POTS is characterised by orthostatic intolerance. This means that patients feel significantly worse when they adopt an upright posture compared to when they are lying down. To try and find effective treatments, it is vital that we try and understand the physiology of what happens in the body when normal healthy people stand up.
When we stand up, blood in our vessels tends to get sucked down into our legs because of the effect of gravity. This means that there is less blood getting to our brain and ordinarily we would all pass out and fall because of a shortage of blood to the brain. This does not happen because two reflex mechanisms come into action which serve to maintain the blood flow to our brains. The first is regulated by stretch receptors in our blood vessels in the legs which try and constrict the best they can to prevent blood from pooling in the legs. Secondly the heart rate increases to try and maintain adequate blood flow to the brain. In some patients, the leg vessels don’t constrict as well and therefore they are not able to contribute to increasing the blood flow to the brain and therefore the body has to compensate for this by increasing the heart rate even further. As the heart rate goes up excessively the heart doesn’t have as much time to fill with blood and therefore pumps out less blood than it should which exacerbates the situation.
If we can in some way reduce the stretching of blood vessels especially in the lower limbs when we adopt an upright posture, it means that there is relatively more blood going round and less blood pooling which can improve symptoms.
Midodrine works by increasing the tone of our peripheral blood vessels and therefore reduces the likelihood of pooling of blood. It doesn’t really directly affect the heart as such but if there is more blood getting to the heart then that means that every heart beat is more effective and that can have the effect of improving orthostatic tolerance. Interestingly though this can also have an unwanted effect on the bladder. Because of the effect of the agent on tone, the bladder does not stretch as much and therefore bladder emptying is delayed.
So is there any evidence it works? Well yes but the studies are very small and therefore it is not a foregone conclusion by any means.
There was a paper in the Clinical Autonomic Research journal in 2000 (lead author: V M Gordon et al) where they found that if you gave 21 patients with POTS Midodrine before tilting them the heart rate did not go up as much.
There was another study of 53 children with POTS in the Circulation Japan journal in 2011 (Chen et al) and they found that compared to conventional therapy and even conventional therapy combined with beta blockers, the combination of conventional therapy and midodrine seemed to work much better and was associated with better symptoms control and higher rates of cure. There was another study published in Clinical Autonomic Research journal (Hoeldtke et al) who found that midodrine reduced the standing heart rate from 114/min to about 93/min.
Finally there was another interesting study which was published in the Clinical Science journal in 2014 (Amanda ross et al) which suggested that it was patients with neuropathic POTS that seemed to benefit more from midodrine than those with hyperadrenergic POTS.
We would normally start the medications at 2.5mg tablets to be taken 3 times daily. The doses can be increased after weekly intervals but most patients if they are going to gain benefit will do so at a total daily dose of less than 30 mg daily.
The times that Midodrine should be taken are important. We generally recommend that midodrine is not taken at least 4 hours before bed-time. This is because there is a risk of the blood pressure going excessively high when the patient lies down. This is known as supine hypertension. The manufacturers say that for a 10mg dose, the blood pressure can increase by 15-30 mmHg. To avoid this, dosing should avoid intake of medications for at least 4 hours before lying down. Typical times for dosing are 6.00 pm, 12.00 pm and 5.00pm.
Midodrine, like any other medication, can have side-effects but again it is important to stress that these side-effects may not affect everyone and if they happen then discontinuing the medications will result in an improvement of symptoms of side effects. I will try and list side effects that patients should look out for:
Supine hypertension (most prevalent when you first start the medications or when the dose is increased). This may also be accompanied with symptoms such as chest pain, headaches, blurred vision and sometimes even palpitations. It is worth noting that many of these symptoms may also just be due to the underlying condition. It is worth saying that in my own practice if the blood pressure exceeds 180/100 whether that be lying down or standing up then I tend to discontinue it
2) Urinary retention
3) Nervous system related side effects such as; altered sensations, restlessness, excitability and irritability
4) Rash, itchy skin especially over the scalp and flushing
5) Gut related side effects such as nausea, vomiting and indigestion.
Whenever we take any medications it is important to ensure that they don’t interfere in a harmful way with other medications. Here are some medications which can interact in a harmful way with Midodrine.
1) Medications that can increase the blood pressure further. These include tricyclic antidepressants, Monoamine oxidase inhibitors, thyroid hormones, corticosteroids and sympathomimetic drugs. There is a medication that we often use in POTS because it helps fluid retention called Fludrocortisone. Although we can use both Midodrine and Fludrocortisone, they both have the effect of increasing blood pressure and especially pressure in the eyes and therefore it is important to monitor very carefully.
2) Alpha blockers can antagonise the blood pressure raising effects of the midodrine and therefore make it less effective
3) Beta blockers and Digoxin can cause the heart rate to slow down excessively when combined with Midodrine.
There are some comorbidities that the patient may be suffering from in which I would not give Midodrine at all because the risk of harm may be greater than the benefits. These comorbidities include:
1) High blood pressure especially if it is poorly controlled
2) Previous stroke
3) Organic heart disease because it can increase pressure on the heart
4) Pheochromocytoma which is a tumor that secretes hormones that can increase the blood pressure anyway
5) Thyrotoxicosis/ hyperthyroidism
6) Acute kidney injury
7) Severe kidney disease/kidney failure
8) Urinary retention and prostate disorder
10) Proliferative retinopathy
I think it is important that before patients start the medication that they have some basic blood tests for kidney and liver function and they have these tests repeated every year. It is also patients who take midodrine have a 24 hour blood pressure monitor to ensure that their blood pressure is not being pushed too high by the medications. This should be done once a year or if the doses are being pushed up.
Please note that none of the lists in this blog are exhaustive and it is therefore vital that patients always seek counsel from their own doctors and pharmacists to get a more informed opinion.
I hope you found this information useful. Here is a video I have done on the subject.
Keywords: Midodrine; low blood pressure; dysautonomia; POTS; postural orthostatic tachycardia syndrome