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DO YOU KNOW?-3

DO YOU KNOW?-3
CREATININE CHEMISTRY

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Sunday, 24 July 2016

CNS-PART-VII-ANESTHETICS-CONTINUED...

ANESTHETICS-Contd...


INTRAVENOUS ANESTHETICS:-

The followings are the general anesthetics that are unlike inhalers that can be given through the intravenous route to produce anesthesia.

Classes of I.V. Anesthetics:-

1.Barbiturates
2.Benzodiazepines
3.Opioids
4.Other Hallucinogens and Dissociative agents

1.BARBITURATES:-


As we have already known barbiturates are derivatives of barbituric acid either as salts or esters(a product with any alcohol). But salts are mostly used in practice.
Thiopental
An ultra short-acting barbiturates widely used as an adjunct with inhalation anesthetics or with any other.
It rapidly induces anesthesia in combination with other anesthetics. It has a fast onset of induction, and anesthesia occurs within 10 to 30 seconds after the injection.

Mechanism:-

As a barbiturates thiopental acting by binding at GABA-A receptor and thereby opening the chloride ion influx to produce hyperpolarization of the neuron beyond the threshold so that an action potential is nullified and the neurons are inhibited to relax.
The ultrashort duration of activity is accounted for by the high lipid solubility of thiopental which leads to the quick entry of the blood-brain barrier into the CNS and produces the anesthetic effect.
The effect lasts so rapidly because of the lipid solubility which results in rapid elimination from the CNS and the drug gets redistributed into the highly vascularised other muscles and fat and the effect lasts. 

Metabolism:

Thiopental is metabolized in the liver more slowly than its redistribution and hence after a prolonged infusion the recovery may be slow.
100% drug is metabolized in the liver.
Thiopental is a teratogenic drug and hence it can cross into the placenta.
Thiopental, after metabolized, is excreted in the urine.

Side Effects:-

1.On Cardio Vascular System:-
Thiopental lowers B.P. and cardiac output. Peripheral vascular resistance is not affected.
2.On Respiratory System:-
Thiopental depresses the respiratory center in the brain.
It decreases carbon dioxide response to the center and causes hypoxia. It reduces cerebral blood flow and thereby decreases the oxygen demand by the brain. This effect is useful in treating patients who has cerebral edema.
3.Laryngospasm
4.Bronchospasm
5.Acute porphyric crisis by inducing the synthesis of delta-aminolevulinic acid in the liver.




Saturday, 23 July 2016

CNS-PART-VII-ANESTHETICS-Contd..

ANESTHETICS-Contd...


General Anesthetics-1.Inhalers:-

1.Halothane
2.Enflurane
3.Isoflurane
4.Desflurane
5.Sevoflurane
6.Nitrous Oxide

MINIMUM ALVEOLAR CONCENTRATION(MAC):-


The concept of MAC is used to define the potency of the inhaler anesthetics.
MAC is the minimum alveolar concentration of the anesthetics necessary to suppress movements among 50% of the individuals challenged by a Standardised Skin Surgical Stimulus at a steady-state(assuming at a minimum concentration for 15 minutes remained in the alveolar chamber) at 1 atmosphere (at sea level) 
The potency is calculated as an inverse proportion to the MAC. That means the greater the MAC for an agent the higher the amount of the agent needed to eliminate the movements of the individual in constant time and the lower the potency. (e.g.-Nitrous Oxide)
The MAC of a safer agent can be reduced by concomitant administration of some adjuncts such as analgesics or opioids.

1.HALOTHANE


The first generation halogenated anesthetic available in the market. Chemically it is Bromo- chlorotrifluoromethane.
It is a colorless, pleasant smelling halogenated ethane, unstable towards the light, and is stored in dark brown colored bottle mixed with thymol as a stabilizer. It is the only brominated anesthetic and because of its bromine content which increases its toxicity it is mostly replaced in developed countries by many modern inhalers.

Clinical Use:-

Because of its pleasant smell and lack of liver toxicity it is still used in pediatrics.

Kinetics and Metabolism:-

80% of the drug is eliminated in the expired air unchanged. The remaining 20% is metabolized in the liver to trifluoroacetic acid which may rarely cause (1 in 10,000) cause liver injury. Trifluoroacetic acid is excreted by the kidneys.

