Categories
PHARMACOLOGY

Constipation: how to treat constipation and Laxatives

Bowel movements differ from person to person. Whatever the bowel movement pattern is, it’s unique for each person. Having fewer bowel movements (less than three a week) technically is constipation. 

The key features that usually define constipation include:

  • Dry and hard stools
  • A painful bowel movement and stools are difficult to pass.
  • Feeling that you have not fully emptied your bowels.

Laxatives: Constipation Remedy

Known by several different names – aperients, purgatives, cathartics; these drugs are used for management and treatment of conditions associated with GIT, wherein the normal motility is greatly reduced. Laxatives aid the patients with fecal retention problems directly by increasing the bulk and smoothening the bowel movement.

Upon long term use, they interfere with the natural bowel movement, causing discomfort.

The distinction of drugs is sometimes made on the intensity of action, as many drugs in low doses act as laxatives and as purgatives at larger doses.

How do Laxatives work?

The laxative drugs primarily aid in increasing the water content in the feces. The action can be achieved by several different mechanisms that form the basis of different types of drugs used for laxative action. The effect is generally achieved by one or more than one of the following mechanisms

  • An osmotic action that causes water and electrolytes accumulation, in intestinal lumen. This increases the volume of fecal content and makes it easier to excrete.
  • Action on mucosa epithelia, decreasing the overall absorption of water and electrolytes. The intestinal transit is enhanced indirectly by the liquid bulk. 
  • Cause an increase in the propulsive activity as a primary action that allows less time for absorption of water and salt as a secondary effect.

Laxatives thus modify the fluid dynamic and mucosal epithelia causing fluid accumulation in the lumen by regulating intracellular responses and physiological processes

Laxatives: Different classes of drugs

Bulk-forming laxatives – the laxatives under this class are high-fiber content compounds that absorb water to increase the bulk, hence the name. The formed bulk then distends the bowel movement to initiate reflex bowel activity. These compounds also help in softening the stool for easy passage. 

Drugs – psyllium husk, methylcellulose, polycarbophil, bran

Emollient – these laxatives are stool softeners and lubricants. These soften stool by water accumulation in the lumen by action on bolus and increase the penetration of water into the feces. Other than water, they also promote fat into the stools, lubricating both fecal material and intestinal walls. 

Drugs – docusate salts (DOSS), liquid paraffin

Hyperosmotic – these are solutes going unabsorbed in the intestine, have a property to retain water osmotically, and distend the bowel; increasing the peristalsis indirectly

Drugs – polyethylene glycol, sorbitol, glycerin, lactulose

Saline – saline laxatives increase the osmotic pressure within the intestinal tract, which results in a higher amount of water to move into the intestinal lumen. The action results in bowel distention, increased peristalsis, and evacuation

Drugs – magnesium sulfate, magnesium hydroxide, magnesium citrate, sodium phosphate

Stimulant – as the name suggests, these agents stimulate the intestinal nervous network. The action on myenteric plexes increases the peristalsis and motility. More importantly, they aid in intestinal water and electrolyte accumulation by modulating the absorptive and secretory activity of mucosal epithelia.

Drugs – castor oil, senna, cascara, bisacodyl

Indications in which they are preferred

  • Adjunct in anti-helminthic therapy
  • Chronic and acute constipation 
  • Hepatocellular failure
  • Preparation and cleaning bowel before radiography of GIT, proctoscopy, or colonoscopy
  • For rapid removal of poisonous substance in the GI tract
  • As a post-operative medication to avoid strain
  • In bedridden patients
  • To avoid strain in patients with a hernia, hemorrhoids, and cardiovascular disease 

Side effects

Common side effects of all laxatives – 

  • Diarrhea
  • Abdominal cramping
  • Nausea
  • Fluid and electrolyte imbalance
  • Sympathetic reactions – sweating, palpitations, flushing, and fainting
  • Cathartic dependence

Specific side effects – 

  • Bulk Forming Laxatives – Impaction and fluid overload 
  • Emollient Laxatives –  Skin rashes and decreased vitamin
  • Hyperosmotic Laxatives – Abdominal bloating and rectal irritations 
  • Saline Laxatives –  Magnesium toxicity (renal insufficient patients), cramping, diarrhea, increased thirst 
  • Stimulant Laxatives – Nutrient malabsorption, skin rashes, gastric irritation, rectal irritation 

Contraindications

  • Appendicitis, diverticulitis, ulcerative colitis 
  • Absence of peristalsis
  • A sudden, unexpected change in bowel movement
  • Oesophageal obstruction 
  • Intestinal obstruction
  • Fecal impaction
  • Undiagnosed abdominal pain
  • Colic pain and vomiting
  • Drug-induced secondary constipation
  • Secondary constipation due to – hypothyroidism, hypercalcemia, malignancies, stricture
Categories
PHARMACOLOGY

Diarrhea: how to treat diarrhea and antidiarrheals

What is Diarrhea?

Diarrhea can be explained as a frequent, often precipitate passage of poorly formed stools. The WHO defines the condition as 3 or more loose or watery stools in a period of 24-hours. Pathologically, it can be explained as a condition where the excess passage of water occurs in the feces.

Diarrhea can be a cause of 

  • Decreased electrolyte and water absorption
  • Increased secretion by the intestinal mucosa
  • Increased luminal osmotic load 
  • Inflammation of mucosa and exudation into the lumen.

The drugs used for such conditions are known as antidiarrheal drugs.

Acute diarrhoeal disease poses a serious risk to elderly patients, and it is one of the leading causes of childhood mortality and morbidity. Traveler’s diarrhea is a frequent health problem that causes an electrolyte imbalance. The therapy prioritizes treating the rootcause, correction of dehydration, and electrolyte imbalance.

Chronic diarrhea, mostly non-infectious, is the fluid loss persisting for longer than a month—the causes include gluten-sensitivity, inherited metabolic disorders, or inflammatory bowel disease.

Diarrhea Medicines (Antidiarrheal Drugs): How do they work?

Diarrhea Medicines
Photo by cottonbro on Pexels.com

Rational management for diarrhea treatment depends on investigating the underlying cause and prescribing drugs for specific therapy (if necessary). Since most diarrheas are self-limiting, it is not advisable to take self-medication until necessary.

The majority of diarrhea-causing entero-pathogens are prevented from causing infection, by motility and other protective gut mechanisms. Drugs for therapeutic management can be broadly grouped into:

(a) Treatment of fluid depletion, shock, and acidosis – rehydration is majorly required that can be done orally or I.V. depending on the severity.

(b) Maintenance of nutrition – the patients of diarrhea should not be starved or given lesser food. This is because fasting decreases the brush-border enzymes that reduce salt, water, and nutrient absorption, leading to malnutrition. Simple food like half-strength buffalo milk, boiled potato, rice, chicken soup, banana should be given as soon as the patient can eat.

(c) Drug therapy – these are the drugs used to calm irritated bowel for symptomatic relief.

The severity and nature of diarrhea govern the relative importance of each measure.

Different classes of antidiarrheal drugs

Rehydrating agents

  1. Intravenous rehydration – needed in severe fluid loss (>10% of body weight). Recommended I.V. fluid composition – 5g NaCl, 1g KCl, 4g NaHCO3 in 1L water, or 5% glucose solution. (Dhaka fluid). The volume equal to 10% body weight is infused over 2-4 hours.
  2. Oral rehydration therapy (ORT) – ORT is the widely used treatment in the cases of mild (5-7% of body weight) to moderate (7.5-10% of body weight) fluid loss from the very beginning. Patients are advised to drink ORS at 30-60 minutes intervals.

