Antihypertensives - a little pharmacology helps

I came across this article recently about some interesting facts about antihypertensive medications and their pharmacology, which I though will be useful for practising clinicians like us!
The article describes about all 4 major types of antihypertensives. But the one which stands out is the angiotension converting enzyme inhibitors----WHY?     due to their difference in pharcological actions compared  to others.Let me start with a question..
If Mr.X tolerates(no hypotension) 5mg of Lisinopril, can we increase the dose to 40mg straightaway?

Most of us would say "NO". But the author says yes....and the explanation is pretty simple, interesting and true!
Unlike the other antihypertensives(beta blockers,CCB,diuretics), ace-i do not have a linear dose-response relationship....meaning that their BP lowering effect is not proportional to the dose. In other words....the efficacy of ace-i is the same irrespective of their dosage. Again...to make it more simple...a dose of 5mg of Lisinopril will lower the BP to the same extent as 40mg of Lisinopril. So why give 40mg in place of 2.5 mg? Well...the dose correlates with the duration of action.the higher the dose...the longer the duration of action!(Brit J Pharm 1984!)
It looks like...we have the low doses of ace-i in the market mainly to be used in patients with heart failure (who might have a low BP due to their other meds) to see if they can tolerate any hypotension induced by addition of ace-i. Also, the common side effect of ace-i...COUGH ..is not dose related.So here again..the dose doesnt matter.

So the article concludes that..ace-i don't have a linear dose-response curve, and so their dose can be increased to the maximal dose without any major concerns for hypotension. But ...one aspect of ace-i that the article doesn't discuss...is hyperkalemia. Well..the risk of hyperkalemia with ace-i is dose related, and whether it would be a good idea to go for a maximal dose straightaway or to increase it gradually, in this aspect.So..bottom line-----beacuse of the risk of hyperkalemia..we may not be able to go to a maximal dose directly, and not because of risk of hypotension.
A quick word abt hyperkalemia with ace-i : the risk is quite low on its own. The risk is high in CKD(4 fold risk), hepatic disease(almost 5 fold risk), taking>15 tablets(5 to 9 fold risk), advanced age(twice likely)...
(Pharm W Sci 2009)

Finally..the above article was published in American J of Cardio vasc Drugs 2011. The graph(above) is a modified graph from the same study. 

Calcium gluconate in a digitalised heart with hyperkalemia! OK...or..NOT OK???

Today's morning report was about a young guy who was admitted with rhabdomyolysis, renal failure and hyperkalemia(K- 12mEq/dl) with sine wave pattern on his EKG. All this was due to a electrocution injury.So ...going through the management of hyperkalemia, someone pitched in the problem of giving Calcium gluconate in patients on Digoxin. Well....we had a couple of explanations for the interaction.So lets review the problem with these two drugs together.
First.....the mechanism of action of Digoxin- Digoxin inhibits the Na⁺/K⁺-ATPase(exchanges 2 K for 3Na) in the cardiac myocyte by competing with potassium,and causes intracellular sodium concentration to increase. This then leads to an accumulation of intracellular calcium by blocking the Na⁺-Ca⁺⁺ exchange system. In the heart, increased intracellular calcium causes more calcium to be released by the sarcoplasmic reticulum, thereby making more calcium available to bind to troponin-C, which increases contractility (inotropy).


Second.....the mechanism of action of Calcium gluconate- a litlte more cellular pathology! . Normally the cardiac myocyte has a resting membrane potential(RMP is -90mV) and a threshold potential at which it is excited(TP is-75mV).So a 15mV depolarisation is needed to excite the myocyte. In hyperkalemia, the RMP becomes less negative (-80mV) , but the TP remains at -75mV. This means that ..now..only a 5mV depolarisation is enough to excite the myocyte. This is the cause of hyperexcitability leading to arrhythmia.Calcium gluconate...by increasing Ca transport across the membrane reduces the TP from -75mV to around -65mV ...restoring the 15mV depolarisation needed to excite the myocyte. (the numbers in mV are just an example)  ...... Annals of Emer Med 2011


Sooo...in patients on Digoxin(which causes positive inotropy through calcium)...if more calcium is given....it can lead to more intracellular calcium in mycocyte leading to what has been described as cardiac tetany due to prolonged depolarisation. So ,does hyperkalemia make this process worse?? Well, probably not. ------Since K+ and digoxin compete for Na/KATPase, the binding depends on the concentration of the two. In hyperkalemic state...K+ binds preferentially than digoxin, on Na/K ATPase, and thus resulting in diminished digoxin action. (to better understand...think about hypokalemic states...where digoxin will bind preferentially to the receptor, and hence result in digoxin toxicity!--which is well known)
A slightly different scenario would be...when some one(with no K+ problems) takes too much digoxin...which will also result in digoxin binding preferentially than K+,  to Na/KATP ase resulting in Dig toxicity. In this setting....pt may go hyperkalemia..as more K+ ends up extracellularly (due to not binding with Na/K ATPase), and if this patient gets Ca gluconate..then again..it can causes arrhythmias.


Bottom line is...if Calcium is given(and pt made hypercalcemic) to any pt on Digoxin ..there is a increased possibility for cardiac arrhythmias(PG Med J 1999) ...irrespective of whether they have hyperkalemia or not. 
Whether these pathophysiologies!! are clinically relevant is not clear, as these interactions are based on few case reports only. Have a look at this animal study (J clin Tox 2004) and this retrospective study on pts ..over 18 years from a hospital in Arizona(J Emer Med 2011).Both of them show no clinically relevant interaction of Calcium administration even in Digoxin toxicity.     !!!!!!!

Hyperkalemia with beta blockers!

I recently had a Chronic kidney diesease patient on low dose Ramipril with a stable potassium level for many months, got admitted to the hospital for an hypertensive urgency.Her renal function & K were stable on admission. She was started on a Labetalol infusion overnight.Next day her potassium level was 6.9mEq/L, and she needed two Insulin dextrose treatment( couple of hours apart) to get that back to normal. Her TTKG(transtubular potassium gradient) was 4. This is hyperkalemia due to Labetalol.

Lets see how........ There are 2 mechanisms by which betablockers can cause hyperkalemia.
1. Beta blockers suppress catecholamine-stimulated renin release, thereby decreasing aldosterone synthesis.
2. More importantly nonselective beta blockers decrease cellular uptake of potassium.(NEJM )
                          
The primary mechanism for handling an acute potassium load is by redistribution into the cells.Normally, agonist binding to the beta2-adrenergic receptor stimulates the formation of cyclic AMP, which acts through protein kinase A to phosphorylate and activate the Na-K-ATPase pump, leading to the influx of potassium into cells. Competitive inhibition of the beta2 receptor by beta blockers decreases Na-K-ATPase function and reduces potassium uptake by cells.
So..this seems to happen only with non-selective beta blockers(Labetalol, Propranolol, Carvedilol, Nadolol).
Based on some retrospective studies, nonselective beta blockers have caused or contributed to hyperkalemia in 4% to 17% of hospitalized patients studied.
Have a look at this study on renal transplant patients receiving Labetalol, ended up having hyperkalemia more frequently than patients treated with agents other than labetalol.(AJNephrology 2002). The fact that hyperkalemia developed immediately after Labetalol infusion strengthens the hypothesis of blocking cellular intake of potassium than catecholamine suppression as the primary cause of Hyperkalemia with non selective betablockers.

So...just add nonselective betablockers to your differential for Hyperkalemia ......especially in patients who cannot excrete potassium properly (renal failure, on ace-i or ARD, spironolactone etc)
Sorry guys...I could not get full text of articles...will update once I get access to them!