MAC of Halothane

MAC = 0.75%

Side Effects:-

1.Arrhythmia (by sensitizing the heart muscles to catecholamines.)
2.Decrease heart rate
3. Decrease cardiac output.
4.Hypotension with reduced peripheral resistance
5.Malignant hyperthermia-a common reaction of inhaled anesthetics composed of higher temperature, metabolic acidosis, tachycardia, and accelerated muscle contraction. Malignant Hyperthermia can be controlled by the administration of Dantrolene.
6.Liver toxicity particularly in adults (Halothane Hepatitis)

2.ENFLURANE:-


Enflurane is used to induce rapid anesthesia.

Metabolism and Kinetics

Approximately 2% of the drug is metabolized to a fluoride ion which is then excreted by the kidney.
The 98% remained is eliminated by expired air unchanged.

MAC of Enflurane

MAC = 1.6%

Side Effects:-

1.Cardio-Vascular-Decreased heart rate, Peripheral vascular resistance, and B.P.
Unlike halothane enflurane does not cause arrhythmias as it does not sensitize the myocardium to catecholamines.
2.Kidney damage by the fluoride ion after prolonged uses
Enflurane is contraindicated to those who have already kidney failure.

3.ISOFLURANE


Almost 100% of this drug is eliminated by expired air and is very safe as it does not pass into the system unless a fraction.
MAC=1.4%

Cardiovascular Effects

1.Increased heart rate
2.Decrease B.P by decreasing peripheral resistance
3.Malignant hyperthermia
Isoflurane does not sensitize the myocardium to catecholamines and hence does not cause 
arrhythmias.

4.DESFLURANE


Very similar to isoflurane this drug also 100% eliminated through expired air unless a fraction can enter into the system on prolonged use.
MAC = 6%

Side Effects:-

1. Cardiovascular effects are similar to isoflurane
2.Higher risk of Malignant Hyperthermia

5.SEVOFLURANE


Metabolism is very similar to enflurane as a small quantity can enter into the system and the remaining portion is eliminated by the expired air unchanged. But it differs from enflurane it does no cause nephrotoxicity as it is hypothesized that it is not excreted by the kidneys.
MAC=2%

Side Effects

1.Cardiovascular-Increase heart rate, lower B.P by reducing peripheral resistance,
It does not cause arrhythmias as with enflurane.
2.Malignant hyperthermia.

6.NITROUS OXIDE 


As it is a weaker anesthetic it is mostly used as an adjunct to induce anesthesia.
It can be administered either by inhalation or by I.V.
Nitrous oxide is expelled out without change as it is not metabolized.
MAC=100%, very weak as even if 100% nitrous oxide is given to the patients it does not attain the stage of surgical anesthesia.

Toxicity

1.Minimal cardiovascular effects
2.Bone marrow suppression if used for a long time
3.Neuropathies.

Contraindication

Pneumothorax-a condition in which there are closed cavities in the lung and the gas cannot escape out and will diffuse within the cavities to increase internal cavity pressure.

Precaution

The patient must be administered with sufficient oxygen during the recovery phase as nitrous oxide from the blood will diffuse into the alveoli and entirely replace the oxygen.






CNS-PART-VII-ANESTHETICS

ANESTHETICS-INTRODUCTORY




Anesthesia can be defined as a medical state which is composed of one or more of the following components of states such as analgesia(relief from the pain), state of muscle relaxation(paralysis), and loss of consciousness.
The patient who is given an anesthetic agent is said to be Anesthetized.
A nursing staff who is not a professional if give an anesthetic to a patient is known as an Anesthetist as in U.S.and North America (including Canada)
A professional who gives an anesthetic to a patient is known as Anesthesiologist.
Medical anesthesia can be divided into two types as 1. General and 2.Local.
General anesthetics are usually given by inhalation or through intravenous.
Local anesthetics are generally injected at the operative site to block the nerve conduction.

Stages of General Anesthesia


1.Analgesia or Stage of Induction:-

Loss of senses to feel pain. Consciousness is retained. The patient can talk.

2.Stage of Excitation:-

Delirium, a mental state of excitement, restlessness, incoherence with sweat.

3.Stage of Surgical Anesthesia:-

The patient is unconscious sufficiently to conduct surgery on him. Regular respiration is safely retained, with muscle paralysis and decreased vasomotor responses to painful impulses.