Drug therapy

  1. Bulking agents (absorbents)– these agents are used for diarrhea in functional bowel disease. Drugs – guar gum or plant fibers (bran, sterculia, isabgol)
  1. Absorbents – absorb toxic substances that cause infective diarrhea. Drug – Methylcellulose, carboxymethyl cellulose, kaolin, pectin, attapulgite
  1. Anti-inflammatory – Locally coat the lining of the GIT to soothe the irritation that may stimulate the reflex. Drugs – bismuth subsalicylate (anti-inflammatory – subsalicylate, anti-bacterial – bismuth)
  1. Anticholinergics – reduce intestinal movement and are effective against both diarrhea and accompanying cramping. Drugs – metoclopramide, neostigmine, atropine
  1. Opioids – Opioids have agonist actions on the intestinal opioid receptors, which when activated cause constipation. Drugs – loperamide, opium tincture, difenoxin, diphenoxylate
  1. Probiotics – used as dietary supplementation for bacterial replacement. Drug- Lactobacillus acidophilus

Antidiarrheal drugs: Indications in which they are used 

antidiarrheal
Photo by Chokniti Khongchum on Pexels.com
  • Acute (2-3 weeks) and chronic diarrhea (>3 weeks)
  • Reduction of fecal discharges from ileostomies
  • Management and treatment of Traveler’s diarrhea
  • Poisoning 
  • Drug allergy
  • GI obstruction 
  • Acute abdominal conditions
  • Ulcerative colitis 

Antidiarrheal drugsSide effects

  • Constipation
  • Nausea, vomiting
  • Abdominal distention and discomfort 
  • Toxic megacolon

Antidiarrheal drugsContraindications 

  • Loperamide contraindicated in children below 4 years of age
  • Loperamide contraindicated in infective diarrhea, ulcerative colitis, irritable bowel syndrome
  • All drugs are contraindicated in bloody diarrhea, fever, or systemic toxicity
  • Discontinue the therapy if the condition does not improve
  • Bile tract disease
  • Crohn’s disease

References:

Categories
PHARMA BRANDS PHARMACOLOGY

Gastroenterology: Which are the popular Brands?

Antacids and Antiulcer Drugs: what are they?

Gastroenterology is the branch of medicine focused on the digestive system and its disorders. This article explains in detail-Antacids and Antiulcer Drugs under gastroenterology.

As the name indicates, antacids are ‘anti-acids.’ Chemically, the drugs of this class are basic compounds that aid in neutralizing the released gastric acid and raise the pH of gastric contents. Under this condition, pepsin activity gets reduced if the pH rises above 4; since pepsin gets secreted as a complex with an inhibitory terminal part that dissociates below pH 5. The optimum peptic activity is in the pH 2 to 4.

Gastroenterology- Commonly prescribed medicines

Ranitidine: It reversibly binds to and antagonizes the histamine H 2
receptors located on the gastric parietal cells. This prevents the binding of
histamine to the receptors and reduces the secretion of gastric acid.

Domperidone: It blocks the peripheral dopamine receptors and facilitates
gastric emptying along with a decrease in the small bowel emptying time.
This is accompanied by an increase in the esophageal and gastric peristalsis
together with a reduction in the esophageal sphincter pressure. It also
blocks the dopamine receptors (D 2 and D 3 ) at the chemoreceptor trigger zone to elicit an antiemetic action and thereby suppresses nausea and vomiting.

Omeprazole: It selectively inhibits the H + K + ATPase enzyme system by covalently binding to cysteine residues on the alpha subunit of this pump. This, in turn, inhibits gastric acid secretion that occurs as a result of both basal and stimulated acid secretion. This drug is also known as proton pump inhibitors and used in the treatment for an ulcer.

Diastase: It is an enzyme that acts as a catalyst in the breakdown of starch
to disaccharide and trisaccharide maltose containing 1,4- linked and 1,6 –
glucose residues. It also aids in digestion.

Pepsin: It is a proteolytic enzyme that metabolizes proteins to peptides by
hydrolyzing the peptide linkages where one of the amino acids is aromatic.
It is responsible for less than 20 % of the protein digestion in the
gastrointestinal tract.

Magnesium hydroxide: As an antacid, it neutralizes the gastric acid
combining the hydroxide ions of the magnesium hydroxide with the
hydrogen ions of the gastric to form magnesium chloride and water. It also
exerts an osmotic effect on the gut by increasing the amount of water
drawn into this region. This in turn softens the stool, increases intraluminal volume, stimulates intestinal motility, and induces the urge to defecate.

Picosulfuric acid: It inhibits the absorption of water and electrolytes along with an increase in their secretion into the intestinal lumen. It is also
hydrolyzed by the bacterial enzyme, sulfatase, to form an active metabolite
that acts directly on the colonic mucosa to stimulate colonic peristalsis.

Dicycloverine/ dicyclomine: It directly inhibits muscarinic M 1 and M 2
receptors and non-competitively inhibit bradykinin and histamine. This in
turn relaxes the smooth muscles and decreases the strength of contraction
seen in spasms of the ileum.

Rabeprazole: It selectively and irreversibly inhibits H + K + ATPase pump that is found on the secretory surface of parietal cells. This in turn prevents the production of gastric acid via inhibition of the final transport of hydrogen ions in exchange for the potassium ions in the gastric lumen. Rabeprazole is a preferred choice in the treatment of an ulcer.

Simethicone: It decreases the surface tension of gas bubbles, facilitates
their coalescence and expulsion as flatulence or belching. It also facilitates
the movement of gas through the bowel lumen prevents the formation
and accumulation of mucous-enclosed gas pockets in the lumen and
reduces the frequency of flatus events.

Lactulose: It is minimally absorbed by the gut and mostly remains in the
gastrointestinal tract. Due to this, it enhances the stool amount and softens
the stool. It also enhances intraluminal gas formation, peristaltic gut motility, and elicits an osmotic effect for softening the stool to increase the
frequency of bowel movements in patients with constipation.

Saccharomyces boulardii: This organism along with the proteins it
secretes elicits anti-inflammatory effect by inhibiting the pro-inflammatory
cytokines through the nuclear factor-kB and mitogen-activated protein
kinases. It also activates the peroxisome proliferator-activated receptor-
gamma which in turn protects gut inflammation. Additionally, it suppresses bacterial overgrowth in the gut and stimulates antibody production against toxin A secreted by Clostridium difficile.

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References: other gastroenterology articles

Categories
PHARMA BRANDS PHARMACOLOGY

Which are the popular Medicines prescribed for Heart Disorders?

A person having heart disorder is more likely to take medication for the rest of life. Medicines in Heart disorders can be of many types. These can be monotherapy or a combination of different drugs.

Commonly prescribed Medicines for Heart Disorders are diuretics, vasodilators, calcium channel blockers, beta-blockers, ACE inhibitors.

The following list provides you a quick look at medications prescribed for heart disorders. Brand names, company, and pack details are shown in parentheses.

Medicines for Heart Disorders
  • Acenocoumarol: It is a vitamin K antagonist and inhibits the reduction of vitamin K by acting on vitamin K epoxide reductase.

This in turn prevents gamma-carboxylation of the glutamic acid residues in the vitamin K-dependent clotting factors such as factor II, VII, IX, and X and anticoagulant protein C and S. As a result of this, thrombin formation is inhibited and clotting cannot occur.

Medicines for Heart Disorders

Amlodipine: It acts directly on the vascular smooth muscle and decreases the peripheral vascular resistance by inhibiting the influx of calcium ions into the vascular smooth muscle and cardiac muscle. This, in turn, causes a decrease in blood pressure.

Medicines for Heart Disorders

Atenolol: It is a beta-blocker and antagonizes the sympathetic innervation.

