COTRIMOXAZOLE

MECHANISM:
                    Cotrimoxazole is a combination of sulfamethaoxazole + trimethoprim in a ratio of 5:1 .
Sulfamethaoxazole and trimethoprim separately are bacteriostatic drugs but when combined together they become bacteriocidal .
Cotrimoxazole is a bacteriocidal drug.
Bacteriocidal activity is due to sequential blockade .
Sulfamethoxazole inhibit folate synthase and trimethoprim inhibits
folate reductase.  

PHARMACOKINETICS:

1. Taken orally 
2. Metabolized in liver
3. Excreted in urine 

USE:

1. UTI
2. RTI
3. MRSA
4. Drug of choice for Pneumocystitis jirovecii and nocardiosis .

ADVERSE EFFECTS:

It has adverse effects of both sulphonamides and trimethoprim .

SULPHONAMIDE ADVERSE EFFECTS

1. Aplastic Anemia 
2. Bilirubin displacement from plasma protein leading to Kernicterus
3. Crystalluria
4. Rash 
5. SLE
6. Hemolysis in patients with G-6PD deficiency  

                  mnemonic : ABC RAsH

TRIMETHOPRIM SIDE EFFECTS 

1. Megaloblastic Anemia
2. Leukopenia
3. Pancytopenia
4. Hyperkalemia ( due to amiloride like action , amiloride is a Potassium sparing diuretic ).

SULPHONAMIDE , TRIMETHOPRIM

SULPHONAMIDE:

MECHANISM:

                         Sulphonamide inhibits folate synthase enzyme . Thus bacteria cannot synthesize the folic acid required for its growth . 

This drug does not affect the folic acid level in humans , because humans acquire folic acid directly from food and it's not synthesized.

DRUGS:
Short acting : Sulfisoxazole
Intermediate acting : Sulfadiazine , Sulfamethaoxazole
Long acting : Sulfadoxime
For use in GIT : Sulfasalazine
For topical use : Sulfacetamide, Silver Sulfadiazine

Pharmacokinetics:

1. Taken orally 
2. Metabolized in liver by acetylation
3. Crosses placenta and Blood Brain Barrier
4. Excreted in urine

Use: 

1. Sulfisoxazole used in UTI
2. Sulfadiazine used in nocardiasis 
3. Sulfadiazine + Pyrimethamine used for Toxoplasmosis and as prophylaxis of Pneumocystitis jiroveci
4. Sulfadoxime + Pyrimethamine used in malaria .
5. Sulfasalazine is used in Ulcerative colitis .
6. Sulfacetamide is used for Ocular infections
7. Silver sulfadiazine is used in burns patients .

Adverse Effects:

1. Aplastic Anemia 
2. Bilirubin displacement from plasma protein leading to Kernicterus
3. Crystalluria
4. Rash 
5. SLE
6. Hemolysis in patients with G-6PD deficiency 

                      mnemonic : ABC RAsH


TRIMETHOPRIM:
MECHANISM:
                         These drugs inhibit Folate reductase enzyme , thus inhibiting the synthesis of THFA required for survival of bacteria . 
It is specific for bacterial folate reductase enzyme and has no effects on humans .

PHARMACOKINETICS:

1. Given orally
2. Metabolized in liver
3. Excreted in urine

USE:

1. It is combined with sulphnomides and used widely.
2. Used alone in UTI and Prostitis .

Adverse Effects:

1. Megaloblastic Anemia
2. Leukopenia
3. Pancytopenia
4. Hyperkalemia ( due to amiloride like action , amiloride is a Potassium sparing diuretic ).

                      

AMINOGLYCLOSIDE

Mechanism:

         They bind on 30S ribosome and does the following actions :

1. Inhibition of formation of initiation complex
2. Inhibition of polysome formation 
3. Misreading of mRNA

DRUGS:

1. Streptomycin
2. Gentamicin
3. Tobramycin
4. Amikacin
5. Neomycin

PHARMACOKINETICS:

1. They are given parenterally, topically, orally[but not absorbed by GI tract].
2. They are not metabolized in body.
3. They are excreted unchanged in urine.
4. They do not cross blood brain barrier.

