Vonoprazan belongs to a new class of drugs called potassium-competitive acid blockers

Inhibits H+K+-ATPase by competitively blocking the potassium-binding site

Compared to PPI:

More suppression of gastric acid secretion

Acid-catalysed activation is not necessary for the action

More rapid onset of action (day 1)

Bioavailability is not affected by food

Primarily metabolised by CYP3A4

Other drugs implicated

CART:

C: Cefepime, ciprofloxacin, cremophor (excipient in paclitaxel)

A: Amphotericin B

R: Rifampin

T: Teicoplanin, telavancin

· Digoxin is metabolized to inactive metabolites, called digoxin reduction products by a bacterium called Eubacterium lentum.

· Eubacterium lentum is present as normal flora in approximately 10 percent of patients.

· Broad spectrum antibiotics like erythromycin/ tetracycline can alter the flora and increase digoxin levels.

Source: https://www.aafp.org/afp/1998/0315/p1239.html

▪️Around 20% of patients will have positive Coombs test.

▪️Positive coombs test is not an indication to stop treatment.

▪️Only around 1–5% of patients with positive Coombs test may develop hemolytic anemia: discontinuation is required; hemolytic anemia resolves within weeks after discontinuation whereas Coombs test remains positive for about a year.

▪️Glucocorticoids are required for severe cases.

The hypotensive effect during long-term therapy is therefore primarily attributed to decreased vascular resistance. The negative Na+ balance has an indirect effect of decreasing peripheral vascular resistance.

• Principal cells of the renal collecting duct system
• Epithelial cells in TAL

Apart from the principal cells, they are present in thick ascending limb also. So, there should be some additional mechanism of action.

Major action:

Rapid insertion of preformed aquaporin-2 into apical membrane of principal cells in collecting duct and increasing water permeability

Minor actions:

• Long term increase in expression of aquaporin-2
• Rapid activation and translocation of Na+/K+/2Cl- symporter in TAL
• Long term increase in expression of Na+/K+/2Cl- symporter
• Rapid activation of VRUT in IMCD

Minor actions result in increase in medullary osmolality and further adds to the water conservation.

Thiazides reduce the kidney’s ability to excrete free water: They increase proximal tubular water reabsorption secondary to volume contraction and block the ability of the DCT to form dilute urine. This effect results in an increase in urine osmolality.

Note: Thiazides are also effective in central diabetes insipidus and is being investigated extensively in this condition.

Source: Thiazide Diuretics in the Management of Young Children with Central Diabetes Insipidus.

Rationale:

Exact mechanism is unknown.

CA inhibitors action on renal tubules results in bicarbonaturia and metabolic acidosis.

The above action results in offsetting hyperventilation-induced respiratory alkalosis and allowance of chemoreceptors to respond more fully to hypoxic stimuli at altitude.

Other factors that can also contribute to its efficacy:

Improvements in ventilation from tissue respiratory acidosis

Improvements in sleep quality from carotid body CA inhibition

Effects of diuresis

Sources:

https://www.ncbi.nlm.nih.gov/pubmed/17023566 https://wwwnc.cdc.gov/travel/yellowbook/2020/noninfectious-health-risks/high-altitude-travel-and-altitude-illness

Atypical antipsychotics are usually implicated in DIP.

The mechanism of antipsychotic efficacy is attributed to its D2 antagonism.

Use of levodopa in such patients:

• Risk of antagonising the antipsychotic effect by competitive antagonism
• Risk of psychosis caused by levodopa itself

Despite the above theoretical limitations, there are limited number of trials done to look into the efficacy and safety.

What do these trials say ?

Do not report any significant increase in psychosis

Also benefits obtained by levodopa treatment are disappointing and non-significant

Note: the above conclusions are for neuroleptic induced Parkinsonism

For other drug induced Parkinsonism like valproate, levodopa treatment has been found to be beneficial.

Source:

https://jnnp.bmj.com/content/jnnp/51/6/850.full.pdf

https://www.dovepress.com/drug-induced-parkinsonism-diagnosis-and-management-peer-reviewed-fulltext-article-JPRLS