Brain State Affects Memory Recall

A paper describing the work is published June 13 in the journal Proceedings of the National Academy of Sciences.
"It's been assumed that the process of retrieving a memory is cued by an external stimulus," said Charan Ranganath, professor at the UC Davis Center for Neuroscience and Department of Psychology. "But we found that the levels of brain activity before items came up were correlated with memory."
Graduate students Richard Addante and Andrew Watrous; Ranganath; Andrew Yonelinas, professor of psychology at the UC Davis Center for Mind and Brain; and Arne Ekstrom, assistant professor of psychology at the Center for Neuroscience, measured a particular frequency of brainwaves called theta oscillations in the brains of volunteers during a memory test.
Theta waves are associated with a brain that is actively monitoring something, Ranganath said. For example, rats show high theta waves while exploring a maze.
In the memory test, the volunteers had to memorize a series of words with a related context. They later had to recall whether they had seen the word previously and the context in which the word was seen.
High theta waves immediately before being prompted to remember an item were associated with better performance.
The work goes against the assumption that the brain is waiting to react to the external world, Ranganath said. In fact, most of the brain is busy with internal activity that is not related to the outside world -- and when external stimuli come in, they interact with these spontaneous patterns of activity.
It's not clear whether it is possible to deliberately put your brain into a better state for memory recall, Ranganath said. The laboratory is currently investigating that area -- with the hope that it might lead to better treatments for memory loss.

Quinapril Hydrochloride




Credit: pfizer.com

It is an ethyl ester of non-sulfhydryl compound, quinaprilat.

Mechanism of Action:
It is an angiotensin converting enzyme inhibitor (ACE) inhibitor. ACE is an enzyme that converts the angiotensin-I to angiotensin-II.

Pharmacokinetics:
Peak plasma concentration of quinapril hydrochloride is found within 1 hour after administration. The extent of absorption is about 60%.

After absorption about 38% of quinapril is converted into its major active metabolite i.e. quinaprilat. About 97% of quinapril or quinaprilat is bound to plasma proteins.
Uses:
It is used in hypertension and congestive heart failure.

Contraindications:

ACE inhibitors are contraindicated in second and third trimester of pregnancy as they may cause injury and sometimes death of the developing fetus.

Brand Name:

Accupril
Accuretic (Quinapril Hydrochloride and hydrochlorothiazide)

Loop Diuretics (Some Questions)

Q:1. Why loop diuretics are often called as high ceiling diuretics?

Ans: They are often called as high ceiling diuretics because they are highly effective in inhibition of coupled transport of Na+/K+/2Cl- through luminal membrane of thick ascending limb of Henle’s loop as ascending limb results in reabsorption of 20-30 percent of NaCl which has already been filtered.

Q:2. Compare loop diuretics and thiazide diuretics.
Ans:
Differences between loop diuretics and thiazide diuretics:
1. Loop diuretics are more effective than thiazide diuretics.
2. The onset of action and duration of action of loop diuretics is shorter than the thiazide diuretics.
3. Loop diuretics show efficacy even in the presence of electrolyte and acid base disturbance unlike thiazide siuretics.
4. Loop diuretics are not good than thiazide diuretics against uncomplicated mild to moderate hypertension.
5. Loop diuretics increase renal blood flow whereas thiazide diuretics have the ability of lessening renal flow of blood.
6. Loop diuretics tend to increase Ca2+ in urine whereas thiazide diuretics cause a decrease in Ca2+ in urine.

Similarities between loop diuretics and thiazide diuretics:
1. They have almost identical side effects.

Loop diuretics

These diuretics act on the medullary and cortical (thick) ascending limb of Henle’s loop, although to some extent they also act on the proximal and distal tubules. They are more effective than thiazide diuretics.


Mechanism of action:

They inhibit Na+/K+/2Cl- symport on luminal membrane of thick ascending limb of Henle’s loop causes
a. Decreased reabsorption of NaCl
b. Lessen the normal lumen positive potential that derives from K+ recycling resulting in increased excretion of Mg2+ and Ca2+

They tend to decrease renal vascular resistance and resulting in increased renal blood flow.

They also promote prostaglandin synthesis. Prostaglandins also have some role as diuretic.