USE:

1. Active against all GRAM -VE organisms
2. Active against GRAM +VE , if used in combination with BETA-LACTAMS or VANCOMYCIN.
3. Streptomycin is used as 1st line drug in TB
   Drug of choice in tularemia and plague
4. Amikacin is 2nd line drug in TB.
5. Neomycin used orally for gut sterilization.Neomycin used topically for skin infections.
6. Spectinomycin used in treating PENICILLINASE-PRODUCING Neisseria gonnorhoea [PPNG].

ADVERSE EFFECTS:

1. OTOTOXICITY:
                 Amikacin, Neomycin causes hearing loss.
                 Gentamicin , Streptomycin causes vestibular toxicity.              Tobramycin causes both.
2. NEPHROTOXICITY:               Neomycin is most Nephrotoxic and not given I.V
                  Gentamycin is most toxic drug given as I.V               Streptomycin is the least toxic.
3. NEURO-MUSCULAR BLOCKADE:
                  These drugs decrease the release of Ach as well as decrease the senstivity of post-synaptic membrane.
   Hence should not be administered in case of Hypocalcemia, Respiratory depression and Neuromuscular blockers .

Fluoroquinolones

MECHANISM:
              Fluroquinolones inhibit DNA GYRASE and TOPOISOMERASE-4. 
Thus inhibiting replication of DNA .

CLASSIFICATION:

1st generation - Norfloxacin, Lomefloxacin
                        ( active against few gram -ve organism )
2nd generation - Ciprofloxacin , Ofloxacin
                        ( active against all gram -ve organism )
3rd generation - Sparfloxacin, Levofloxacin , Gatifloxacin 
               ( active against all gram -ve organism and few gram +ve)
4th generation - Moxifloxacin , Trovafloxacin
                (active against all gram -ve and gram +ve )

Pharmacokinetics :

1. All drugs can be given orally and parenterally . 
2. Metabolized by liver
3. Moxifloxacin and Trovafloxacin excreted in feces 
4. Others are excreted via urine

Uses:

1. Norfloxacin is excreted in urine in large quantities , hence used in UTI
2. Ciprofloxacin and Ofloxacin used in gonorrhoea , pseudomonas , anthrax , meningococcal meningitis , TB 
3. Levofloxacin , Gatifloxacin , Sparfloxacin are active against all gram -ve , few gram +ve and atypical microoraganisms . Hence used in respiratory infections
4. Moxifloxacin amd Trovafloxacin are the broadest spectrum antibiotic.

ADVERSE EFFECTS:

1. GI distress
2. Affect cartilages and hence not used in children below 18 yrs 
3. They cause tendinitis 
4. Photosenstivity
5. Seizures
6. Moxifloxacin and Trovafloxacin causes hepatotoxicity.

PATHOGENESIS OF NEPHROTIC SYNDROME

In a normal kidney glomerulus doesn't let the proteins to get filtered because of the presence of 

1. Tight junctions in the glomerular capillary wall
2. Negative charge of GLOMERULAR BASEMENT MEMBRANE (proteins are also negatively charged)
3. Presence of  PODOCYTES .  

If any one of these components gets damaged , it will lead to Nephrotic syndrome .

NEPHROTIC SYNDROME is a condition characterized by 

1. Proteinuria 
2. Hypoalbuminemia 
3. Generalized edema
4. Hyperlipidemia and Lipiduria

PATHOGENESIS:

• When a damage of glomerular capillary wall or basement membrane or podocytes happen , proteins escape into the glomerular filtrate .
• Thus it leads to proteinuria , primarily albumin is lost hence also called as albuminuria . 
• Albumin level in blood decreases due to loss in urine leading to hypoalbuminemia
• Due to Hypoalbuminemia there is fall in osmotic pressure leading to edema .
• Due to hypoalbuminemia , liver tries to compensate the loss of albumin by increasing it's synthesis, On the process lipid synthesis gets triggered as well leading to HYPERLIPIDEMIA. Albumin is the carrier protein of lipid. Due to hypoalbuminemia there is abnormal lipid transport leading to LIPIDURIA.

PATHOGENESIS OF LIVER CIRRHOSIS

In simple words , 'Liver cirrhosis' means fibrosis of liver and formation of nodules on its surface .

Before we see about the pathogenesis of liver cirrhosis . Let's review about the structure of liver .

Above picture shows that liver gains nutrients from hepatic artery and portal vein , And venous blood is drained by hepatic vein . Bile duct is draining bile from the liver .

