QB Pharmacology 2

Calcium (Ca2+) is an essential mineral that plays a critical role in numerous physiological processes throughout the body. While it is most widely associated with bone health, calcium also has far-reaching effects on muscle function, nerve signaling, cellular communication, and hormone regulation. Building and Maintaining Strong Bones and Teeth: Calcium is the primary structural component of bones and teeth, providing them with their characteristic strength and rigidity. Muscle Contraction and Relaxation: Calcium ions are essential for muscle contraction and relaxation. In skeletal muscles, the release of calcium from the sarcoplasmic reticulum triggers the interaction of actin and myosin filaments, leading to muscle fiber shortening and contraction. In smooth muscles, calcium ions regulate the contraction and relaxation of muscles in the blood vessels, airways, and digestive tract. Nerve Impulse Transmission: Calcium ions are crucial for nerve impulse transmission. The influx of ca

Clinically Available Insulins  Modern genetic engineering techniques enable specific amino acids in the molecule to be changed and the molecule subtly altered to form new preparations with advantageous properties for people with diabetes. Classification of Clinically available Insulin Preparations - Rapid Acting : Insulin lispro, Insulin Aspart Short Acting : Regular Human insulin Intermediate Acting : NPH Human   Long Acting : Insulin Detemir , Insulin Degludec .  Pharmacokinetics of Insulin preparations:  Administered via SQ injection and absorbed directly to the systemic circulation Majority of insulin degradation happens in the Liver and Kidney  Kidney is the main metabolism site  Do not enter the Hepatic portal system.  CLASS Onset of Action DOA Example Rapid Acting Inhaled 10 – 30 m 2-4 hrs Afrezza Oral 15 – 30 m 3 hrs Lispro; Aspart Short A

Discuss the thermo-genic effects of thyroid hormone on body temperature Thermogenesis is the process of heat production in organisms, and it’s a vital part of the metabolic rate. Thermogenic Effects if Thyroid Hormone: Thyroid Hormone Increases The O2 consumption. Most peripheral tissues contribute to this response; heart, skeletal muscle, liver, and kidney are stimulated markedly by thyroid hormone. As a result cardiac contractility is increased.  In response to cold exposure, there are  low hypothalamic thyroid hormone concentrations  but increased thyroid hormone levels in the periphery.  When thyroid hormone levels are high, such as in hyperthyroidism, this can cause a person to feel too hot. Conversely, when thyroid hormone levels are low, as in hypothyroidism, this can cause a person to feel too cold. 

Mode of action of Oral hypoglycemic Agents  Sodium-glucose cotransporter 2 (SGLT2) inhibitors, also known as gliflozins , are a class of oral hypoglycemic agents used to lower blood glucose levels in adults with type 2 diabetes. Examples: Dapagliflozin, Empagliflozin etc.   Mode of Action: They work by blocking the function of the SGLT2 protein within the kidneys (PCT, 90% glucose reabsorption). This protein is primarily tasked with the reabsorption of glucose from the glomerular ultrafiltrate .  By inhibiting SGLT2, these drugs prevent the reabsorption of glucose, leading to increased urinary glucose excretion. This mechanism corrects hyperglycemia independently of insulin. As a result, blood glucose levels are reduced.  Note: In addition to their glucose-lowering effect, SGLT2 inhibitors have been found to have benefits on cardiovascular and renal outcomes, independent of their effects on blood glucose. They may also promote weight loss and modest improvements in blood pressure and

Side effects of Alpha-glucosidase inhibitors  α-Glucosidase inhibitors cause dose-related malabsorption , flatulence , diarrhea , and abdominal bloating. 

Low Molecular Weight Heparins (LMWHs) are a type of anticoagulant medication that work by inhibiting factor Xa, a key component in the blood clotting process. Therapeutically, LMWHs are used to prevent and treat deep vein thrombosis (DVT) and pulmonary embolism (PE), conditions that occur when blood clots form in the deep veins of the body.  MOA It inhibits activated coagulation factors of the intrinsic and common pathways, including thrombin , Xa , and IXa ; however, it has relatively little activity against factor VIIa .  Low-molecular weight heparin preparations produce an anticoagulant effect mainly through inhibition of Xa by antithrombin , because the majority of molecules are of insufficient length to catalyze inhibition of thrombin . THERAPEUTIC USES OF LMWHs Prevention of deep vein thromboses in the middle and high-risk populations (surgical, orthopedic, and medical patients). Treatment of pregnancy venous thromboembolism.