4.Stage of Medullary Paralysis:-

An irreversible stage if unattended, in which respiratory depression followed by coma and death occurs.
The pharmacokinetics of drugs plays an important role in attaining the different stages.
A slow-acting anesthetic like ether can give a well-distinguished stage. A fast-acting anesthetic would lead to the rapid occurring of the stages.
Induction of Anesthesia can be well defined as from the time of administration of the anesthetic 
up to the achievement of the state of surgical anesthesia.
The induction goal can be achieved as quickly as the drug reaches the central nervous system (CNS)
The complication of inducing anesthesia can be avoided by first injecting an ultra fast-acting and ultra short-lived anesthetic such as Propofol through I.V. so that the patient will rapidly progress through the first and second stages so that the anesthesia can easily enter into the state of surgical anesthesia.
The recovery from the anesthesia is the reverse process of induction. This depends on how fast the drug is removed from the CNS.
There are five factors influence the inhalation anesthesia as follows:-
1.Solubility
2.Pulmonary ventilation
3.The partial pressure of the inhaled drug
4.Alveolar blood flow.
5.Arteriovenous concentration gradient.
1. Solubility-This factor affects the rate of induction by the blood-gas partition coefficient. A low coefficient implies low solubility and a low soluble agent require fewer molecules to raise the partial pressure of the agent in the blood. Thus the equilibrium between the arterial partial pressure and the alveolar partial pressure is attained rapidly which leads to rapid induction. Recovery is similarly hastened by discontinuing the agent.
2. Pulmonary Ventilation-The rate and depth of lung ventilation (the minute ventilation) affect the rate of increase in the partial pressure of the anesthetic in the blood. An increase in minute ventilation results in an increased amount of agent and this effect is very important for agents with low solubility because they require a higher amount of the agent to attain equilibrium.
3. Partial Pressure-An increased concentration of the drug in the inhaled air mixture leads to higher concentration in the alveoli and thus increases the arterial partial pressure of the drug. Therefore a greater concentration is given initially to speed induction and then it is reduced to a maintenance level.
4. Alveolar Blood Flow-Increased blood flow causes more rapid uptake of the agent which attain quicker effect on the CNS.
5. Arterio-Venous Concentration Gradient-This depend on the tissue uptake of the drug. If more tissue uptake of the agent is there then there is a decrease venous concentration of the agent, which leads to a longer time to achieve an equilibrium between the arteriovenous concentration.

Factors Affecting Tissue Uptake Of the Anesthetics:-

1.Blood Partition Coefficient
2.Rate of blood flow to the tissue
3.Concentration Gradients between artery and vein.
Highly perfused tissues like the brain, heart, liver, and kidneys will exert greater influence on the arteriovenous concentration gradient.
Skin and skeletal muscles are low perfused and hence they exert a low influence.

Mechanism

The mechanism of action of the GA depends upon the availability of the agent in molecules. All anesthetics are assumed by acting on the action potential by nullifying them through increasing the threshold. Also acting by inhibiting the entry of sodium ion by decreasing the membrane permeability to them. The mechanism is not clear but on assumption, only.No receptors are involved inbound up with anesthetics.

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Thursday, 21 July 2016

CNS-ANTICONVULSANTS-PART-VI-Contd..

ANTICONVULSANTS-Contd..

 ANTICONVULSANTS

4.Primidone (Mysoline)


It is chemically related to barbiturates and also it works very similar to phenobarbital.
Primidone is used in adults as an alternative medicine to treat grand mal and partial seizures.
It can be given orally
Primidone is metabolized in the liver to little phenobarbital with a compound of phenyl ethyl melon amide (PEMA) as a major metabolite.
Primidone is mostly excreted in the urine as unchanged(53%) along with its metabolites PEMA (43%) and a little phenobarbital(4%).

Side Effects

Very similar to phenobarbital
1.Sedation
2.Ataxia
3.Nausea
4.Vomiting 
5.Drowsiness

5.Valproic Acid (Depakene)


It is medically used as a sodium salt.
It is the drug of choice in the treatments of myoclonic and absences seizures.
It is also used to relieve migraine and bipolar psychoses.

Mechanism

Works by prolonging the inactive state of Na+(sodium) channels and increasing the cerebral GABA concentration.
It can be given orally and it is well absorbed thereby.
After absorption 90% of the drug is bound to plasma proteins.