This, in turn, increases the release of norepinephrine from the peripheral nervous system and prevents the increase in the heart rate, electrical conductivity, and contractility in the heart. 

Medicines for Heart Disorders

Ticagrelor : The drug and its major metabolite reversibly binds to the allosteric site of the P2Y12 subtype adenosine diphosphate receptor and prevents signal transduction and platelet activation.

Medicines for Heart Disorders

Cilnidipine: It acts on and inhibits the L-type and N-type calcium channels of blood vessels.

This in turn inhibits the influx of calcium and contraction of blood vessels that finally reduce the blood pressure. It also inhibits the emission of norepinephrine at the sympathetic nerve and aids in the reduction of stress blood pressure.

Medicines for Heart Disorders

Telmisartan: It is an angiotensin (AT) receptor blocker and prevents the binding of angiotensin-II with the AT receptors located in the vascular smooth muscles, adrenal gland, and other tissues.

This in turn blocks the vasoconstrictor and aldosterone-secreting effects produced by angiotensin-II.

Medicines for Heart Disorders

Clopidogrel: It is a prodrug and gets metabolized by carboxylesterase-1 to form the active form that irreversibly binds to the P2Y12 Adenosine diphosphate receptors on the platelets.

This in turn inhibits the binding of adenosine diphosphate to the receptors and thereby blocks the ADP-mediated activation of glycoprotein GP IIb/IIIa complex. All these ultimately prevent the aggregation of platelets.

Medicines for Heart Disorders

Bisoprolol: It selectively and competitively blocks the stimulation of β1 adrenoreceptors by the adrenaline that in turn reduces the contractility and heart rate of the heart muscle and pacemaker cells.

As a result of this, the cardiac output and blood pressure also decrease. It also reduces the secretion of renin by the kidneys.

Medicines for Heart Disorders

Torsemide: It is a loop diuretic and acts on the thick ascending loop of Henle. It inhibits the Na+/K+/Cl cotransporter by binding to the chloride ion binding site of this pump.

It also reduces the expression of aldosterone synthase, thromboxane A2 and transforming growth factor beta-1. These changes along with a reduction in aldosterone receptor binding are due to the inhibition of the downstream cascade following angiotensin-II activation.

Medicines for Heart Disorders

Acetylsalicylic acid: It irreversibly inhibits cyclooxygenase-1 (COX-1) enzyme in the platelets and megakaryocytes.

This in turn prevents the formation of thromboxane A2 that is essential for the platelet aggregation and clot formation. Thereby it acts as an antiplatelet agent.

Medicines for Heart Disorders

Atorvastatin: It is a lipid-lowering drug that competitively inhibits HMG-CoA reductase (3-hydroxy-2-methylglutaryl Coenzyme A) enzyme and prevents the conversion of HMGCoA to mevalonate.

It also enhances the uptake of low-density lipoproteins (LDL) in the liver by upregulating the LDL receptors. It also elicits its action by reducing the very low-density lipoproteins- cholesterol, serum triglycerides, and intermediate-density lipoproteins.

Medicines for Heart Disorders

Trimetazidine: It inhibits β-oxidation of free fatty acids and increases the metabolic rate of glucose as well as pyruvate dehydrogenase activity.

This corrects the imbalance between glucose oxidation and glycolysis. It also directly inhibits cardiac fibrosis.

Medicines for Heart Disorders

Ivabradine: It lowers heart rate by selectively inhibiting the channel responsible for the cardiac pacemaker current.

It also prolongs diastolic depolarization and reduces myocardial oxygen demand by disrupting the flow of this current.

Medicines for Heart Disorders

Losartan: Losartan and its 5-carboxylic acid metabolite selectively inhibit angiotensin-II receptor type-1 (AT1) and reduces the end-organ responses to angiotensin-II.

It antagonizes the release of aldosterone, reduces total peripheral resistance and cardiac venous return. These changes facilitate its use as an antihypertensive agent.

Medicines for Heart Disorders

Hydrochlorthiazide : It is a thiazide diuretic that acts on the distal convoluted tubule by inhibiting the reabsorption by the sodium-chloride symporter.

This in turn reduces the difference in concentration gradient between the epithelial cells and the distal convoluted tubule and thereby prevents reabsorption of water.

Medicines for Heart Disorders

Metoprolol: It is a selective beta-1 blocker that specifically inhibits the beta receptors present in the cardiac cells. This causes negative chronotropic and ionotropic effects that in turn reduces cardiac output and heart rate. It also reduces cardiac excitability and myocardial oxygen demand.

Medicines for Heart Disorders

Prazosin: It inhibits post-synaptic α1 ­adrenoreceptor and prevents the vasoconstricting effect of catecholamines on the peripheral blood vessels.

This in turn leads to peripheral vessel dilation and reduces the blood pressure.

Medicines for Heart Disorders

Nebivolol: It inhibits the beta-1 adrenoreceptors present in the heart and decreases cardiac contractility, heart rate, cardiac output, and ultimately blood pressure.

It also potentiates the effects of nitric oxide to exert a vasodilatory effect on the vascular smooth muscle.

Medicines for Heart Disorders

Nicorandil: It activates ATP-dependent potassium channels and causes hyperpolarization that in turn limits the duration of action potential and prevents intracellular calcium overload.

It also reduces calcium influx and mobilization in smooth muscle cells and produces vasodilation. The nitrate moiety of nicorandil also dilates the vascular smooth muscles by the stimulation of guanylyl cyclase and by increasing intracellular cGMP levels.

Medicines for Heart Disorders

Nitroglycerin: It forms a free radical nitric oxide that activates guanylate cyclase and results in an increase of guanosine – 3’,5’- monophosphate (cyclic GMP) in smooth muscles and other tissues.

These changes lead to the dephosphorylation of myosin light chains that are essential for maintaining the contractile state of the muscle and ultimately result in vasodilation.

Medicines for Heart Disorders

Rosuvastatin: It is a lipid-lowering agent that inhibits HMGCoA reductase and prevents the conversion of HMGCoA to mevalonate.

It also enhances the uptake of low-density lipoproteins (LDL) in the liver by upregulating the LDL receptors. It also elicits its action by reducing the very low-density lipoproteins- cholesterol, serum triglycerides, and intermediate-density lipoproteins.

Medicines for Heart Disorders

Sacubitril: It is a prodrug that gets converted to sacubitrilat by the action of esterases.

The active metabolite inhibits neprilysin, an enzyme that is responsible for the degradation of atrial and brain natriuretic peptide and other peptides like bradykinin. Inhibition of this enzyme in turn exerts a vasodilatory and antihypertensive effect.

Medicines for Heart Disorders

Valsartan: It is angiotensin – II receptor blocker that selectively binds to the ATreceptor and prevents the binding of angiotensin-II with this receptor to exert its hypertensive effects.

As a result of this, it reduces blood pressure, lowers aldosterone levels, reduces cardiac activity, and increases the excretion of sodium.

Heart Disorders Medicines

Enlisted herewith are the details of popularly used Medicines for Heart Disorders; brands, pack details.

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References : Medicines for Heart Disorders

  1. drug bank-1
  2. Acenocoumarol
  3. drug bank 2
  4. drug bank 3
  5. wikipedia- Ticagrelor#Mechanism_of_action
  6. brilinta-drug
  7. drug bank 4
  8. drugs at fda
  9. drug bank 5
  10. Bisoprolol
  11. Bisoprolol Mechanism
  12. Bisoprolol cardioprotective
  13. drug bank 6
  14. drug bank 7
  15. antiplatelet-drugs
  16. drug bank 8
  17. Trimetazidine
  18. drug bank 7
  19. Wikipedia-Losartan
  20. drug bank 8
  21. drug bank 9
  22. drug bank.com 10
  23. Nebivolol
  24. drug bank 11
  25. drug bank 12
  26. Wikipedia- Sacubitril
  27. drug bank 13
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PHARMACOLOGY

Important Terms used in Pharmacology

accuracy

Accuracy: Accuracy is the extent to which a value from a test reflects or agrees with the reference value of the analyte being tested, measured statistically by standard deviations. In general, accurate test methods measures what it is supposed to measure.

