Recall that direct-acting cholinergic agonists mimic the actions of ACh and are categorized as choline esters and alkaloids. Choline esters—including ACh and its synthetic derivatives—being quaternary amines, are hydrophilic in nature. So, they have poor oral absorption and fail to cross the blood-brain barrier or BBB. ACh—the endogenous choline ester, is rapidly inactivated by AChEs and hydrolyzed into choline and acetate. As a result, a higher IV dose is essential to induce its pharmacological action. Synthetic choline esters are relatively more stable and resistant to hydrolysis by AChEs, correlating with their longer duration of action. In general, choline esters are short-acting agents as they are rapidly eliminated via the urine. The naturally occurring alkaloids are tertiary amines, except muscarine. So, they are readily absorbed from the site of administration, can cross the BBB, and are eliminated via the renal route. Acidification of the urine can accelerate the clearance of alkaloids. As protonation of tertiary amines reduces their lipophilicity, acidification promotes rapid renal elimination.