Diuretics

It is good to revise on renal system so that we can understand mechanism of diuretics easily. Diagram 1 below gives an overview of the tubule transport systems and site of actions of diuretics.

Diagram 1

(RA=reabsorption)

There are two types of diuretics: 

(i) Direct action on the cell of nephron 

(ii) Indirect action

Diagram 2: classification of the diuretics

Table 1 and 2 summarises the properties of diuretics act directly on nephron.

Table 1

In the management of hypertension,

Diuretics

•Reduce BP by 10 – 15 mmHg
•Thiazides used in moderate HPT
▫Chlorothiazide, Hydrochlorothiazide,Bendroflumethiazide•Loop diuretics use for severe HPT:
▫Furosemide, Torsemide

Table 2

For potassium sparing diuretics:

1. They are usually use with diuretics that deplete potassium in the body.

2. Spironolactone is used in primary hyperaldosteronism (Conn's syndrome) & secondary hyperaldosteronism (hepatic cirrhosis complicated by ascites).

3. triamterene and amiloride are better tolerated than spironolactone.

4. main side effects of potassium sparing diuretics are hyperkalaemia. others include metabolic acidosis, skin rashes and GIT disturbances.

Osmotic diuretic:Mannitol
- use is limited
-side effects: expansion of ECF and hyponatremia

Carbonic anhydrase blockers: Acetazolamide
-used for treatment of glaucoma

Antihypertensive treatment:Vasodilator

Vasodilators can be used as a part of antihypertensive treatment.

About calcium channel blockers:I AM HERE

Oral vasodilators are seldom used today due to their side effects (tachycardia). The example of parenteral vasodilator is sodium nitroprussides. 

This table is based on Dr.Subrat's notes (hypertension 4). I put them into table so it is easy to read. Besides, I highlight the similarities between the medication with same colours to help in memorising. 

Cardiac Muscles and Calcium Channel Blockers

The topics in this post include structure of cardiac muscles, mechanism of muscles contraction, as well as different type of CCB and their uses.

A.Structure of Cardiac Muscles 

Figure 1: structure of cardiac muscles (source)

Figure 2: The diagram shows the thin and thick filaments.

Sarcomere is the contractile unit of the cardiac muscle. It contains thin filament (actin), thick filament (myosin), troponin and tropomysin. If you have difficulties in differentiating thin and thick filament (just like me), just remember "actin" has a sound like "thin".

Figure 3: this diagram shows the position of actin, troponin and tropomyosin. There is calcium ion binding site on troponin which regulate the movement of tropomyosin. (source)

Actin contains actin binding sites which allow myosin head to bind to carry out sliding mechanism. However, they are covered by tropomysin. Troponin regulates the movement of tropomysin through the binding of calcium ion. 

b Mechanism of  Muscle Contraction

Figure 4: the diagram showed the flowchart of cardiac muscle contraction. Note that the troponin complex here means tropomysin. Step no.4 is shown in Figure 3.

Figure 5: Sliding mechanism(source)

C. Calcium Channel Blockers

    Calcium channel blockers (CCB) can be considered as a vasodilator. CCB interfere with the inward displacement of calcium ions through the slow channels of active cell membranes. They influence the myocardial cells and the cells of vascular smooth muscle. Thus, they may reduce 

(a) myocardial contractility 

(b) the formation and propagation of electrical impulses within the heart

 (c) coronary or systemic vascular tone may be diminished.    [Reference:BNF (May)]

1. Type of CCB:
(i) Dihydropyridines 

• amlodipine

• felodipine

• isradipine

• nicardipine

• nifedipine

• nimodipine

• nitrendipine

(ii) Non-dihydropyridines 
-Diltiazem
-Verapamil

CCBs differ in their predilection for the various possible sites of action and, therefore, their therapeutic effects are disparate.

(i) Dihydropyridines 
- most vaso-selective, least cardiac effect

 The side effects include:
-flushing and headache(associated with vasodilation)
-ankle swelling (which may respond only partially to diuretics) are common.

(ii)non-dihydropyridines

So all type of CCB can be used to treat hypertension. Verapamil has the highest cardiac depressant effect, followed by diltiazem and nifedipine.
V,D,N= Very Dangerous Neighbour

Reference: Dr.Subrat notes on hypertension & British National formulary (May).