Therapeutic uses:

They produce large amount of urine.
1. Acute pulmonary edema of heart failure
2. Acute pulmonary edema (When given IV)
3. Impaired renal function
4. Hypercalcemia
They causes an increased tub ular Ca2+ excretion.

5. Hyperkalemia
6. Increased intracranial pressure
7. Diabetic nephropathy
8. Hypertensive situations

Pharmacokinetics:
They have short duration of action of approximately 2-4.5 hours. They are eliminated by glomerular filtration and tubular secretion. Their half life depends on the renal function. They are excreted through urine.

Adverse effects:
They have almost similar adverse effects as those of thiazide diuretics. But they may cause severe electrolytic imbalances and water depletion.

• Hypersensitivity reactions:
Skin rash, interstitial nephritis

• Water, electrolytes and acid-base balance:
Voiding of extra water, Hypercalcemia, hyponatremia, Hypomagnesemia,

Hypokalemic metabolic alkalosis:
More Na+ at the collecting tubule results in more K+ exchange with Na+ in the tubule. This results in hypokalemia.

More K+ loss results in more H+, resulting in hypokalemic alkalosis.

This can be reduced by the use of potassium sparing diuretics or potassium rich foods.

• Blood:
Transient granulocytopenia and thrombocytopenia

• Muscles:
Severe pain and tenderness in patients with renal failure

• Miscellaneous:

Ototoxicity:
Affect on hearing.

Hyperuricemia:
Blocks secretion of uric acid by competitively working at renal and biliary secretary systems. This results in gouty attacks.

Acute hypovolemia:
They cause a reduction in blood volume. This results in hypotension, shock and cardiac arrhythmias.

Contraindications:
It is contraindicated in patients with hepatic coma, hypokalemia, hypotension and hypersensitivity to sulfonamides.

Interaction:
Indomethacin interferes with the production of prostaglandin synthesis, so that is why causes some inhibitory effects on diuretic action of loop diuretics.

Chlorothiazides

Chlorothiazed is the prototype of thiazide diuretics. This is used widely, orally effective and well tolerated.

They are effective in edema of hepatic cirrhosis and heart failure.

Pharmacokinetics:
Onset of action is 2 hours after oral administration and 10-15 minutes after IV administration. Its duration of action is about 4-12 hours.

Thiazides and related agents

They are developed in efforts to develop more potent carbonic anhydrase inhibitors. So, that is why they are structurally similar to the carbonic anhydrase inhibitors.

Mechanism of action:
1. They cause the inhibition of Na+/Cl- cotransporter reabsorption from luminal side of epithelial cells in
    a. early distal convoluted tubule and also
    b. in late proximal tubule but not to a lesser degree.

This causes an increase in the concentration of NaCl in the tubular fluid resulting in urinary excretion of sodium and water.
2. They also cause an increase in Ca2+ reabsorption in distal convoluted tubule that may be due to lowering of cell Na+.
3. They also increase excretion of chloride, potassium and to some extent bicarbonate ions.

The excretion of Na+ and Cl- result in a very hyperosmolar urine.

4. They also directly relax arteriolar smooth muscle and cause a decrease in peripheral vascular resistance, resulting in continued hypotensive effect.

The hypotensive effect is also attributed to the decreased sodium level and as a result in the reduction of plasma volume which leads to decreased cardiac output.

5. They also decrease glomerular filtration rate.
Thiazide diuretics interfere with the dilution of the urine but not with the concentration of the urine due to the site of action.

Therapeutic uses:
1. Mild to moderate cases of Hypertension:
Three to seven days of continued treatment leads to lower peripheral resistance resulting in the stabilization of blood pressure.

2. Congestive cardiac failure:
They have the ability of reducing plasma volume helping in mild to moderate heart failure.

3. Diabetic nephropathy

4. Edema which may be due to congestive heart failure, renal dysfunction or corticosteroid therapy

5. Nephrosis

6. Prevent the formation of calcium stones in hypercalciuric and normal calciuric patients. As thiazide diuretics have the ability of inhibiting urinary Ca2+ excretion

Pharmacokinetics:
They are effective orally. There half life is about 35-42 hours. They are excreted by the kidney by organic acid secretary system of proximal tubule.

