channel openers with hyperglycemic effect
Diazoxide, Proglycem*, is used for its inhibiting effect on insulin secretion for the treatment of certain hypoglycemias such as the leucine-sensitive hypoglycemia and certain hypoglycemias of tumoral origin. In this case, it is administered by oral route in a sustained way. Hypertrichosis is a frequent adverse effect observed in children treated for a long time by diazoxide.
When it is used as an hypotensive, hypoglycemia can be an adverse effect, and conversely. The vasodilation can cause headache.
Note:
Antiarythmic drugs of the Ib group inhibit sodium influx into cells and accelerate the repolarization by inducing potassium efflux.
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