Drugs act on RAAS - ACEI,ARB,Renin inhibitor

To understand how the drugs work, we must understand how RAAS work.
ACE= angiontensin-converting enzyme

This diagram summarises how the system work (from google). Note that angiotensin II (Ag II) increases aldosterone secretion which increase the reabsorption of sodium & chloride ions as well as excretion of potassium ions.

The main target of drugs are renin, ACE and angiotensin II receptors (where Ag II bind to and generate responses).

   This diagram gives an overview with main points for each drugs.

Renin inhibitors

• interact with ACEI /ARB especially in diabetic pt

-aliskiren can increase adverse events (non-fatal stroke, renal complications, hyperkalemia, hypotension) with no apparent additional benefits when added to treatment with an ACEI or ARB in diabetic patients.

ACEI:

• Uses:

1. can be used in all grades of heart failure. It is usually combined with a beta blockers.
2. antihypertensive treatment. 
3.It is particularly indicated for hypertension in pt with type 1 diabetes with nephropathy.
4. used in early and long-term management of pts who have had a myocardial infarction.

• Side effects

1. Profound hypotension
2. dry cough and angioedema are related to bradykinin (ACEI blocks ACE, preventing the deactivation of  bradykinin).

3.GIT effects: nausea,vomiting,constipation, abdominal pain etc.

• Captropril has other minor side effects due to sulphydryl group, include:altered taste, skin rash, drug fever, neutropaenia, proteinuria.

• contraindicated in pregnancy
• Drug-drug interaction:

(i) hyperkalaemia with K+-sparing diuretics or with K+ supplements.

Explaination: 

        1. Ag II =>potassium excretion.

        2. ACEI (-) AgII,=> (-) potassium excretion (K+retain in the body)

       3. K+ sparing diuretics and K+ supplement also retain K+ in the body=>hyperkalaemia

(     (ii) NSAIDs 

     -may reduce hypotensive effect by blocking bradykinin-induced vasodilation (partly PG-mediated) 

•       History of Development (covered in Semester 4 Biotechnology)  

       1. ACE is a zinc protease and carboxypeptidase is a zinc protease too.
        2. Benzylsuccinic acid can inhibit carboxypeptidase, thus make it a model for designing ACEI. 3.However, there is a difference between carboxypeptidase and ACE: ACE cleaves a dipeptide wherease Carboxypeptidase cleaves 1 peptide chain.
      4. It is proposed that the linker between carbonyl groups should be longer and a series of dicarboxylic acids were proposed but they are not very stable/potent.
     5. the carboxyl group (COO-) group binding to Zn2+ was exchanged with thiol group (SH).
   

(from Dr.Mai Chun Wai notes on Drug Design Based On Protein Structure)

   From here I just screenshot the notes from Drug Design Based On Protein Structure by Dr.Mai Chun Wai, because I think his explanations are clear with figure of structure.

    

ARB

The side effects do not include dry cough and angiodema as it has no effect on bradykinin.
   1. antihypertensive
    2.alternative to an ACEI in the management of heart failure (HF) / diabetic nephropathy.


Reference: Dr.Subrat notes on hypertension 3, British National Formulary (May), Drug Design Based On Protein Structure by Dr.Mai Chun Wai

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Related: drug acts on sympathetic N.S:http://louisastudy129.blogspot.my/2016/06/antihypertensive-treatment-drugs-act-on.html