This is a simplified diagram showing the course of hepatic artery , portal vein and bile duct inside the liver parenchyma . 
Hepatic artery and portal vein form a sinusoid and drain into the central vein. Central veins will join together to form the hepatic vein . 
In the sinusoid KUFFER CELLS(macrophages) are present.
There is a space between the sinusoids and hepatocytes . It is called as SPACE OF DISSE . It contains STELLATE CELLS. Nutrients from the sinusoids reaches hepatocyte passing through the space of disse .

CAUSATIVE AGENTS:

1. Chronic Alcoholism
2. Hepatitis B & C
3. Hemochromatosis
4. Genetic factor

PATHOGENESIS:

1. Due to the causative agents , hepatocytes gets destroyed
2. Damaged hepatocyte will produce CYTOKINES
3. Cytokines will activate the kuffer cells present in the sinusoids.
4. Activated Kuffer cells will produce GROWTH FACTOR and TNF.
5. GF and TNF will activate the stellate cell . Stellate cell now will convert into a myofibroblast.    
6. Myofibroblast will produce collagen which accumulates in the space of disse
7. Thus space of disse gets thickened due to accumulation of collagen . So transfer of nutrients from the sinusoids to hepatocyte becomes difficult. 
8. This will lead to death of hepatocytes 
9. Some hepatocytes are spared . They will multiple profusely to compensate the lost liver function .
10. This compensatory multiplication leads to the formation of nodules on the liver surface .

CHLOROQUINE

One must be thorough with malarial parasite life cycle to understand about the chloroquine well . So i advice the readers to learn about the life cycle of plasmodium before reading this post.

CHLOROQUINE IS THE DRUG USED WIDELY FOR TREATING MALARIA . BEFORE WE SEE ABOUT THE DRUG IN DETAIL . LET'S REVIEW ABOUT THE DIFFERENT STAGES OF MALARIAL LIFE CYCLE AND THE SCHEMA OF TREATING MALARIA .

IN HUMANS MALARIAL PARASITE UNDERGOES 2 STAGES

1) PRE - ERYTHROCYTIC STAGE ( parasite is inside the liver ) 

2) ERYTHROCYTIC STAGE ( parasite is inside the RBC )

SCHEMA FOR TREATING MALARIA:

1. DRUGS TO TREAT THE ACUTE ATTACK : These drugs kill the plasmodium in the RBC .eg- chloroquine , mefloquine, artemisnin derivatives . 
2. DRUGS FOR RADICAL CURE :  For radical cure , combination of drugs that kill the erythrocytic stage + drugs that kill the exo-erythrocytic(liver) stage is used .
   eg- chloroquine + primaquine
3. DRUGS FOR PROPHYLAXIS : These drugs kill the plasmodium in the exo-erythrocytic(liver) stage.
   eg- primaquine , proguanil 
4. DRUGS FOR PREVENTING TRANSMISSION: These drugs kill the gametes . eg - chloroquine  

                                   CHLOROQUINE

MECHANISM :

                          Chloroquine accumulates in the food vacuole of PLASMODIUM ,  thus it is selective for erythrocytic stage of malaria ( food vacuole in the plasmodium is found only in the erythrocytic stage ). 

Then it inhibitis the conversion of heme to hemozoin .

Heme is toxic to the parasite , thus the parasite in the rbc gets killed.

OTHER ACTIONS of chloroquine:

1. Anti-inflammatory 
2. Anti-histamine
3. Anti-arrythmic
4. Local anesthetic 
5. Active against Giardia lamblia and Entamoeba histolytica

PHARMACOKINETICS :

1. Given orally 
2. Partly metabolized in liver
3. 70% excreted in urine unchanged
   30% excreted in urine as a metabolite .

USE:

1. R - Rheumatoid arthritis
2. E - Extra-intestinal amoebiasis
3. D- Discoid Lupus Erythromatosis
4. L - Lepra reaction
5. I - Infectious mononucleosis
6. P - Photogenic reaction
7. M - Malaria 
8. G - Giardiasis

   RED LIP Mahatma Gandhi is the mnemonic to remember the uses of chloroquine .

ADVERSE EFFECTS:

1. Skin rashes ( Lichenoid eruptions )
2. Peripheral neuropathy
3. Auditory impairment 
4. Blindness due to retinal damage ( bull's eye maculopathy)
5. Porphyria

BULL'S EYE MACULOPATHY