Validity

Validity: It refers to the ability of a device to measure what it intends to measure. It is not an intrinsic test property and is an essential element of medical diagnosis.

Reliability

Reliability: It is the ability to produce reproducible results. Reliability is a prerequisite for the validity of a test that consistently produces true measurements.

Sensitivity

Sensitivity: It is used to describe how well a test can detect a specific disease or condition in patients who actually have them. It also refers to the way the body
reacts to the environment, drugs, chemicals, and other substances.

Precision

Precision: It is a measure of test or assay reproducibility that is capable of producing the same results when performed on the same specimen under the same condition. The amount of random variation is less when the test method is precise.

addiction

Addiction: It is a biopsychological disorder that is characterized by compulsive engagement in activities that help to achieve the desired effects, such as alcohol
an intoxication to attain euphoria despite the harm and adverse effects to self and others.

affinity

Affinity: It is a measure of tightness with which a drug binds to the receptor. It is also defined as the probability that a drug molecule will bind to an available receptor at any given instant of time.

agonist

Agonist: Agonists are drugs that bind to and activate receptors to elicit a pharmacological or biological response. It has good affinity and efficacy.
Hormones and neurotransmitters are also known as endogenous agonists.

Partial Agonist

Partial Agonist:

These bind to and activate a given receptor but only have partial efficacy even at maximal receptor occupancy. It has both agonistic and antagonistic activities and is often used by physicians to elicit a desired submaximal response in the patients. Eg. Buspirone

Full agonist

Full agonist:

These drugs bind to and activate the receptors to elicit the maximal response that an agonist is capable of producing. Eg. Isoproterenol
acts as a full agonist at beta receptors by mimicking the action of adrenaline.

Inverse Agonist

It binds to the same receptor as that of the agonist but
induces a pharmacological response that is opposite to that of the agonist. An inverse agonist has negative efficacy. Eg. Naloxone and naltrexone act as partial
inverse agonists at mu-opioid receptors.

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Allergic Response:

It is a hypersensitive immune response to a substance (food, chemicals, drugs or pollen grains) that is normally harmless and would not cause an immune response in everyone. Itching, inflammation and tissue injury are some of the well-known allergic responses.

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Analgesic:

Analgesics are medicines that help to produce analgesia or provide relief from pain. It is also known as pain relievers or pain killers and act at the
peripheral and central nervous system. Eg. Paracetamol, codeine etc.

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Anesthetic:

It is a drug that induces anesthesia or temporary loss of sensation or awareness. General anesthetics cause a reversible loss of consciousness while local anesthetics cause a reversible loss of sensation in a restricted region without affecting consciousness.

Antagonism:

Antagonists are drugs that bind to and block the receptors to dampen a pharmacological or biological response. It has good affinity but no efficacy. It will inhibit the binding of the agonists or inverse agonists with the receptors and is also known as blockers.

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AUC (Area under the curve): It is the total integrated area under the plasma drug concentration versus time curve and expresses the total amount of drug
that reaches the systemic circulation following its administration. Drugs administered via intravenous route has higher AUC than the oral drugs.

BIOASSAYS

Bioassay or Biological assay: It is an analytical method used to determine the potency or concentration of an active principle in the unit quantity of preparation by measuring its biological response in living tissues. It compares the activity of the test substance with that of the standard.

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Bioavailability:

It is also known as biological availability and is the rate and extent (amount) of absorption of the unchanged form of the drug from the dosage form at the site of administration. Medications administered intravenously show 100 % bioavailability.

Biopharmaceutics

Biopharmaceutics:

It is the study of the factors influencing the rate and amount of drug that reaches the systemic circulation and the use of this information to optimize the therapeutic efficacy of the drug products.

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Biotransformation:

It is also known as metabolism and refers to the chemical alteration of chemicals like nutrients, amino acids, toxins, and drugs in the body. This helps to convert the non-polar and hydrophobic compounds into polar and hydrophilic compounds to facilitate its excretion from the body.

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Blind Experiment:

It is a type of experiment in which the experimenter does not know which treatment is given to the subject. This helps to eliminate the bias that might be introduced by the researcher. In pharmacological studies, both patients and experimenters are blinded and this is called a double-blind experiment.

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Cmax:

C max is the peak plasma concentration that a drug
achieves in a specified compartment after initial administration and prior to the administration of the second dose.

Cmin:

C min is the minimum blood plasma concentration of the drug prior to the administration of the second dose. It must be above the minimum inhibitory concentration to produce therapeutic effects.

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Ceiling:

The ceiling effect is a phenomenon in which a drug reaches a maximum effect, such that a further increase in drug dosage does not increase the effectiveness. Eg. Nalbuphine produces a ceiling effect. Increasing the dose of nalbuphine beyond a certain value leads to smaller gains in pain relief.

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Chemotherapy:

It is a type of cancer treatment that uses chemotherapeutic agents or anti-cancer drugs as a part of standardized therapy. It is given with
either a curative intent or to prolong the life of the patient.

Clearance:

Clearance: It is the hypothetical volume of body fluids containing drug from which the drug is removed or cleared completely in a specific period of time. It is measured in L/hr or mL/min and reflects the rate of drug elimination divided by the plasma concentration.

Therapeutic Index

Clinical Therapeutic Index: It is a quantitative measurement of the relative safety of the drug. It refers to the ratio of the dose of the drug that causes adverse effects (TD50) to the dose that leads to the desired pharmacological effect (ED50).

Compartment(s):

Compartment(s): It is a fictitious or virtual tissue or group of tissues that have similar drug distribution characteristics (similar blood flow and affinity to the drug). These are mathematical constructs and do not correspond to the fluid volume of the body that is defined- physiologically and anatomically.

Compliance

Compliance: It describes the degree to which a patient correctly follows medical advice. It commonly refers to medication or drug compliance but may also be applicable to other self-directed exercises and therapy sessions.

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Cross-Over Experiment: Cross-over experiments are experiments in which each subject acts as his/her own control as they take each of the treatments under investigation on different occasions. It is particularly efficient in the cases of large inter-individual variation.

Cross-Tolerance:

Cross-Tolerance: It is a phenomenon that occurs when the tolerance to the effects of certain drugs produces tolerance to another drug. This is especially seen when the two drugs have similar functions or effects. Eg. Cross-tolerance between amphetamine and caffeine.

CT Index

CT Index: It is a measure of the drug potency that is calculated by multiplying the concentration (C) of a therapeutic agent administered to the body to produce a specific response with the duration of application (T) applied to elicit the effect.

Dependence:

Dependence:

It is synonymous with addiction and habituation and refers to the somatic state that is attained following chronic administration of certain drugs. In this state, the individual becomes dependent on the drug and sudden discontinuation of this drug produces withdrawal symptoms that may even prove to be fatal.

Pharmacology

Desensitization: It refers to the reduction in the subject’s response following repeated use of the drug. Desensitization occurs when the individual receptors become less responsive to the drug post its repeated administration.

Disintegration Time:

Disintegration Time: It is the time required for the dosage form to break up into granules of specified size under carefully specified test conditions. It is very important in the case of solid dosage forms like tablets and capsules and is directly related to the amount of binder present in the solid dosage form.

