Antibiotics:Cell wall synthsis inhibitor-Cephalosporins

Cephalosporins

•  closesly related both structurally & functionally to the penicillin. 
• (from cell membrane 2 by Dr.Arjun)
• same mode of action as the penicillin. 

Advantages over penicillin:

1.Resistance to inactivation by b-lactamase

2.Permeability into cell envelopes of gram negative bacteria

3.Intrinsic activity against bacterial enzymes involved in cell wall synthesis and cross-linking

Side effects: cross-sensitivity with penicillin, GI distress, renal impairment, bleeding (especially with cefoperazone,cefmetazole,cefotetan)

  There are many generations of cephalosporins. For me their names seem similar so they are quite hard to remember. However as an IMUnians, for exam point of view, please memorize them with all of your heart <3. This is covered in Semester 3, and sorry to say that I don't remember which belong to which generations now. Thats why revision is important. When memorizing, take note on the spelling such as "cefa","Cepha","cefo","cefu".

= means it is the same as that in the first row.

Tips is how I remember their name. Sometime it doesn't make sense at all. I spell their name on a paper repeatedly to memorise them. 

4th generation

Example: cefepime.

Spectrum: gram negative aerobic bacteria (enteric E.coli, Klebsiella pneumoniae etc).

5th generation

example:ceflobiprole

Spectrum: MRSA, penicillin resistant streptococcus pneumonia,p.aeroginosas.

Interactions of 4th and 5th generation are the same as other (1 and 2).

Cephalosporin also covered in Medicinal chemistry, Semester 4.

Antithrombotics & thrombolytic

Diagram 1:Overview of blood clotting mechanism & antithrombotics,thrombolytic agent

only now I noticed that the upper part of the note is disappear. The top of the note is 

"Tissue damage->stop protacyclin"followed by " release vWF factor"．

 Von Willebrand factor (vWF) is a blood glycoprotein involved in hemostasis.

Please note that antithrombotics are the agents that reduce the clot formation whereas thrombolytic agents dissolve blood clots.

                                       

Diagram 2: Summaries of different type of antithrombotics and thrombolytics agent. 

AR=adverse reaction

The differences between Unfractional heparin and low molecular weight heparin is summarised as below:

Antibiotics: Cell wall synthesis inhibitors-Penicillin

Here is my way to remember the type of cell wall synthesis inhibitors, but it is in chinese.

CW C C MB P. -宗伟 常常 慢 半 拍

CW- Cell wall (cell wall inhibitors)

C -cephaloporins

C-carbapenems

MB-monobactam

P- penicillin.

The mechanism of penicillin(in short)

-binds to penicillin binding protein (PBPs)=>inhibit transpeptidase-catalysed reaction=>hinder the formation of crosslink which is essential for  bacterial cell wall integrity. 

The following tables summarises the types, examples and spectrum of penicillin. 

1. The side effects of penicillin includes:

• hypersensitivity
• GI distress (for ampicillin-diarrhea is common)
• bone marrow suppression, anaemia
• renal impairment

2. Interactions

-probenecid increases blood level of penicillins.

3. Bacterial Resistance

-penicillin is degraded by beta-lactamase produced by bacteria.

4. Structure Activity Relationship (covered in Medicinal Chemistry, Sem 4)

notes from Dr.Arjun: Drugs that affect microbial cell walls.

Parent compounds: penicillin G

There are some disadvantages of penicillin G. To improve the properties, some changes can be made. 

5. Allergic reaction

• due to the presence of impurities called penicilloyl proteins obtained during their biosynthesis.

- these penicilloyl proteins are formed by reaction of penicillins, their degraded products & rearranged products with lysine amino groups of proteins of strains.

• Ampicillin-allergic reactions due to the presence of polymeric impurities having antigenic properties.

- ampicillin undergoes pH dependent polymerization reaction -between amino group of acyl side chain of one molecule & beta-lactam carbonyl carbon atom of second molecule.

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

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