Adverse effects:
1. Gastrointestinal
Gastric irritation, anorexia, nausea, vomiting, diarrhea, constipation

2. Central nervous system
Weakness, fatigability, dizziness, vertigo, headache

3. Hematological
Leukopenia, agronulocytosis, aplsatic anemia

4. Cardiovascular
Orthostatic hypotension can be caused by volume depletion.

5. Hypersensitivity
Generalized dermatitis, hemolytic anemia, photosensitivity, rash, purpura

6. Hypercalcemia

7. Hypokalemia
Decreased intravascular volume activates rennin angiotensin aldosterone system resulting in K+ loss with urine.

This potassium loss can be decreased by spironolactone which interferes with aldosterone action or by giving triamterene. This can also be done by in creasing the intake of citrus fruits and bananas which are rich in potassium.


8. Hyponatremia:
This can be decreased by less water intake and decreasing the dose of thiazide diuretics.


9. Muscle spasm.

10. Hyperglycemia:
This may be due to impaired release of insulin and the uptake of glucose by the tissues.

11. Hyperuricemia:
Thiazide diuretics decrease the amount of acid excretion from the organic acid excretory system resulting in increased uric acid in the serum. This results in the gouty attacks.

Contraindications:
It is contraindicated in patients who are hypersensitive to thiazide or sulfonamides. It is also contraindicated in anuria, healthy pregnant women and hepatic cirrhosis.

Precautions:
It should be used with caution in patients of renal disease, gout or diabetes. In patients of renal disease it may initiate azotemia.

Drug Interaction:

Classification of Diuretics

Classification according to different groups:

Antidiuretic (ADH) hormone antagonists:
Lithium salts, demeclocycline, conivaptan

Carbonic anhydrase inhibitors:
Acetazolamide, Acetazolamide sodium

Loop (High ceiling) diuretics:
Bumetanide, Ethacrynic acid, Ethacrynate sodium, Furosemide, Torsemide, Umetanide, Piretanide

Mercurial diuretics:
Mercaptomerin, Calomel, Mercuhydrin, Meralluride, Mercumatilin, Mersalyl

Methylxanthine diuretics:
Aminophylline, Theobromine, caffeine, Theophylline, Oxtriphylline (A salt of theophylline)

Osmotic diuretics:
1. Osmotic electrolytes:
Sodium and potassium salts

2. Osmotic non-electrolytes:
Mannitol, Urea, Isosorbide, Sucrose, Glycerin

3. Acid-forming salts:
Ammonium chloride

Plant products:
Taraxacum, Cornsilk, Allium (Syn. Garlic), Buchu (dried leaves of Barosma betulina), Oleander, Turpentine oil

Potassium sparing diuretics:
Amiloride hydrochloride, Triamterene

Aldosterone antagonist:
Spironolactone, Aldadiene (A metabolite of apironolactone)

Thiazide diuretics:
Buthiazide, Chlorothiazide, Chlorthalidone, Hydrochlorothiazide, Indapamide, Metolazone, Cyclothiazide

Uracil derivatives:
Aminometramide

Miscellaneous diuretics:
Dextran, Ammonium benzoate, Dimethylpiperazine tartarate

Classification according to site of action:

Direct diuretics
1. Drugs acting on proximal tubule
Osmotic diuretics, Carbonic anhydrase inhibitors, Methylxanthine diuretics

2. Drugs acting on ascending limb of loop of henle
Loop (high ceiling) diuretics, Mercurial diuretics

3. Drugs acting on distal tubule
Thiazide diuretics

4. Drugs acting on collecting tubule
Potassium sparing diuretics, ADH antagonists, Aldosterone antagonists

Indirect diuretics
Cardiac diuretics

Diuretics

Introduction:

Diuretics are the drugs that cause the increased outflow of urine.

General action of diuretics:
Many types of diuretics
1. Decrease that amount of fluid which is reabsorbed by the renal tubules, from where the fluid returns to the blood
2. Increase glomerular filtration

General uses of diuretics:
They are used to remove excess water from the body which may contain some salts, toxins and other accumulated waste products such as urea.

They have the ability of getting rid of excess fluid from the body which may cause edema, which contains an abnormal accumulation of fluid from serum resulting in some of the disease.

Aprotinin

It is inhibitor of proteolytic enzymes.


