Indirectly Sympathomimetics

Now, a quick word about the so-called indirect acting sympathomimetics. Ephedrine is capable of stimulating norepinephrine and epinephrine, (ephedrine can be consumed orally, and is common over the counter [otc]). Now ephedrine is popular at raves because it is a sympathetic-like drug, it causes massive release of catecholamines; heart rate goes up, BP goes up, there’s a lot of energy, tremors, etc. People have died from overdosing on oral ephedrine.

Tyramine is a product that is frequently encountered in foods such as Chianti wines and aged cheeses, and is metabolized by a monoamine oxidase enzyme (MAO). So if a person is on an MAO inhibitor and has a tyramine-rich diet, it causes the release of epinephrine and norepinephrine, sympathetic activity goes way up, blood pressure goes way up, the person has a stroke or heart attack and dies. So people on MAO inhibitors are warned to stay away from foods containing tyramine. This is because tyramine is indirectly releasing catecholamines, which are usually broken down by MAO.

If you give norepi to arteries, you’ll get alpha-1 receptor mediated constriction. If you pre-treat that artery with an alpha-blocker like phentolamine (which is the prototype drug), the dose response curve is shifted parallel and to the right. It is thus a competitive alpha-1 blocker. Although phenoxybenzamine will also knock out the effect of norepinephrine on the alpha-receptor, but the norepinephrine curve in the presence of the phenoxybenzamine (a non-specific agent) is flat, so it is non-competitive. Clinically, these drugs won’t be encountered in your practice. However, we can substitute other similar acting drugs and see the same effects (prazosin and terazosin, for example).

The receptors that we’re most concerned with when we talk about alpha blockade, is really alpha-1 receptor blockade. So here’s the post-synaptic alpha-1 receptor on the vascular smooth muscle, when its activated by any catecholamine (epinephrine, norepinephrine, phenylephrine…) you get activation of alpha-1 and powerful vasoconstriction. The older alpha-blockers (ie. phentolamine) were non-specific and tended to block, in addition to alpha-1 receptors, presynaptic alpha-2 receptors so that there was a mix of effects. Now, with the advent of selective alpha-1 blockers like prazosin, we have better results. They are used as arterial vasodilators and to treat benign prostatic hypertrophy (BPH) because the prostate also has a lot of alpha-1 receptors.

What we see here in blue is blood pressure, and in red is heart rate. If given a high dose of epinephrine, there is a pressor response (mediated mostly by alpha-1) resulting in a transient increase in heart rate, then there is a reflex bradycardia due to the pronounced pressor effect.

If we pre-treat the patient with an alpha-blocker, the resting BP is lower than the control (a hypotensive effect). Now, when we inject epinephrine, the heart rate (in red) is a little greater due to epinephrine stimulating the beta-1 receptor on the pacemaker. With respect to blood pressure, there is a transient pressor response, and then a depressor effect. So we’ve reversed the pressor effect, called “epinephrine reversal”. What mediates this effect is that the alpha-1 receptor on the blood vessel (which is the dominant receptor on the blood vessels) is blocked, so that the beta-2 receptor (the minor receptor on blood vessels) is unmasked. The epinephrine then “sees” the beta-2 receptor to get vasodilation. The clinical lesson is that if your patient is on an alpha-blocker, and you need to give them epinephrine, the epinephrine may not work.

Category: Pharmacology Notes