Classify Antiplatelet Side effects of Antiplatelet Agents: Aspirin:  Aspirin induced Asthma : Blockage of COX enzyme indirectly induces the production of Leukotrienes which is a cause of Asthma.  Excessive Bleeding : Aspirin blocks the production of TXA2 in mature platelets throughout its life time (10 days). so, After using aspirin there is a greater chance of Bleeding.  Clopidogrel: Gastrointestinal Hemorrhage  Melena  Rectal Hemorrhage  Rash  Abciximab:  Hemorrhage  hypotension  Myocardial Infraction Cardiac Arrest 

Which fibrinolytics principally used in surgical procedures? tenecteplase or reteplase Enumerate the most prevalent side effects of fibrinolytic Fibrinolytic agents are a class of medications used to dissolve blood clots. They work by breaking down fibrin, the protein that forms blood clots. Fibrinolytics are most commonly used to treat heart attacks and strokes, but they can also be used to treat other conditions such as pulmonary embolism and deep vein thrombosis. The major toxicity of all thrombolytic agents is hemorrhage, which results from two factors:   (1) the lysis of fibrin in “physiological thrombi” at sites of vascular injury; and  (2) a systemic lytic state that results from systemic formation of plasmin, which produces fibrinogenolysis and destruction of other coagulation factors (especially factors V and VIII) Other Side effects: Headache  Cerebral Haemorrhage  Nausea Fever  Rash etc 

Heparin Types  Heparin Type Description Example Standard heparin (unfractionated heparin or UFH) Inhibits Factor Xa and IIa (1:1 ratio) Heparin Lower Molecular Weight Heparin (LMWH) Majorly inhibits Factor Xa Enoxaparin Heparan Sulphate   Danaparoid Fondaparinux     Mechanism of Oral Anticoagulants  Vitamin K inhibitors   Antifactor Xa inhibitor Apixaban Binds with Factor Xa ¯ Inhibits action of FXa ¯ ¯ formation of Thrombin ¯ ¯ Rate of blood Clotting Direct Thrombin Inhibitor Binds to active site of Factor IIa ¯ Inactivate both free and fibrin bound thrombin ¯ ¯ Thrombin ¯ ¯ Fibrin formation from fibrinogen ¯ ¯ Coagulation

Mechanism of Drug Interactions 1.       Metabolism Interaction (Pharmacokinetic) (of Warfarin/ vit K inhibitors) ( disulfiram, clopidogrel, amiodarone ) ¯ Inhibits CYP2C9 (Responsible for Warfarin Metabolism) ¯ ¯ Metabolism of Warfarin ¯ ­ Risk of Haemorrhage 2.       Pharmacodynamic Interactions: Synergistic or Antagonistic Effect by another drug. Heparin ¯ Inhibition of Factor II a and X a ¯ No blood Coagulation + Aspirin (blood thinner) ¯ Risk of bleeding Adverse Drug Reactions of Oral anticoagulants 1 . Risk of Bleeding 2. Rash 3. Impaired Hepatic Function 4. Hyperthyroidism 5. Congestive Heart Failure 6. Gastric Ulcer haemorrhage

 Classification of Fibrinolytic Agents based on their Target of Action  Based on the Target of Action. Fibrinolytic Drugs are classified into 3 generations- 1st Generation: Acts by Fibrinolysis + Fibrinogenolytic action (Non-selective)  Site of Action: Free Plasminogen and Fibrin found in Plasminogen (Less Specific).   Examples: Streptokinase, Urokinase Mode of Actio n:  Binds to Free Plasminogen: Depletes free fibrinogen (Fibrinogenolysis) Bleeding Complication  Binds to Fibrin bound Plasminogen: Fibrinolysis (Less Specific)  2nd Generation: Acts by mostly on Fibrinolysis (75 % Selective) Site of Action : Fibrin found in Plasminogen.  Examples : Alteplase  Mode of Action :  Binds with  Fibrin found in plasminogen (75%): Fibrinolysis  More Fibrin Specific (75%)  3rd Generation: Acts selectively on Fibrinolysis (Selective) Site of Action : Fibrin  bound Plasminogen.  Examples : Reteplase, Monteplase  Mode of Action :  Binds selectively with Fibrin Bound Plasminogen Activation of Plasm

Classification of Anticoagulant Drugs 

Supraventricular tachycardia (SVT) is an irregularly fast or erratic heartbeat that affects the heart’s upper chambers. The mechanism by which adenosine reduces the incidence of SVTs, particularly atrioventricular nodal reentrant tachycardia (AVNRT) and atrioventricular reentrant tachycardia (AVRT), involves its effects on the AV node.

