"Senators Flake and Corker are simply a continuation of the destruction of the Republican establishment that began with then-candidate Trump's evisceration of presidential candidates like Jeb Bush, John Kasich, Marco Rubio, and even a relative upstart like Ted Cruz."

Let's start with 2018 and Arizona in particular. With Flake out of the running and Senator John McCain ailing with brain cancer, there's a chance that the not-so-red anymore state could be a major battleground next year. Remember, Donald Trump won Arizona in 2016 by just 3.5 percentage points over Hillary Clinton. So the state seems to be in play.

But before the Democrats get too excited, they need to remember this name: Kelli Ward. The Republican physician and former state senator seems to be the big winner in this story right now. She had been polling ahead of Flake as she prepared to challenge him in a GOP primary and she's already declaring victory of sorts in the general election. Ward has been pounding on the door of both Senators Flake and McCain for years with her assertions that they have betrayed core conservative Republican causes. She unsuccessfully challenged McCain in the Republican primary last year and then immediately shifted to going after Flake.

She will almost certainly face a serious challenge from the Democrats in that election anyway, but Ward's name recognition alone will make her hard to defeat. And speaking of name recognition, Arizona has a Republican governor in Doug Ducey. If McCain has to step down for health reasons, he will almost certainly appoint a Republican to replace him until the 2018 election. And that Republican will have name recognition and some form of incumbency advantage as well.

But let's take the focus beyond Arizona and look at the bigger picture for 2018 and beyond for the GOP.

In his speech on the Senate floor Tuesday, Flake cited "reckless, outrageous, and undignified behavior" that "is dangerous to a democracy." Even though he doesn't mention Trump by name, even the most ardent Trump supporter can admit that this president is not much for civility and discretion. But when it comes to the dangers to a democracy, it's the establishment GOP that's responsible for a more serious brand of that thanks to the Republicans' willful disregard for their own base's demands.

In 2016, the base of the Republican Party decided it had seen enough and decided to overwhelmingly choose a brash and blunt outsider to be its presidential nominee, rejecting 16 more experienced and "respectable" GOP candidates. They wanted to punish the establishment Republicans for not using the congressional majorities the GOP base handed them in 2010 and 2014 to block the funding for Obamacare. They wanted to punish them for their failure to block the nuclear deal with Iran. Many even wanted to punish them for not even attempting to impeach President Barack Obama for his many executive orders they believed were inherently unconstitutional. And as the Trump campaign proved more clearly than anything else, the GOP base wanted to punish the establishment for going along with what those voters saw as a too lenient immigration policy that they believed threatened their economic and personal safety.

Senators Flake and Corker are simply a continuation of the destruction of the Republican establishment that began with then-candidate Trump's evisceration of presidential candidates like Jeb Bush, John Kasich, Marco Rubio, and even a relative upstart like Ted Cruz.

In order to stay in the game, GOP candidates are going to have to start listening to their base. Of course, roping in the conservative base with a more positive message is easier said than done. To date, only President Ronald Reagan has had the talents and instinctive common sense to pull it off. That's why no one should be surprised if more establishment Republicans drop out or lose primaries in the coming years.

Senate Majority Leader Mitch McConnell seems especially vulnerable with his 18 percent approval rating in his own home state of Kentucky, according to a Public Policy Polling survey. And if the tax-reform effort fails, other top GOP leaders like House Speaker Paul Ryan and Texas Senator John Cornyn could lose or step down, too.

Those Republicans who remain in Congress now have a stark choice in front of them: They can either try to swim against their own base and President Trump and likely fail, or press on and accomplish something legislatively before the die is cast on the 2018 elections and beyond.

The easiest way to do that is not only pass a tax reform, but work with President Trump to do a better job of making the case for the bill in the first place.

Otherwise, what's their option? Voters like to see a difference between candidates when they go to the polls. And if the GOP presents them with a handful of candidates who sound just like the Democrats bashing President Trump, they will likely choose the Democrats every time.

Senator Flake is out not because of President Trump, but because he's part of the punishment the GOP base is still doling out against ineffective leaders. If the remnants of the Republican Congress fail in 2018, it will be because they didn't learn that actions speak louder than words.

Commentary by Jake Novak, CNBC.com senior columnist. Follow him on Twitter @jakejakeny.

For more insight from CNBC contributors, follow @CNBCopinion on Twitter.