Metabolism

Extensively metabolized in the liver by the CYP-450 system and hence care and dosage adjustment should be considered if taken along with any medicine which affects the CYP-450 system either by induction or suppression.
This drug anyhow is not an inducer of the CYP-450 system.
Excreted in the urine as its metabolites (97%) with a little unchanged.

Side Effects

1.Liver damage
2.Nausea and Vomiting
3.Ataxia
4.Tremor
5.Lethargy

Use in Pregnancy and Lactation

Safety is not well established.
If taken during the first trimester there are high possibilities of neural tube damages.

6.Ethosuximide


It is the drug of choice for absences (Petit mal)
Chemically it is a succinimide derivative.

Mechanism

It is a calcium channel inhibitor and inhibits the influx of Ca++ into T-type channels of thalamic neurons and thereby it regulates abnormal electrical conduction in the brain.

Metabolism and Kinetics

The drug is well absorbed orally.
It is mostly metabolized in the liver by CYP-450 system
It is not inducing the enzyme

Side Effects

1.Dizziness
2.Agitation
3.Nausea
4.Vomiting
5.Diarrhea
6.Mental confusion
7.Liver damage
6.Kidney damage
Blood dyscrasias-Leukopenia, Aplastic anemia, and thrombocytopenia in sensitive patients
7.Allergic skin reactions-Stevens-Jonson syndrome

7.Benzodiazepines


Benzodiazepines are already presented in last posts (Anti-anxiety drugs) well in details however here we see some of them used as anticonvulsants.
1.Diazepam (Valium)
2.Clonazepam
3.Clorazepate

Therapeutics

Diazepam can be given as an intravenous injection in the emergency situation of Status Epilepticus.
Clonazepam can be used in treating myoclonic seizures in children
Clorazepate may be used for partial seizures (simple or complex) in combination with phenytoin or carbamazepine.

Side Effects

Even though the side effects are mild but we should take care of the following effects:-
1.Drowsiness
2.Respiratory depression
3.Cardiac depression.

8.Gabapentin


Gabapentin is chemically a GABA derivative.
It is used to treat partial seizures both simple and complex.
It is acting by increasing GABA secretion in the CNS.
It is excreted unchanged in the urine.

Side Effects

1.Ataxia
2.Somnolence
3.Fatigue

9.Lamotrigene


It is used to treat partial seizures in adults in combination with other drugs.

Mechanism

It is acting by blocking voltage dependant active sodium channels and thereby preventing the sustained firing of action potentials.
The drug is metabolized in the liver

Side Effects

1.Dizziness
2.Blurred vision
3.Rash
4.Urinary retention
5.BPH.




CNS-PAR-VI-ANTICONVULSANTS-Contd..

ANTICONVULSANTS

ANTICONVULSANTS

Seizures can be controlled if not completely treated by various drugs known as Anticonvulsants mentioned below.
1.Phenytoin (Dilantin)
2.Carbamazepine
3.Phenobarbital
4.Pirimidone
5.Valproic Acid
6.Ethosuximide
7.Benzodiazepine
8.Gabapentin
9.Lamotrigine

1.Phenytoin (Dilantin)


Phenytoin is used in treating tonic/clonic seizures and partial seizures. Chemically it is a hydantoin derivative.
Phenytoin is not effective in treating Absences.
Used in treating Status Epilepticus by intravenous route as an adjunct with diazepam.
Phenytoin is acting by blocking voltage-gated sodium channels and thereby prevent the neurons to get depolarized sufficiently to excite an action potential.

Kinetics and Route

Phenytoin can be administered either by intravenous and oral routes.
Since the absorption through the GI system is slow the oral route may have a longer gestation period to reach the required effects pharmacodynamically.
In contrast the intravenous route is rapid and reaches the required effect within minutes and lasts for 24 hours.
Phenytoin is metabolized in the liver by hydroxylation by the endometrial CYP-450 enzymes such as CYP-3A4 and CYP-2-C19. Watch for toxicity if these two enzymes induced by phenytoin get consumed completely.