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Dissolution Time:

It is the time required for the given amount or fraction of the drug to solubilize in a given solvent, i.e., mass transfer from the solid surface to the liquid phase.

Pharmacology

Dosage Form:

It refers to pharmaceutical drug products in the form in which they are marketed for use, with a specific mixture of active ingredients and excipients, in a particular configuration, and apportioned in a particular dose.

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Dose:

It is the measured quantity of a therapeutic agent that is to be taken at a specific time. Each dose corresponds to a single unit.

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Dose-Duration Curve:

It is a curve describing the relationship between the dose and the duration of the drug effect. It is used to infer the pharmacokinetic and pharmacodynamic properties of the drug including elimination half-life and threshold dose. It always has a positive slope.

Dose-Effect Curve

Dose-Effect Curve: This curve correlates the effect produced with the dose administered. It is continuous, monotonic, and always approaches some maximum value as an asymptote.

Pharmacology

Drug:

It is any substance that causes a change in the organism’s physiology or psychology on consumption and is used in the treatment, cure, prevention or diagnosis of a disease. It can also be used to enhance the physical or mental well-being of the individual.

Drug abuse

Drug Abuse:

It refers to the use of a certain drug for the purpose of creating pleasurable effects on the brain. It is also defined as the use of illegal drugs or the use of prescription and over-the-counter drugs for purposes other than those for which they are meant to be used or in excessive amounts.

Drug Dependence

Drug Dependence:

It is also known as substance dependence and refers to an adaptive state that develops from repeated drug administration which results in withdrawal upon cessation of drug use.

dummy

Dummy:

It is a counterfeit object used in the experimental investigation of the drug effects and is rendered to be biologically inert. It is used to get an unbiased assessment of the result of a pharmacological experiment.

EC50

EC50:

EC50 or Half maximal effective concentration refers to the concentration of the drug, antibody or toxicant (agonist) which induces a response that is halfway between the baseline and maximum after a specified exposure time. It can also be defined as the concentration required to obtain 50 % effect.

ED50

ED50:

It is the median effective dose and is defined as the dose of the drug that produces 50% of the maximal response to that drug. It is used when the measurements are taken in-vivo.

Pharmacology

Effective drug:

A drug is considered to be effective if it achieves its intended effect in the usual clinical setting. It is evaluated through observational studies of real practice.

Efficacy

Efficacy:

It is the maximum response achievable from the applied or dosed agent in research and clinical settings. It is independent of potency or affinity but is related to the intrinsic activity.

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Equipotent

Two drugs are said to be equipotent if they are equally capable of producing a pharmacological effect of specified intensity. Drugs with the same intrinsic activities and ceiling effects are called equipotent.

Equivalent Dose & Drug Conversions / Transfers / Switching

Equivalence:

Pharmaceutical equivalence means that the two products have the same active ingredients in the same dosage form and are intended for the same route of administration. Biological equivalence refers to the chemical equivalents which when administered in the same amount will produce the same bioavailability.

Pharmacology

First-Order Kinetics: It occurs when a constant proportion of the drug is eliminated per unit time. It is a concentration-dependent process in which the clearance is faster at higher concentrations.

First Pass Effect

First Pass Effect:

It is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced in the liver before reaching the systemic circulation. It is also known as pre-systemic metabolism.

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Food and Drug Administration (F.D.A.):

The FDA is a federal agency of the United States Department of Health and Human Services  that is responsible for protecting and promoting public health through the control and supervision of food safety, tobacco products, dietary supplements, medications and veterinary products among others.

Generic Drugs:

Generic Drugs:

It is a pharmaceutical drug that contains the same active ingredient as the drug that was originally protected by chemical patents. These are allowed for sale after the patents of the original products expires. The pharmacological effects of the generic drugs and the patented products are the same.

habituation

Habituation:

It is the process of forming a habit and refers to the psychological dependence on the continued use of a drug to maintain a sense of well-being which can result in addiction. Tolerance to the effect of the drug is acquired through its continued use.

Drug Half-life

Half-Life:

It is the time required for the concentration or amount of the drug in the body to be reduced by one-half of its steady-state. It helps to determine the drug dose and frequency of administration.

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Harrison Act:

The Harrison Narcotics Tax Act was a United States federal law that regulated and taxed the production, importation and distribution of opiated and coca products. It was approved in 1914 and enacted in 1915.

Hazard and Risk

Hazardous drugs

In pharmacology, hazardous drugs are drugs that are known to cause harm, which may or may not include genotoxicity, carcinogenicity, teratogenicity, fertility impairment, or serious organ or other toxic manifestations at lower doses in humans or experimental animals.

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Hypersensitivity:

It is an exaggerated immune response to a specific antigen or drug. Hypersensitivity reactions may be damaging, uncomfortable, or occasionally fatal and are due to the pre-sensitized immune state of the host.

Sedative Hypnotic(Act on gaba, Na, K)

Hypnotic:

It is also known as soporific drugs or sleeping pills and are a class of psychoactive drugs whose primary function is to induce sleep. It is used for the treatment of insomnia or for surgical anesthesia and is related to sedatives.

Idiosyncratic Response:

Idiosyncratic Response:

It is also known as type B adverse drug reactions that occur rarely and unpredictable among the population. Eg. Development of rashes following ampicillin administration in individual with infectious mononucleosis.

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Infusion Kinetics:

Infusion in drug administration refers to the continuous flow of drug solution into the bloodstream over a relatively long period of time. It is used to maintain a steady plasma concentration of the drug and is directly proportional to the rate of drug administration.

Intrinsic Efficacy

Intrinsic Efficacy (or Intrinsic Activity):

It is the measure of the ability of a drug that is bound to the receptor to generate an activating stimulus and produce a change in the cellular activity. It refers to the relative ability of the drug-receptor complex to produce a maximum functional response.

ka

ka:

  1. The absorption rate constant (Ka) is a pharmacokinetic constant that is used to describe the rate at which a drug enters into the system. It is expressed in time-1. It is related to the biological half-life as follows:

Ka = ln/t1/2

METAMETER

Metameter:

It is a quantity derived from a measurement used in evaluating biological tests. It facilitates statistical summary and analysis of data. Eg. Metameters of dose includes “milligrams”, “moles”, “log milligrams”, etc.

Elimination Rate Constant

kel:

­The elimination rate constant (Ke)  is a pharmacokinetic constant that is used to describe the rate at which the drug is removed from the human system. It is equivalent to the fraction of the drug that is removed per unit time measured at any particular instant and has the unit of time-1.

Latent Period or Latency

Latent Period or Latency:

It is the period between infection with a microorganism and the onset of symptoms or between the exposure of radiation and appearance of cancer.

Loading Dose

Loading Dose:

It is an initial higher dose of a drug that is given at the beginning of a course of treatment before dropping down to a lower maintenance dose. Drugs with long systemic half-life require a low loading dose.

Maintenance Dose:

Maintenance Dose:

It is the dose at which the maintenance rate of drug administration is equal to the rate of drug elimination at a steady state. It is calculated from the desired peak concentration multiplied by the clearance rate.

Median Effective Dose

Median Effective Dose:

It is the dose or concentration of the drug that produces a biological response. It is generally defined as the lowest dose level of a pharmaceutical product that provides a clinically significant response in average efficacy.

PK/PD Studies

Multiple Dose Regimens:

It refers to the administration of a successive dosage of a drug in which the drug is administered frequently with constant dose interval. It aims at maintaining the plasma drug concentration within the therapeutic range and to produce the maximum therapeutic effect.