It causes blockage of plasmin resulting in stoppage of bleeding.

It can cause inhibition of streptokinase.

It is used prophylactically for reducing blood loss around the time of operation. It is also used for hyperplasminaemia developed as a result of fibrinolytic drug overdosage.

It may start certain inflammatory conditions.

Vitamin K

It can be used for oral anti-coagulants.

Mechanism of action:
It causes post-translational modification of factors VII, IX and X.

Therapeutic uses:
It is usually administered to all newborn babies in order to prevent vitamin K deficiency leading to hemorrhagic diseases which is common in premature infants.

It is also used as an antidote of warfarin.

Adverse effects:
Rapid infusion of vitamin K may lead to chest pain, back pain and dyspnea.

Protamine sulfate

It is an antidote for heparin.

It is obtained from fish sperm.

It is strongly basic macromolecule due to the presence of more amount of arginine.

In this positive charge of protamine forms complex with negative charge of heparin (a polyanionic macromolecule) neutralizing its activity.

It is administered IV after proper dilution with physiological salt solution. Its duration of affect is 2 hours.

Hypersensitivity reactions may develop. On rapid injection, flushing, dyspnea, hypotension, and bradycardia may be caused.

Aminocaproic acid and Tranexamic acid

These are synthetic inhibitors of plasminogen activator with antiplasmin activity.

These are active orally and excreted in urine. Tranexamic acid can cross placenta.

Therapeutic uses:
Aminocaproic acid is effective in the treatment of complications caused by fibrinolysis such as in the treatment of cardiac bypass or major thoracic surgery. It is also found useful in the treatment of subarachnoid hemorrhage and angioedema.

The most important use of tranexamic acid is in the treatment of ovarian tumor which is malignant.

Adverse effects:
They may cause IV thrombosis.

Aminocaproic acid may cause rash, erythema, nausea, diarrhea and heartburn. It also some of the antiadrenergic effects leading to hypotension and nasal stuffiness.

Dosage:
Tranexamic acid is administered as 15mg/kg orallyas a loading dose then 30 mg/kg four times a day.

Classification of Coagulants

Introduction:

These are the substances which are helpful in the coagulation of the blood.

Bleeding can be caused by
1. Fibrinolytic states arising after prostatectomy or gastrointestinal surgery.
2. Hemophilia

In this case, hemophilia can be caused due to decrease of plasma coagulation factors such as factor VIII or IX.

Classification of Coagulants:
Protamine sulfate, Vitamin K, Aprotinin

Fibrinolytic inhibitors:
Aminocaproic acid, Tranexamic acid

Atorvastatin

Salt form of Atorvastatin is used i.e. atorvastatin calcium. It belongs to a drug calss of Statins.

Structure:

Credit: Drugbank.ca

Mechanism of Action:
It works by inhibiting the enzyme HMG-CoA (Hydroxymethyl glutaryl Coenzyme-A) reductase, which is present in the tissues of the liver and is responsible for the production of cholesterol in the body via mevalonate pathway.

Pharmacokinetics:
Maximum plasma concentrations is found within 1 to 2 hours. Absorption increases with increasing the dose of the drug. The absolute bioavailability is found to be 14%.

Uses:

It is used for the treatment of Cholesterol i.e. hyperlipidemia, dyslipidemia and hypercholesterolemia. It is used to reduce the risk of myocardial infarction, stroke and angina.

Side effects:
It may cause diarrhea, apin in extremeties and urinary tract infections.

Brand Names:

• Atogal (Ingers (Czech Republic))
• Atorpic
• Cardyl (Pfizer (Spain))
• Faboxim (Fabop (Argentina))
• Hipolixan (Pasteur (Chile))
• Lipitor (Pfizer, Elea (Argentina))
• Lipotropic (Drugtech (Chile))
• Lipovastatinklonal (Klonal (Argentina))
• Liprimar (Pfizer (Hungary, Ukraine), Goedecke (Russia))
• Lowden (Saval (Chile))
• Normalip (Quesada (Argentina))
• Sincol (Indeco (Argentina))
• Sortis (Pfizer (Austria, Czech Republic, Germany, Hungary, Poland, Portugal, Switzerland), Godecke (Germany), Parke, Davis (Germany))
• Sotis
• Torvacard (Zentiva (Czech Republic, Hungary, Poland, Russia, Ukraine))
• Torvast (Pfizer (Italy))
• Totalip (Guidotti (Italy))
• Tozalip
• Tulip (Lek (Czech Republic, Russia), Wermar (Mexico), Sandoz (Poland, Ukraine), Pharmacia (Spain))
• Vastina (Penn (Argentina))
• Xanator (Sieger (Greece))
• Xarator (Parke, Davis (Italy))
• Xavator
• Zurinel (Prater (Chile))

It is also available in the combination with amlodipine with the name of "Caduet".