Side Effects

1.Gingival Hyperplasia-A major toxicity in which there is a painful enlargement of teeth gum. Folic acid supplementation is recommended
2. Megaloblastic Anemia-Because phenytoin interferes with folic acid metabolism. Folic acid supplementation is required.
3.Hirsutism-Unwanted growth of hair.
4.Diminished deep tendon reflexes in the extremities.
5.Stevens-Jonson Syndrome-Severe skin rashes with cell necrosis with fever and usually a life-threatening reaction.
6.CNS depression
7.Endocrine reactions-Diabetes Insipidus(Watery Urine), Hyperglycemia, glycosuria, and osteomalacia(bone weakness)

Drugs Interactions

The following three drugs are competing with phenytoin for the enzyme CYP-450 successfully, by decreasing its metabolism and thereby increasing its plasma concentration.
1.Chloramphenicol-Anti typhoid
2.Isoniazid-Anti T.B.
3.Cimetidine.-Antihistamine to reduce hyperacidity
Dosage adjustment should be necessary when giving Phenytoin concomitantly with the above drugs.
Carbamazepine by inducing rapid metabolism of phenytoin decreases its plasma concentration. Dosage adjustment of phenytoin is important accordingly if given along with carbamazepine.

Use in Pregnancy and Lactation

Phenytoin is a teratogenic drug as it can cross into the placenta and milk and hence it should not be given during pregnancy and lactation as serious reactions such as prenatal growth deficiencies, congenital malfunctions such as the cleft palate and heart malfunctions may occur.

2.Carbamazepine (Tegretol)


Carbamazepine is a neuroleptic drug that can be used as an antipsychotic agent and to relieve neuropathic pain.
Carbamazepine is effective as well as phenytoin and valproic acid in the treatment of grand mal and petit mal as a drug of choice but not in treating absence seizures and myoclonic seizures.

Mechanism of Action

Very similar to phenytoin

Metabolism and Kinetics

Similar to phenytoin but given orally only 
metabolized by the CYP-450 hepatic enzyme system similar to phenytoin but successfully compete with it.

Drug Interactions

The following drugs are competing successfully for CYP-450 enzyme with greater affinity than carbamazepine and hence they increase the carbamazepine plasma level by inhibiting its metabolism.
1.Erythromycin-Antibiotic
2.Isoniazid-Anti-T.B.
3.Propoxyphene-A pain killer
4.Verapamil-Calcium Channel Blocker for B.P
5.Cimetidine-A histamine H-2 receptor blocker used for reducing acid secretion in the stomach.
Hence dosage should be adjusted accordingly.

Side Effects

1. Acutely can cause respiratory depression and coma
2.Liver toxicity-Require frequent liver tests.
3.Aplastic anemia-Lack of blood cells formation due to bone marrow and erythropoietic stem cells damage
4.Agranulocytosis-A deficiency of granulocytes in the blood.
5.Drowsiness
6.Ataxia-Loss of full control of body movements.
7.Nystagmus-Involuntary movements of eyeballs.

3Phenobarbital (Luminol)


Chemically phenobarbital is a barbituric acid derivative.

Mechanism

Phenobarbital enhances the action of GABA at its receptors and thereby inhibiting the neuronal excitation.

Uses

1.Drug of choice for treating febrile seizures.
2.Used to treat grand mal in children
3.Partial seizures

Metabolism and Kinetics

Absorbed well by the oral route. Three fourth of the drug is metabolized in the liver.
It is a potent inducer of the CYP-450 enzyme in the liver.
Care should be taken when given along with any drug metabolized by or inducing this enzyme.
The metabolites are excreted in the urine.

Side Effects

1.Sedation
2.Nystagmus
3.Psychotic reactions
4.Allergic reactions such as serious Stevens-Jonson syndrome
5. Overdosage may result in respiratory depression, coma, and death.
Will be continued.....






Wednesday, 20 July 2016

CNS-PART-VI-ANTICONVULSANTS

SEIZURES-TREATMENTS-INTRODUCTORY

ANTI CONVULSANTS

Seizures are pathological conditions in which the patient frequently suffered by abnormal synchronized electrical depolarization of neurons in the central nervous system.The episodes are commonly called as convulsions and more technically by the name seizures.
Seizures are generally caused by the following factors:-
1.Idiopathic
2.CNS Infecions
3.Fever
4.Metabolic Defects
5.Cerebral Trauma

Types Of Seizures

1.Partial
2.Generalized tonic/clonic
3.Status Epilepticus
4.Absence
5.Febrile
6.Myoclonic

1.Partial Seizures

 

A partial seizure is the one in which abnormal discharges occur from a focal area within the brain.

a)Simple Partial Seizure 

In this type a focal neurological symptom involves that can be sensory like visual or auditory hallucinations,motor or psychomotor.Conciousness always retained.

b)Complex Partial Seizures

In this type the initial focus of abnormal discharge spreads so that patient will loose conciousness and have post seizure confusions.Symptoms can include coordinated motor activity and olfactory hallucinations.
Complex partial seizures most probably originates in the temporal lobes.

