ROLE OF LIVER IN DRUG DETOXIFICATION

Liver is the gateway to body and plays very important role in drug detoxification.

• Filtering blood to remove large toxins.
• Enzymatically breaking down unwanted chemicals. It usually occurs in two steps: phase 1- modifying the chemicals to make them on easier target for phase 2 enzyme system.
• Synthesizing and secreting bile for excretion of fat soluble toxins and cholesterol.

PHASE 1 :

It consist of oxidation reduction and hydrolysis. It is catalyzed by 50-100 enzyme referred as cytochrome P450 enzyme group or mixed function oxidase MFO. They reside in hepatocytes or liver cells. They detoxify both exogenous and endogenous compounds, as well as play an important central role in the synthesis of steroids hormones and bile acids. The wide effect of this metabolic activity is the production of free radicals. The most important antioxidant for neutralizing those free radicals is glutathione, which is needed for both phases. 

Human liver cell possess the genetic code for many isozymes P450 whose synthesis can be induced upon exposure to some drugs.

PHASE 2:

It is called conjugation pathway whereby the liver cells and another substances (cysteine glycine or a Sulphur molecule ) to a toxic chemical or drug to render it less harmful.It makes drug water soluble so it can be excreted from body via watery fluids such as bile, urine. Besides glutathione conjugation, the other pathways are amino acid conjugation, methylation,  sulfation,  sulfoxidation, acetylation and glucuronidation. These enzyme system need nutrients and metabolic energy to function. If liver cells do not function properly, phase 2 detoxification slows down and increases the load of toxic intermediates. 

FOR EXAMPLE : Barbiturate, such as phenobarbital, is a drug that acts as a central nervous system depressant, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia.     

Sensations from skin, muscles, tendons and bones are initiated by variety of somatic receptors.

Sensations from skin, muscles, tendons and bones, joints - somatic sensations-  are initiated by variety of somatic receptors collectively called somatic receptors. Some of these receptors respond to mechanical stimulation of  the skin, hair and underlying tissues, whereas others respond to temperature or chemical changes. Distinct receptors exist for heat, cold, touch, pressure, limb portion or movement and pain.
Touch and pressure : Stimulation of different types of mechanoreceptors in the skin lead to a variety of touch and pressure experience - hair bending, deep pressure, vibrations and superficial touch for example. These mechanoreceptor are highly specialized neuron endings encapsulated in elaborate cellular structures. The neuron endings are linked to networks of collagen fibers within a capsule that is often filled with fluid. These networks transmit the mechanical tension in the fluid filled capsule to ion channels in the neuron endings and activate them.
 Posture and Movement : The senses of posture and movement are complex. The major receptors responsible for these senses are the muscle-spindle stretch receptors and golgi tendon organs. These mechanoreceptor occur in skeletal muscles and the fibrous tendons that connect them to bone . Muscle spindle stretch receptors respond to both the absolute magnitude of muscle stretch and to the rate at which the stretch occurs, and golgi tendons monitor muscle tension. 

RENAL FAILURE

Also known as kidney failure, is a medical condition in which the kidneys no longer work. It is further divided into acute kidney failure (cases that develop rapidly) and chronic kidney failure (those that are long term). Causes of kidney or renal failure include low BP, blockage of urinary tract, certain medication, muscle breakdown and hemolytic uremic syndrome. Causes of chronic type include diabetes, high BP, nephrotic syndrome and polycystic kidney diseases. Diagnosis of chronic disease is often based on a combination of factors such as decreased urine production or increased serum creatinine. Diagnosis of chronic disease is typically based on GFR of less than 15. Symptoms of this condition include nausea, vomiting, blood in urine, pressure or difficulty in urinating, less frequent urination. The treatment given is a low protein diet, dialysis and minimizing exposure to nephrotoxins such as intravenous contract.

LIVER CIRRHOSIS

Cirrhosis is a condition in which the liver does not function properly due to long term damage. This damage is characterized by the replacement of normal tissues by scar tissue. Typically, the disease develops slowly over months or years. As the disease woruns, a person may become tired, weak, itchy, have swelling in lower legs and have fluid build-up in the abdomen.
Cirrhosis is most commonly caused by alcohol, hepatitis B, hepatitis C and non-alcoholic fatty liver diseases.
The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma. This scar tissue blocks the portal flow of blood through the organ, raising blood pressure and distributing normal function. As this cascade of processes continues, fibrous tissue bands separate hepatocyte nodules, which eventually replace the entire liver architecture leading to decreased blood flow throughout. The spleen becomes congested and portal hypertension is responsible for the most severe complications. A healthy diet is encouraged and alcohol consumption is strictly prohibited as a part of treatment.