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Narcotic:

It refers to any psychoactive compound with sleep-inducing properties and euphoric properties. It is also defined as an addictive drug that reduces pain, induces sleep and alters mood and behavior. Eg. Morphine, codeine

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National Formulary (N.F.):

It is an official publication that contains the standards of purity, methods of assay of some drugs, formulae, methods of manufacture of various pharmaceutical preparations, list of standard excipients, botanicals and other similar products. It was formerly published by the American Pharmaceutical Association.

Negative Control Drug or Negative Control Procedure:

The negative control drug used in pharmacological experiment lacks the active ingredient that elicits the biological response. It helps to prevent erroneous conclusions about the apparent activity of the test preparation.

Parameter

Parameter:

It is an element of the experiment that can be varied but which the experimenter tries to control or maintain constant during the course of a specific experiment, while intentionally altering the independent variable and observing the changes on the dependent variable.

ADME Pharmacodynamics

Pharmacodynamics:

It is a branch of pharmacology that deals with the biochemical and physiological effects of the drug on the body. It relates the response produced to the concentration of drug in the body.

Pharmacogenetics

Pharmacogenetics:

It is the branch of pharmacology that analyzes how the genetic makeup of an individual affects his/her response to the drugs. It deals with the influence of acquired and inherited genetic variation on drug response in patients by correlating gene expression with pharmacokinetics and pharmacodynamics.

Pharmacokinetics

Pharmacokinetics:

It is the study of the time course of a drug’s absorption, distribution, metabolism and excretion and its relationship with the toxic and therapeutic effects produced by the drug. It is simply defined as the study of what the body dose to the drug.

Pharmacology

Pharmacology:

It is a branch of medicine and pharmaceutical sciences that is concerned with the study of the uses, effects, and mechanisms of action of drugs. The origin, composition, pharmacokinetics, therapeutic use, and toxicology of the drug are studied under this.

Placebo

Placebo:

Placebos are substances that are made to resemble drugs but do not contain the active ingredient. It has no inherent pertinent pharmacologic activity but is rendered effective by the psychological suggestion given during administration.

Positive Control Drug

Positive Control Drug:

It is a drug preparation incorporated into an experiment with the intention that it has effects on the experimental system qualitatively similar to those expected of the independent variable. It is used for validating the experimental system.

Potency

Potency:

It is a measure of the drug activity expressed in terms of the amount required to produce an effect of the required intensity. Highly potent drug evokes a given response at low concentrations while a drug of lower potency evokes the same response at higher concentrations.

Potentiation

Potentiation:

It is the interaction of two or more drugs or agents resulting in a pharmacological response that is greater than the sum of the individual responses of each drug or agent. Eg. Combination of sedative drugs with alcohol.

Priming Dose

Priming Dose:

It is also known as the loading dose. It is defined as an initial higher dose of a drug that is given at the beginning of a course of treatment before dropping down to a lower maintenance dose. Drugs with long systemic half-life require a low loading dose.

Prodrug

Prodrug:

It is a medication or compound that, after administration, is metabolized into a pharmacologically active drug. It is a precursor of the drug and is used to alter the pharmacokinetic properties of the drug. Eg. Sulfasalazine

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Receptors:

These are chemical structures composed of proteins that bind to the ligands to elicit a physiological response. These proteins recognize and respond to endogenous chemical signals that are integrated into biological systems.

Reference Standard

Reference Standard:

A pharmaceutical reference standard is a highly characterized material  suitable to test the identity, strength, quality, and purity of substances for pharmaceutical use and medicinal products

RISK

Risk:

It is the likelihood that harm will result from exposure to a hazard. It implies future uncertainty of the effects of activity with respect to something that humans value, often focusing on negative and undesirable consequences.

Selectivity

Selectivity:

It is the degree to which a drug acts on a given site relative to other sites. It refers to the drug’s ability to preferentially produce a particular effect and is related to the structural specificity of drug binding to receptors.

Side Effects

Side Effects:

It is an effect that may be therapeutic or adverse and is secondary to the one intended. It predominantly refers to the adverse effects that are either harmful or unpleasant to the patient.

Spare Receptors

Spare Receptors:

Spare receptors are present when an agonist induces a maximum response while occupying less than 100 % of the available receptors. It reflects a circumstance in which the maximum effect produced by an agonist is limited by some factor other than the number of activated receptors.

Specificity

Specificity:

It is a measure of the receptor’s ability to respond to a single ligand. A drug of good specificity of action will increase or decrease a specific function of a given cell type. Eg. Atropine is specific in blocking the actions of acetylcholine.

Supersensitivity

Supersensitivity:

It refers to the increased responsiveness or reactivity to a neurotransmitter or drug especially in a structure deprived of ita normal nerve supply (denervation). It can also be induced due to the administration of some other drug.

 Synergy

Synergy:

Drug synergy is the interaction of two or more drugs to produce a total effect that is greater than the sum of the individual effects of each drug. It can be either beneficial or harmful. Eg. Enhanced liver injury is produced due to synergism between carbon tetrachloride and ethanol.

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Tachyphylaxis:

It refers to an acute, sudden decrease in response to a drug after its administration; i.e. a rapid and short-term onset of drug tolerance. It can occur after an initial dose or after a series of small doses. Increasing the dose of the drug might be able to restore the original response.

Therapeutic Index

Therapeutic Index:

  1. It is a quantitative measurement of the relative safety of the drug. It refers to the ratio of the dose of a drug that causes adverse effects (TD50) to the dose that leads to the desired pharmacological effect (ED50).

Therapeutic index = TD50/ED50

Therapeutics

Therapeutics:

It is a branch of medicine that deals with the treatment of disease and the action of remedial agents. It can also refer to the therapy and drug used to remediate a health problem following diagnosis.

Threshold Dose

Threshold Dose:

It is the minimum dose of ionizing radiation, drug, or chemical that will produce a detectable degree of any therapeutic effect.

Time-Concentration Curve

Time-Concentration Curve:

It is the graphical representation of the relationship between the concentration of dose of the drug and its latency or latent period. It is usually hyperbolic in nature and is characteristic for each drug.

Tolerance

Tolerance:

Drug tolerance is a pharmacological concept that is used to describe the patient’s reduced reaction to a drug following its repeated use. Increasing its dosage may re-amplify the drug’s effects but this may also accelerate tolerance and reduce the drug’s effects

Toxic Effects

Toxic Effects:

Toxic effects are responses to a drug that is harmful to the health of the individual. It refers to the adverse effects produced by poisons and can range from mild symptoms like headaches or nausea to severe symptoms like coma, convulsions, and death.

Toxicology

Toxicology:

It is a branch of science that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating exposures to toxins and toxicants. It is concerned with the nature, effects and detection of poisons in living beings.

Two-state Model

Two-state Model:

It is a simple linear model used to describe the interaction between a ligand and its receptor. This model proposes that ligand binding results in a change in receptor state from an inactive to an active state based on the receptor’s conformation

United States Pharmacopoeia (U.S.P.)

United States Pharmacopoeia (U.S.P.):

The U.S.P is a pharmacopoeia for the United States published annually by the United States Pharmacopeial Convention. It is published in a combined volume with the national formulary and establishes written and physical standards for medicines, food ingredients, dietary supplement products and ingredients.

Volume of Distribution

The volume of Distribution:

  1. It is a theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration as that observed in the blood plasma. It is also known as the apparent volume of distribution (Vd) and is calculated as follows:

       Vd = Total amount of drug in the body/drug concentration in blood plasma

Zero-Order Kinetics

Zero-Order Kinetics:

These are reactions in which the rate of elimination of the drug is independent of the concentration of the drug. The amount of drug eliminated per unit time decreases linearly with time. Eg. Phenytoin, warfarin and ethanol follow zero order kinetics.