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

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

Drugs act on sympathetic nervous system: Alpha & Beta blocker, Centrally acting drug

Today post focuses on drugs that alter sympathetic nervous system. They are

(i)  Adrenoceptor blockers- a-blockers, b-blockers

(ii) Centrally acting drugs

To understand the mechanism of adrenoreceptor blockers, let us revise on the functions of different receptors.

1. How do alpha blockers work and how to relate them to their side effects?
 Activation of alpha 1 leads to vasoconstriction-> increase the blood pressure (BP).
Blocking alpha-1 prevent vasoconstriction -> decrease in BP (alpha-1 selective).
therefore, the main side effects include first dose phenomenon and orthostatic hypotension (postural hypotension).

 Activation of alfa-2 :inhibits the release of noradrenaline (NA)->decrease heart rate and contractility.
the non-selective alpha blocker blocks alfa-2->  increase heart rate and contractility.
Side effect: decrease BP (from blocked alpha-1) + increase HR (from blocked alpha-2) = reflex tachycardia.

2.How do beta blockers work?
Non-selective beta blocker block both beta-1&2.
Blocking beta-1 (in heart)->decrease heart contractile force and HR->side effect:bradycardia.
Blocking beta-2 ->inhibit the relaxation bronchus muscles->contraindicated in patient (pt) with COPD/asthma.
                          ->also inhibit vasodilation->peripheral vasoconstriction.

Summary

alpha blockers

• Type

this is a screenshot from Dr.Mai Chung Wai's notes on Drug Design Based On Protein Structure, covered in Sem 4 Biotechnology.

• Use

-can be used with other antihypertensive drugs in the treatment of resistant hypertension.

Beta blocker

• Type

beta 1 selective: Practolol, Atenolol, Metoprolol (P.A.M)

non-selective: propranolol,pindolol,timolol

• Uses 

1. Management of stable angina & acute coronary syndromes

2. Hypertension treatment

3.reduce recurrence rate of myocardial infarction.

4.Management of arrhythmias

5.Heart failure treatment

• Development:

The following diagrams are the screenshoots from Dr.Mai Chung Wai's notes on Drug Design Based On Protein Structure, covered in Sem 4 Biotechnology.

                            

The development of beta blockers.

                                  

Structure of propanolol. It is good to memorise these properties for examination purpose.

for selective beta1 blocker, para-substitution is essential.

The table below summaries the properties of alpha and beta blockers.

                                             Table 1: summary of alpha and beta blockers.

Beta 1 selective blockers are useful in pt with impaired pulmonary functions and diabetics pt.

Centrally acting drugs

Table 2: centrally acting drugs

oopsss hope my handwriting is understandable.

To remember the name of centrally acting drugs, you can try to think of MCM.

a brand endorsed by EXO (based on google, not sure about 2016 tho)

Hypertension at a glance: Introduction & Treatments

Hypertension is covered in Cardiovascular System module, Semester 2, Bachelor of Pharmacy in IMU.

First,we must know what hypertension (HPN) is.
These notes are based on Dr.Subrat lecture slides. When comes to studying I prefer to use mind map and tables.

Introduction:
Before that, let us revise what are the functions of some adrenergic receptors. Familiar with these receptors is definitely going to help us in understanding the mechanism of HPN and its pharmacological treatments.


It is the best if you can memorise this! In higher semester you are going to deal with these too. OK lets us move on to HPN.


 Hypertension (HPT) is defined as persistent elevation of SBP of > 140mm Hg and / or DBP of > 90mm Hg.

This is the simple outline of introduction of hypertension. 

The risk factors and effects are pretty easy to understand. The risk factors for primary hypertension include overweight, smoking, alcohol, sedentary lifestyle etc. Hypertension cause damage to arteries and increase the risk of getting other diseases.

RAAS stands for Renin-Angiotensin Aldosterone system. There are plenty of information on internet about this system. As a student, you must understand and remember this mechanism well, as this will help you in the following semester.

source: google image

I think this summarises the introduction of hypertension. Wow it really take a lot of time to type this up.  

Overview of the pharmacological treatment:

1. Drugs act on RAAS: click me
2. Drugs act on sympathetic nervous system: poke here!!
3.Diuretics:Diuretics
4.Calcium Channel Blockers: Cardiac muscles and CCB
5. Vasodilators: http://louisastudy129.blogspot.my/2016/06/antihypertensive-treatmentvasodilator.html