2.Generalized Tonic /Clonic(Grand mal)

This type of seizures originates from the entire cerebral cortex(The whole brain)

a)Tonic Phase

The symptoms are loss of conciousness,rigidity,and loss of motion and urine control

b)Clonic Phase

The symptoms are jerking of the entire body.
Grand mal can develop at any time even from a partial seizure if unattended. 

c)Status Epilepticus

 

Grand mal with tonic seizure can develop this state of medical emergency which contains continuous seizures without regaining conciousness.

3.Absences (Petit mal)

These types of seizures usually occur in children of age 2 to 12 years of age.
They are characterized by very brief (10 seconds) loss of conciousness with the episodes of stop doings and stare or facial twisting.
Following the attack the child become immediately alert and is seldom even aware that it has occured.

4.Febrile Seizures

Usually occur in small children
They loss less than 10 minutes.
Sympoms are usually a fever without a cause or infection.

5.Myoclonic Seizures

The usual symptoms are sudden short episodes of either local or generalized muscle contractions.
They can occur at any age.
They are associated with very rare variety of hereditary neurodegenerative disorders.

6.Epilepsy

Epilepsy is a group of chronic recurrent seizures with periods of conciousness.This condition is usually affecting a 1% population.


Tuesday, 19 July 2016

CNS-PART-V-MANIA-TREATMENTS

MANIA-TREATMENTS


Mania is a kind of mental disorder just opposite to depression in which there are uncontrolled mood elevation,with practically impossible grandiose ideas,expansiveness,pressurised talks,flow of ideas,decreased sleep,restlessness,and over activities.

Schizophrenia and other bipolar affective diseases may induce mania into a person.

Anti-Manic Drugs:-


1.Lithium-Drug of choice
2.Antiepileptics-Valproic acid,and carbamazepine are he best choices.We will discuss about these drugs later on under a separate post wih the heading Antiepileptics.

Lithium:-

Lithium is a metallic basic element with a light alkaline property and mostly available in medicine as slow and controlled release carbonate.


Mechanism

The mechanism of action is still not clear but thought to affect the enzyme inositol-I-phosphate which affects neurotransmitters.

Clinical Use

Mostly to control both positive(schezophrenia and mania) and negative (Depression) bipolar mental disorders.Litghium is a primary choice of manic disorders but can be used as an adjuant in the treatments of schezophrenia and depression.

Kineics

Well absorbed orally and excreted through the kidneys.

Contraindications

Because lithium can cross into the placenta and milk it is highly contraindicated during pregnancy and lactation.

Side Effects

1.In acute intoxication severe tremor,ataxia,seizures,and confusion leads to coma ma may occur.
2.Diabetic insipidus (Lithium is a potential inhibitor of Anti Diuretic Hormone-See he video below)

3.Weight gain
4.Stomach pain and vomiting and diarrhea
5.Thyroidal dysfunction-Hypothyroidsm
6.Depression of T-waves in ECG
7.Leucocytosis (Elevation of WBC count to above normal)

In general lithium has a very narrow therapeutic index and hence all lithium medication should be taken under a doctor's strict supervision.

Drug Interaction


Since lithium competes with sodium in absorption and as well as in tubular elimination effectively  by inhibiting the antidiuretic hormone  and excessive intake of sodium may cause a dip in lithium plasma level.
Thiazide diuretics may enhance sodium excretion and thereby elevate lithium plasma level.

Toxicity Antidotes

1.Diuretics other than thiazides may decrease plasma levels of lithium by increasing its excretion.Sodium bicarbonate can be used effectively.
2.Hemo or peritonial dialysis.

BRAIN MAPPING

BRAIN MEANDERING PATHWAY                                                                         Maturity, the thinking goes, comes with age...