REFERENCES:

Categories
PHARMACOLOGY

Autacoids- Histamine, Serotonin and Prostaglandins

Autacoids

The term autacoids is derived from the Greek words: autos-self and akos-healing.

They include a wide variety of substances which are locally released (in a paracrine fashion) and act for a short distance at their sites of release. In contrast to hormones, they are not released in the blood.

They may act as: Immunomodulators (increase or decrease the immune response and the associated inflammation) or transmitters. Besides, they have a role in normal physiology and pathophysiological conditions.

Autacoids are broadly classified as:

  • Amine Autacoids: Histamine, Serotonin (also known as 5-Hydroxytryptamine/ 5-HT)
  • Lipid-derived Autacoids: Prostaglandins, Leukotrienes, etc
  • Peptide Autacoids: Bradykinin, Angiotensinogen
  • Miscellaneous: Cytokines (Interleukins, TGF-beta, TNF-alpha, Epidermal Growth Factors, etc), gastrointestinal peptides (bombesin, gastrin, Vasoactive intestinal peptide/VIP

Histamine

It is a tissue amine (histo-tissue), which is closely associated with allergic reactions (Type I Hypersensitivity Reactions)

Found in: Mast cells and basophils(predominant stores of histamine), skin, gastric mucosa, lungs, liver, placenta.

It is also found in blood, body secretions, venoms, etc.

Synthesis: It is synthesized from amino acid histidine.

Storage: In storage granules and is held by acidic proteins (Histamine itself is positively charged)

Release: It is released by the process of exocytosis in response to allergens which are detected by the receptors on mast cells. However, beta-agonists inhibit release of histamine.

Action on Receptors: Histamine acts on four types of receptors, based on specific receptor antagonists as:

  • H1
  • H2
  • H3- Auto-receptor with no clinical application
  • H4- Has found a role in inflammatory states and rhinitis, allergy

Actions on Body Systems:

  • Nervous System- Stimulate sensory nerve endings which transmit pain and itch sensations
  • Cardiovascular System- Decrease blood pressure (systolic and diastolic)
  • Respiratory System- Cause bronchoconstriction
  • Gastrointestinal System- Intestinal smooth muscle contraction and peristalsis. Increased secretion of gastric acid, pepsin and intrinsic factor (for Vit.B12 absorption)
  • Uterus- Uterine smooth muscle contraction and abortion

Thus, excessive release causes flushing, vasodilation, pain (typical of acute inflammation), hypotension and tachycardia (characteristic of anaphylactic shock) and angioedema, bronchospasm, increased wakefulness and increased gastric acid secretion (acidity). These actions are antagonised by the specific receptor antagonists.

Histamine Antagonists:

Depending upon their receptor action, as mentioned above, the histamine antagonists are classified as follows:

H1 Antagonist: They are the most widely used anti-histaminics. However, second generation anti-histaminics are preferred today over the traditional first generation anti-histaminics since latter have marked sedative effects and CNS actions.

First Generation Anti-Histaminics:

Being lipid soluble, they cross the blood brain barrier and enter the CNS, having marked sedative action. They include:

  • Promethazine, Diphenhydramine, Dimenhydrinate-Potent and Marked Sedation
  • Chlorpheniramine, Chloryclizine- Potent and Moderate Sedation
  • Mepyramine and Pheniramine- Less Potent and Mild Sedative

Second Generation Anti-Histaminics:

Being less lipid soluble, they do not enter the CNS and thus, have no/negligible sedative action. They include the widely used over-the-counter medications such as:

Cetrizine, Levocetrizine, Terfenadine, Astemizole, Ketotifen, Loratadine

Serotonin

Synthesis: It is a monoamine derivative of tryptophan amino acid, also known as 5-Hydroxytryptamine.

Storage: Nearly 90% of serotonin is found in the entero-chromaffin like cells in the alimentary canal (regulate intestinal movements) while 10% is found in the nervous system in the brain (regulate mood, appetite, sexual desire, attitude, memory and behaviour). It is synthesized in the brain, but CANNOT cross the blood-brain barrier.

Serotonin in the blood is also stored in the platelets, which release it during bleeding from the vessel. Serotonin causes vasoconstriction and thus, limits blood loss.

Patho-Physiological Effects: They can be either due to an excess or deficiency of serotonin.

High Serotonin Levels:

  • Obsessive Compulsive Disorder
  • Pulmonary Vasoconstriction leading to pulmonary hypertension
  • Mania and Elation

Low Serotonin Levels:

  • Mood lability, including depression and suicidal ideation
  • Unexplained tears, disturbed sleep cycle

Release: It occurs by serotoninergic neurons in the CNS in response to various stimuli, and is also affected by normal Circadian Rhythm.

Receptors and Mechanism of Action: The action of serotonin is mediated by serotonin receptors numbered from 5HT-1 to 5HT-7.

Except 5HT-3 (which is ligand gated receptor), all the other receptors are G-Protein Coupled Receptors (which act via a secondary messenger signalling pathway)

Prostaglandins

They are hormone like lipid compounds which are derived from fatty acids. They are synthesised from essential fatty acids.

Description: Overview of prostaglandin (PG) synthesis and main functions ...

Release: They act in an autocrine and paracrine fashion to bring out their desired effects. They are released by two main transporters: Multidrug-Resistance Protein (MRP4) and ATP-Binding Cassette transporter (ABCC4).

Pharmacological Actions:

Blood Pressure Regulation: PGE2 and PGI2 (Prostacyclin), result in vasodilation and a fall in blood pressure. Thus, they are used in treatment of pulmonary hypertension.

Inflammation: PGD2 is anti-inflammatory while PGE1 and PGE2 are pro-inflammatory (redness, swelling, transudation of fluid and pain)

Uterus: PGE2 and PGF2-alpha cause uterine contraction. Thus, during induction of abortion, the analogues of the above two prostaglandins are used.

Pain and Fever: PGE2 acts on thermoregulatory centre present in the hypothalamus causing fever (pyrogen). Thus, NSAIDS, which inhibit the prostaglandin formation such as Aspirin, Paracetamol and Ibuprofen are used as first line drugs for management of fever.

Gastrointestinal System: Prostaglandins decrease gastric acid secretion and are thus muco-protective and ulcero-protective. However, they increase pancreatic secretions and increase intestinal motility.

Immune System: Prostaglandins decrease the immunological functions of B and T lymphocytes.

Respiratory System: PGEs causes smooth muscle relaxation whereas PGFs cause bronchoconstriction. Thus, they have antagonistic effects on the bronchi.

Renal System: PGE2 is the most abundant prostaglandin in the kidneys. They increase GFR and thus, urine output.

Platelets: PGI2 inhibits platelet aggregation (Clopidogrel is used in maintenance treatment of myocardial infarction as it is anti-aggregatory for platelets). PGE2 and Thromboxane A2 promotes platelet aggregation and thrombosis.

Eyes: They decrease the intraocular pressure and are thus used in the treatment of glaucoma. Eg. Latanoprost, Carboprost, Travoprost.

Categories
PHARMACOLOGY

Pharmacology of drugs: Nasal Decongestants

Nasal congestion refers to increased blood flow to the nose and the adjoining paranasal sinuses. It is in response to an inflammatory condition (an infection) or allergic congestion. It generally results in a blocked nose or a stuffy nose due to nasal obstruction. Nasal decongestants are used to relieve these symptoms. Some of the common conditions causing nasal congestion include:

  1. Allergies like hay fever, pollen
  2. Common cold or influenza
  3. Deviated nasal septum
  4. Sinusitis
  5. Infected nasal polyps

Nasal decongestants directly act on the blood vessels and cause vasoconstriction.  A vast majority of them are sympathomimetics. They induce vasoconstriction and thus decrease vascular permeability and the resultant inflammation.