PULMONARY DISTRESS

It is also known as Acute respiratory distress syndrome (ARDS) is a medical condition occuring in critically ill patients characterized by widespread inflammation in the lungs. ARDS is not a particular disease, rather it is a clinical phenotype which may be triggered by various pathologies such as trauma, pneumonia and sepsis. The hallmark of pulmonary distress is diffuse injury to cells which form the barrier of the microscopic air sacs of the lungs, surfactant dysfunction, activation of the innate immune system response etc. In effect, this condition impairs the lungs ability to exchange O2 and CO2 with the blood across a thin layer of the lungs alveoli.
Pulmanory distress may be seen in the setting of pneumonia or sepsis, or severe inflammation. It is a form of fluid accumulation in the lungs not explained by heart failure. It is typically provoked by an acute injury to the lungs that results in flooding of alveoli. Neutrophils and some T-cells quickly migrate into the inflammed lung tissue and contribute in the amplification of the condition. It is usually treated with mechanical ventilation in the ICU.    

JAUNDICE

The buildup of very high pressure in a blocked common bile duct is transmitted back to the liver and interferes with the further secretion of bile. As a result, bilirubin, which is normally secreted into the bile by uptake from the blood in the liver, accumulates in the blood and diffuses into tissues, producing a yellowish coloration of the skin and eyes known as jaundice.
Causes of jaundice vary from non-serious to potentially fatal. Levels of bilirubin in blood are normally below 1.0 mg/dL and levels over 2-3 mg/dL typically results in jaundice. High bilirubin is divided into two types: indirect or unconjugated and conjugated or direct.
Conjugated bilirubin can be confirmed by finding bilirubin in the urine. High unconjugated bilirubin may be due to excess red blood cell breakdown, genetic conditions (Gilbert's syndrome), newborn jaundice, or thyroid problems. It may be due to liver diseases such as cirrhosis or hepatitis, infections, medications or blockage of the bile duct. Blockage of the bile duct may occur due to gallstones, cancer or pancreatitis.
Hyperbilirubinemia due to the unconjugated fraction, may cause bilirubin to accumulate in the gray matter of CNS, potentially causing irreversible neurological damage leading to a condition known as kernicterus.
At birth, the liver's capacity to secrete bilirubin is not fully developed. During the first few days of life, this may result in hemolytic jaundice of the newborn. Excessive accumulation of bilirubin during the neonatal period carries a risk of damage to CNS.
Treatment of jaundice is typically determined by the underlying cause. If a bile duct blockage is present, surgery is typically required. Among newborns, it is treated with phototherapy or exchanged transfusion. 

DIALYSIS

The general term dialysis means to separate substances using a permeable membrane. The clinical techniques used to perform the kidney's functions are hemodialysis and peritoneal dialysis. 
The artificial kidney is an apparatus that utilizes a process termed hemodialysis to remove wastes and excess substances from the blood. During hemodialysis, a blood is pumped from one of the patient's arteries through tubing that is surrounded by special dialysis fluid. The tubing then conducts the blood back into the patient by way of a vein. The dialysis tubing is generally made of cellophane that is highly permeable to most solutes but relatively impermeable to protein and completely impermeable to blood cells.- characteristics quite similar to those of capillaries. The dialysis fluid is a salt solution with ionic concentrations similar to or lower than those in normal plasma, and it contains no creatinine, urea, or other substances to be completely removed from the plasma. As blood flows through the tubing, the concentrations of nonprotein plasma solutes tend to reach diffusion equilibrium with those of the solutes in the bath fluid. For example, if the plasma potassium conc. of the patient is above normal, potassium diffuses out of the blood across the cellophane tubing and into the dialysis fluid. Similarly, waste products and excesses of other substances also diffuses into the dialysis fluid and thus are eliminated from the body.
Another way of removing excess substances from the blood is peritoneal dialysis, which uses the lining of the patient's own abdominal cavity (peritoneum) as a dialysis membrane. Fluid is injected, via a needle inserted through the abdominal wall, into this cavity and allowed to remain there for hours, during which solutes diffuse into the fluid from the person's blood. The dialysis fluid is then removed by reinserting the needle and is replaced with new fluid. This procedure can be performed several times daily by a patient who is simultaneously doing normal activities.