Classify antithyroid agents in terms of their mechanism of actions. Thyroid hormone synthesis inhibitors : These drugs inhibit the enzyme thyroid peroxidase, decreasing iodide oxidation, iodination of tyrosyl residues in thyroglobulin, and coupling of iodotyrosyl and iodothyronyl residues.  EXAMPLES : thioamides, which include propylthiouracil , methimazole , and its prodrug carbimazole. Iodide uptake inhibitors/ ionic Inhibitors : They decrease the uptake of iodide ions into follicular cells of the thyroid gland.  EXAMPLES : potassium perchlorate, pertechnetates, thiocyanates, and nitrates. Thyroid hormone release inhibitors : They inhibit the release of thyroid hormones by the thyroid gland. EXAMPLES : The most studied drug in this class is lithium . Thyroid hormone receptor antagonists : These drugs block the action of thyroid hormones at the cellular level. They do this by binding to thyroid hormone receptors and preventing thyroid hormones from exerting their effects. Examples in

Synthesis of Thyroid Hormones  The synthesis of the thyroid hormones is unique , complex , and seemingly grossly inefficient .  The major steps in the synthesis, storage, release, and interconversion of thyroid hormones are the following: Uptake of Iodide (I-) ion by the gland;  Oxidation of iodide and the iodination of tyrosyl groups of thyroglobulin; Coupling of iodotyrosine  residues by ether linkage to generate the iodothyronines; Resorption of Thyroglobulin colloid from the lumen into the cell  Proteolysis of thyroglobulin.   Release of thyroxine and T3 into the Blood.  Conversion of thyroxine (T4) to T3 in peripheral tissues.  UPTAKE OF IODIDE Iodine is actively transported via a specific membrane bound protein termed as the sodium-iodide symporter (NIS) . TSH stimulates the NIS controlled by an autoregulatory mechanism. Thus, decrease stores of Thyroid iodine enhances iodine uptake .  OXIDATION & IODINATION (of tyrosyl group of thyroglobulin) The oxidation of iodine to its a

Illustrate the mechanism of action of sulfonic urea used as oral hypoglycemic agents. Enumerate the role of insulin on glucose utilization. MOA of Sulfonyl Acid Derivatives Sulfonylureas ( Tolbutamide, Chlorpropamide ), a class of sulfonyl acid derivatives, have a significant action in lowering blood glucose levels in normal subjects and in  type 2 diabetics . The mechanism of action of sulfonylureas involves provoking a brisk release of insulin from the pancreas. MOA:  (1) They act on the so-called  ‘sulfonylurea receptors’ (SUR1)  on the pancreatic β cell membrane.  (2) This action causes  depolarization  by reducing the  conductance of ATP-sensitive K+ channels .  (Raised ATP production followed by raised Glucose also reduces the conductance of ATP sensitive K+ Channels) (3) This process enhances  Ca2+ influx  (Followed by the stimulation of Voltage sensitive Ca++ Channel)   and degranulation (followed by calcium dependent translocation), which  increases the rate of insulin secret

In spite of its effective analgesic activity aspirin is used in prevention of formation of atherosclerotic disorder – explain why?? Aspirin , also known as  acetylsalicylic acid  ( ASA ), is a  nonsteroidal anti-inflammatory drug  (NSAID) used to reduce  pain ,  fever , and/or  inflammation , and as an  antithrombotic .   Aspirin is widely known for its analgesic (pain-relieving) properties, but it also plays a crucial role in the prevention of atherosclerotic disorders. Aspirin irreversibly inactivates the Cyclooxygenase Enzyme ( Prostaglandin Endoperoxide Synthase ) in the Arachidonic Acid Metabolism Pathway , and supress the production of Prostaglandin (PGs) and Thromboxane (TXs) and Prostacyclin ( Prostanoids ).  Atherosclerosis, also known as arteriosclerosis, is a condition where the arteries become thick and stiff due to the buildup of plaque. The plaque can also burst, leading to a blood clot.  ASPIRIN EFFECT ON PLATELETs (TXA2 mechanism):  Aspirin irreversibly blocks both C

Ondansetron is an antiemetic medication, which means it’s used to prevent nausea and vomiting. It works by blocking the action of a chemical messenger known as serotonin in the brain and the gut. It is a serotonin 5-HT3 receptor antagonist ("setron") which inhibits serotonin binding to the 5-HT3 receptors  in the terminals of afferent fibres of the vagus nerve. This inhibits the activation of the vomiting center in the medulla oblongata. and in the CTZ of Medulla oblongata of brain. 