Histamine is a local molecule that is implicated in local allergic reactions.
Some nasal decongestants block the action of histamine as well and thus, limit the congestive symptoms. It is particularly helpful in patients of seasonal allergy.

allergen
Some nasal decongestants reduce the host response to the allergen/foreign agent.

 
 
Some nasal decongestants reduce the host response to the allergen/foreign agent. This provides symptomatic relief to patients. Corticosteroids are thus widely used for this purpose. However, they have a doubtful efficacy in the treatment of congestive symptoms.

They are widely available as topical nasal drops, in the form of oral preparations and also as inhalers.

Different Drug Classes:

Indirectly acting sympathomimetics:

  • Ephedrine – Indirectly increases the release of norepinephrine to cause vasoconstriction. It is non-selective and low efficacy.
  • Levomethamphetamine- (Vicks)
  • Phenylpropanolamine
  • Propylhexedrine
  • Pseudoephedrine (Sudafed) – can be given orally.

α-Adrenergic receptor agonists:

  • Naphazoline- It is marketed as Privine
  • Oxymetazoline-It is marketed as Nasivion and Sinarest
  • Xylometazoline- It is marketed as Otrivin

Corticosteroids:

  • Beclomethasone dipropionate- (Beconase, QNASL)
  • Budesonide- It is marketed as Rhinocort.
  • Fluticasone

Side-Effects and Extra-Nasal Action:

Inhalers are generally preferred over topical preparations since they are easy to self-administer, have a wide surface area of activity and thus have a rapid onset of action. However, there may be initial tingling or burning sensation (especially with drugs like naphazoline). It is mild and transient.
Sustained use may predispose to atrophic rhinitis (due to vascular contraction) and will lead to anosmia (lack of perception of smell).

Long term use of nasal decongestants is not advised as it can lead to desensitization and tachyphylaxis. Thus, the blood vessels no longer contract and there is no significant relief. Besides, prolonged usage of adrenergic agonists may lead to paradoxical nasal congestion. They should not be used for more than 3 days in a row. This condition is called rhinitis medicamentosa. It is more pronounced with sympathetic drugs and corticosteroids. This precludes long-term usage.


Long term corticosteroids may also lead to immunosuppression and lead to opportunistic fungal infections including candidiasis and aspergillosis. They may induce diabetes as well. Hence, they are not the first-line drugs and are only used for severe cases.


Caffeine in coffee can increase the side effects of these medications. Theophylline (used in bronchial asthma), theobromine (in chocolates) can also supplement the activity of the above drugs. Thus, large doses should be avoided.


In patients with systemic hypertension, vasoconstriction can further increase blood pressure. They may face serious side-effects such as throbbing headache, micro-vascular hemorrhages, dizziness, retinal bleed, etc.


Many nasal decongestants should not be taken by individuals who are also taking MAO inhibitors (selegiline and rasagiline). MAO-inhibitors inhibit the degradation of epinephrine and norepinephrine. Along with sympathomimetics, they may precipitate a hypertensive crisis. In patients with an enlarged prostate, it may aggravate the symptoms and cause urinary incontinence.


The CNS effects of the nasal decongestants are variable. They include excitability, restlessness, and insomnia. Thus, they are combined with an anti-histaminic which has a sedative property. However, many fixed dosed combinations are under review by the FDA with respect to actual efficac

Categories
PHARMACOLOGY

Pharmacology of drugs: Respiratory Stimulants

Respiratory Stimulants: Types and Uses

Respiratory stimulants are a subset of drugs referred to as analeptics. They are shown to mildly increase alertness, lessen the fatigue and decrease drowsiness. However, higher doses may cause nervousness and precipitate convulsions.

Thus, respiratory stimulants have a narrow margin of safety for clinical use. They require therapeutic dose monitoring. They are primarily used to stimulate respiration, in post-anesthesia states, coma or respiratory muscle weakness. Thus, their primary use is to treat respiratory depression in emergency cases and post-anesthesia recovery.

The drugs in this category include:

  1. Doxapram
  2. Prethcamide
  3. Pentylenetetrazole
  4. Nikethamide (It is now withdrawn as it can cause convulsions)

Historically, strychnine which is a spinal poison was used to treat the overdose with sedative-hypnotic drugs. It antagonizes the action of glycine which is itself an inhibitory neurotransmitter.

Bicuculline and Picrotoxin are other drugs. They antagonized the action of GABA, which is another inhibitory neurotransmitter. Thus, inhibition of an inhibitory transmitter leads to excitation.

All three drugs today have no medical significance. They are relevant from a toxicologic point of view.

(For clarity; Inhibitory neurotransmitters: Glycine, GABA

Excitatory neurotransmitters: Glutamate, Serotonin, Dopamine, Acetylcholine, etc)

The therapeutic indications of these respiratory stimulants include:

  1. Following hypnotic poisoning (for e.g. Barbiturate overdose) till the time mechanical ventilation is made available.
  2. Suffocation (due to poisonous gas inhalation) or drowning, both of which signify acute respiratory insufficiency.
  3. Apnea in premature infants (for eg. due to underdevelopment of respiratory center in the medulla oblongata)
  4. To aid in spontaneous ventilation after general anesthesia.

Mechanism of Action: Respiratory Stimulants

respiratory stimulant

Since these groups of drugs act on the Central Nervous System, they have complex interactions with receptor-channels and neurotransmitters.

Doxapram is a potassium channel blocker in the carotid and aortic chemoreceptors. This leads to increased positivity inside the cell, calcium entry and depolarization. Thus, they lead to afferent impulses, which stimulate respiration. Side effects are comparatively rare.

Caffeine is an adenosine antagonist. Adenosine causes CNS depression through various pathways, leading to sleepiness and fatigue. Caffeine, being an antagonist reverses these effects. The side effects include insomnia, diuresis, tinnitus (ringing in the ears), and psychological dependence.

Drugs like buspirone and mosapride are serotonin agonists. Serotonin is a neurotransmitter which leads to wakefulness and produces an analeptic response.

Another class of drugs called AMPAkines (amino-hydroxy-methyl-aspartate) causes stimulation of neurons in the ventral group of the Respiratory Centre. Prolonged action potentials in this area are responsible for an increase in the rate of respiration. The endogenous neurotransmitter Glutamate acts through these AMPA receptors.

Therapeutic Uses of drugs:

Doxapram- It is a selective respiratory center stimulant with little convulsant potential. It is a short-acting drug and is excreted rapidly. It promotes the excitation of neurons in the central nervous system. Respiration is stimulated through activation and discharge of aortic and carotid chemoreceptors. Nausea, coughing, and restlessness are side effects.

There is a marked rise in the blood pressure of hypotensive patients. Apnoeic premature infants who do not respond to theophylline, do respond to doxapram given through continuous IV infusion.

Caffeine- It is a potent analeptic as well. Therapeutically, it is used for respiratory stimulation in cases of apnoea and bronchopulmonary dysplasia in infants. It does not treat it. However, the occurrence is reduced.

Theophylline, another closely related drug to caffeine is not used in infants because of its toxicity and adverse drug profile.

Respiratory Stimulants: Existing Scenario 

Respiratory stimulants are rarely used nowadays. Many short-acting anesthetic agents, including thiopentone sodium, sevoflurane, and desflurane, etc preclude the need for a respiratory stimulant.

Barbiturate overdoses today, are treated more efficiently with alkaline diuresis and other supportive measures, thus obviating the need for doxapram.

In infants, recent studies have shown that doxapram may increase cerebral oxygen demand, leading to delayed milestones. Hence it is cautiously and sparingly used.