Serotonin receptor blockers

5-HT3 serotonin receptor blockers include Ondansetron and granisetron.

Action:
It blocks 5-HT3 receptors in the periphery (visceral afferent fibers) and in the brain (chemorecptor trigger zone).

Pharmacokinetics:
• Orally or IV
• Prevents vomiting in 50 – 60% of patients treated with Cisplatin.

Clinical Uses:
It is used as prophylaxis of nausea and vomiting associated with cancer chemotherapy.

Side affects:
Headache.

5-HT1c and 5-HT2 receptor blockers include Ketanserin.

Action:

This drug potently blocks vascular α1-adrenoceptors resulting in hypotensive action. It antagonizes platelet aggregation caused by serotonin by blocking 5-HT2 receptors on platelets.

Uses:
It is used in hypertension and vasospastic conditions.

Serotonin

It is also known as 5-Hydroxy Tryptamine. It is an indole-ethylamine.
Synthesis:

Mechanism of action:
Seven families of 5-HT receptor sub-types (subscripts 1-7) are there. They act through a variety of cell membrane receptors that include:
1. Six involved G-protein coupled receptors.
2. One uses ligand gated ion channels.

Action:
It acts as a neurotransmitter causing strong inhibitory effect. It acts on chemosensitive endings causing bradycardia and hypotension. It can cause aggregation of platelets. It may cause hyperventilation due to chemoreceptor reflex.

Clinical uses of serotonin analogues:
1. Buspirone (a 5-HT1A agonist) is used as non-benzodiazepine anxiolytic.
2. Sumatriptan can be used in acute migraine and cluster headache.
3. Appetite suppression appears to be caused by the agonist action at 5-HT2C receptors in the central nervous system.
4. Cisapride (a 5-HT4 agonist) was used for gastroesophageal reflux disease and motility disorders.

Ergot Alkaloids

Ergot alkaloids are produced by Claviceps Purpurea.


Pharmacokinetics of Ergot Alkaloids:
It is effective in 50% of patients. The oral dose is about 10 times larger than IM dose although gastrointestinal absorption can be increased by caffeine.

Action of Ergot alkaloids:
As described of ergotism, some of the naturally occurring alkaloids are powerful hallucinogens. They constrict most human blood vessels which may be due to partial agonist effects at α-adrenoceptors. In very low doses, ergot preparations can evoke rhythmic contraction and relaxation of the uterus.

Clinical uses of ergot alkaloids:
1. Migraine.
2. Hyperprolactinemia.

Increased serum level of prolactin (Anterior pituitary hormone).

3. Postpartum Haemorrhage.
Oxytocin is usually used to control postpartum haemorrhage but if this is insufficient than ergonovine maleate can be used.

4. Senile Cerebral Insufficiency.
Once the headache starts, Analgesics or NSAIDs can be helpful in reducing the pain such as aspirin, naproxen, propoxyphene and caffeine.

Dihydroergotamine

Derivative of ergotamine, IV use, ≈ sumatriptan, nausea may occur.

Ergotamine

Same action as that of sumatriptan but has less specificity for 5-HT receptors and is weak α-adrenoceptor blocker. It can be given orally, sublingually, nasally or rectally. Side effects include diarrhea, nausea and vomiting.

Sumatriptan

Introduction:

It is 5-HT receptor agonist acting on 5-HT1D that innervates the intracranial vasculature.

Action:
It decreases the release of sensory neuropeptides, such as substance P.

Pharmacokinetics:
• Use orally or SC.
• Its onset of action is 20 minutes parenterally and 1-3 hours orally.
• T1/2 = 2 hrs.
It is effective in 80% of patients.