Second-generation antihistamines (eg, cetirizine, loratadine)

Angiotensin I is a ten amino acid peptide formed by renin cleavage of angiotensinogen. REFERENCE 

Serotonin reuptake inhibition and Depression  Serotonin have potent anti-migraine activity by action on 5-HT1B/1D receptor.    5-HT, or serotonin, is a neurotransmitter that plays a crucial role in mood regulation. Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs commonly used to treat depression.  They work by inhibiting the reuptake of serotonin into neurons, which results in increased serotonin levels in the synaptic cleft enhancing its binding to post-synaptic neurons leading to increased Serotoninergic neurotransmission.  Depression is a monoamine deficiency syndrome. So, the treatment may by in such a way in which the 5-HT level may be increased. This is done in 2 ways- Decreased MAO action: MAO is an enzyme, which is responsible for the metabolic breakdown of serotonin. Inhibiting the MAO, the overall concentration of Serotonin can be increased in the synaptic cleft.  Selective serotonin reuptake inhibitors (SSRIs)  MODE of ACTION: (SSRIs)   

Regular administration of broken tablet of aspirin may increase the chances of gastric ulcer – enumerate the reasons Aspirin, also known as acetylsalicylic acid (ASA), is a commonly used drug for the treatment of pain, fever, and inflammation. Aspirin comes with Enteric Coating. this type of coating is made to withstand the tablet in strong acidic condition of stomach acid. As aspirin is a Acidic drug its absorption will be greater in basic pH. As stomach has Acidic pH, an enteric coating is made so that the tablet can pass through the stomach and can reach intestine and absorbed.  Breaking the Aspirin tablet Damages the coating also and makes it readily dissolve inside stomach due to increased surface area after broken. It increasing the chance of gastric ulcer due to several reasons: Blockage to Prostaglandins: Prostaglandins are responsible for the inhibition of Gastric acid release and mucosal Protection. Aspirin blocks the action of PGs leading to risk of developing Ulcers.  Decr

  Open-angle glaucoma is a chronic condition that can lead to v ision loss due to damage to the optic nerve . This damage is often caused by an increase in intraocular pressure (IOP) , which is the pressure inside the eye. Prostaglandin agonists, such as travoprost and latanoprost , are often used as a first-line treatment for open-angle glaucoma.  Mechanism Of Action: PGs binds with FP receptor of ciliary muscle cells inducing the expression of Matrix metalloprokinase (MMP) enzyme. MMP is responsible for the fragmentation of Collagen fibers.  Fragmentation of Collagen Fibers increases the Uveoscleral outflow (Aqueous humor outflow) to the extracellular space.  That results in decrease intraocular pressure reducing the risk of damage to the optic nerve.  In summary, prostaglandin agonists can help arrest the progression of open-angle glaucoma by effectively reducing intraocular pressure, which is a key factor in the development of this condition

Prostaglandin has significant constitutive role on gastric acid secretion – explain the mechanism Prostaglandins are locally produced signaling molecules derived from arachidonic acid, an essential fatty acid. In the stomach, prostaglandins are mainly synthesized by gastric parietal cells, the primary acid-secreting cells. The enzyme cyclooxygenase-1 (COX-1) is responsible for prostaglandin production in these cells. Prostaglandins, particularly Prostaglandin E (PGE), play a significant role in gastric acid secretion. They are involved in the regulation of various gastric functions that contribute to gastric protection.  Mechanism  PGE2 and PGI2 have significant role in gastric acid secretion . Prostaglandins bind with EP receptor (a GPCR) and stimulate the Gi protein. Gi pathway is responsible for the inhibition of Adenylyl Cyclase Pathway .  So, AMP can not converted to cyclic AMP thereby reducing the PKA and decrease in Gastric Acid Secretion by Proton Pump.  Prostaglandins decreas

Describe the pharmacological function of histamine on induction of inflammation. Explain the mechanism of gastric acid secretion and antiulcer activity of H2 blockers Histamine plays a crucial role in the induction of inflammation. It is a biogenic vasoactive amine that impacts the immune system, usually as proinflammatory factors Induction of Inflammation Histamine acts on four different histamine receptors: H1, H2, H3, and H4. The H1 & H4 receptor is responsible for most of the effects of histamine on the triple response as well as for the induction of inflammator y response. Mechanism –  (H1 Receptor)  Histamine induces inflammation by binding to H1 receptors on blood vessels and other cells. ¯ This binding causes vasodilation and increased vascular permeability (leakiness of the blood vessels). ¯ This leads to increased blood flow and fluid accumulation (with inflammatory mediators) in the tissues (Exudation) ¯ Results in the redness , swelli