Pharmacology-I Spring 2024 Autocoids Lecture 5 PDF

# Pharmacology-I ## Spring 2024 ### (PCL332/PO315/POC316) ## AUTACOIDS (PART 1) ### Lecture 5 #### By ###### Dr/Sarah Baraka ##### Lecturer of pharmacology & Toxicology ###### Dr/Sarah Baraka ## Lecture learning outcomes - Identify the pharmacological actions, side effects, drug interactions of dr...

# Pharmacology-I ## Spring 2024 ### (PCL332/PO315/POC316) ## AUTACOIDS (PART 1) ### Lecture 5 #### By ###### Dr/Sarah Baraka ##### Lecturer of pharmacology & Toxicology ###### Dr/Sarah Baraka ## Lecture learning outcomes - Identify the pharmacological actions, side effects, drug interactions of drugs acting locally (autacoids). - Utilize data from basic sciences to address therapeutic issues. - Select the appropriate pharmacotherapeutic approaches based on the etiology, pathophysiology and clinical features of different diseases. - Recognize the pharmacological properties of different drugs. ## Contents - What are the autacoids? - Histamine. - Serotonin - Angiotensin - Bradykinin - Endothelin - Nitric oxide ## WHAT IS AUTACOIDS - Greek autos (“self”) - Akos (“cure”): Healing Substance, medicinal agent, or remedy - Definition: are a group of naturally occurring endogenous compounds that are being formed by the tissues on which they act so they function as local hormones (at the site of synthesis and release). - They differ from circulating hormones in that they are produced by many tissues rather than in specific endocrine glands - Paracrine effect: Secreted by one cell & acts upon adjacent cells or surrounding extracellular matrix. - Autocrine effect: Secreted from a cell and acts on the same cell. ## Classification - Biogenic amines - Histamine & Serotonin - Lipid derived - Prostaglandins & Thromboxane - Peptides - Angiotensin, Bradykinin, Endothelin - Gases - Nitric Oxide (NO) ## Function - Modulate blood flow in specific tissues - PGs maintain renal blood flow - Modulate secretory processes - Histamine on gastric acid secretion - Play a key role in allergy, inflammation, pain, and certain types of drug reactions - Histamine, Bradykinin There are drugs that activate autacoid receptors (autacoid agonists) or drugs that inhibit the synthesis of certain autacoids or that interfere with their interactions with receptors (autacoid antagonists) ## Biogenic amines ### 1- Histamine - **Synthesis of histamine** - L-histidine amino acid - Decarboxylation - Histamine - L- histidine decarboxylase - **Location of histamine** - Stored in mast cells and basophils which present mostly in the skin, respiratory tract, blood vessels, - produced by enterochromaffin-like (ECL) cells (paracrine cells) in the GIT - where it stimulates acid secretion by parietal cells - As a neurotransmitter in the brain. - Histamine has no clinical applications, but agents that inhibit the action of histamine (antihistamines or histamine receptor blockers) have important therapeutic applications ## Biogenic amines ### 1- Histamine - **RELEASE OF HISTAMINE** - Histamine is stored in granules (vesicles) in mast cells and basophils - It is released from mast cells when membrane-bound immunoglobulin E (IgE) interacts with an antigen to cause mast cell degranulation - **TRIGGERS OF HISTAMINE RELEASE:** - 1- Allergies and anaphylaxis - 2-Cold, toxins from organisms, venoms from insects and spiders, and trauma. ## Histamine Receptors and Effects ### 1- Histamine - **H receptors** **G protein** **2nd messenger** **Effects** - H1 Gq ↑PLC ↑IP3→↑ Ca release - Vascular SM: - Contraction of all SM Except VSM - VD of small BV (↑ endothelial release of nitric oxide) - ↑↑vascular permeability ⇒ erythema (heat and redness), congestion, edema. - Bronchial SM: - Bronchial SM contraction (Bronchoconstriction) ⇒ ↑ the cough reflex, Asthma?? - Intestinal SM: Contraction (intestinal cramps and diarrhea) - Mucocutaneous nerve endings (stimulates sensory nerve endings) ⇒ pruritus (itching) - If ↑↑histamine levels are released into the circulation→↓ PR and BP →anaphylactic shock. - Exocrine gland: Increase production of lacrimal, nasal & bronchial secretions (respiratory symptoms) - CNS - Distributed in the brain (wakefulness in the brain) How?? ## Role in allergy and anaphylaxis ### 1- Histamine - **Allergic inflammation:** - localized allergic reaction. - Effects, usually restricted to the tissue in which they are formed (skin, respiratory tract, blood vessels) - Signs & Symptoms - H1 receptors are involved in allergic reactions that cause atopic dermatitis, allergic rhinitis, conjunctivitis, Urticaria and asthma. - **Anaphylaxis:** It is a life-threatening generalized or systemic rapid-onset hypersensitivity reaction, it is fatal due to its rapid progression to respiratory collapse - If large amounts of histamine are released into the systemic circulation or if histamine release is too fast (reaches the circulation) - signs & symptom - Hypotension, bronchospasm, angioedema which may progress to anaphylactic shock ## Histamine Receptors and Effects ### 1- Histamine - **H receptors** **G protein** **Effects** - H2 GS - GUT: - Histamine is released from enterochromaffin like cells (ECL)⇒stimulates the parietal cells in the stomach ⇒↑↑ gastric acid secretion - Heart: - ↑↑ the heart rate and contractility - CNS (presynaptic receptors) - act as autoreceptors on histaminergic neurons to inhibit histamine release. - H3 GS ## Histamine H1 Antagonists=H1 receptor blockers ### 1- Histamine - **First generation** - **Examples:** Chlorpheniramine, Clemastine, diphenhydramine, meclizine, and promethazine, Cyproheptadine, azelastine, and ketotifen - More lipid soluble ⇒ Penetrate BBB more sedating - Short duration - **Second generation** - **Examples:** Cetirizine, fexofenadine, loratadine, and desloratadine. - Less lipid soluble ⇒ do not Penetrate BBB less sedating - Specific for peripheral H₁ receptors - Long duration (Once daily) - **MECHANISM OF ACTION:** - H1 blockers are competitive antagonists at the H1 receptor (they block the receptor-mediated response of a target tissue) - these drugs have no effect on histamine release from storage sites ⇒ They are more effective if given before histamine release occurs (preventing symptoms than reversing them once they have occurred) - persons with seasonal allergies (allergic rhinitis) should take them on a regular basis throughout the allergy season ## Histamine H1 Antagonists=H1 receptor blockers ### 1- Histamine - **Adverse Reactions** - **First generation** - As long as they penetrate CNS ⇒ they can cause other CNS side effect - 1-Sedation: bind to H1 receptors and block the histamine effect in the CNS. - 2- Autonomic receptor-blocking effects: - Because their structure resembles that of muscarinic blockers and a-adrenoceptor blockers - Block muscarinic receptors ⇒ Atropine like action (blurred vision- dry mouth-dry skin-urinary retention-constipation-glaucoma- tachycardia) - Elderly patients are more sensitive to these effects. - Alpha1 receptors blockers ⇒ VD: hypotension - Block Serotonin receptors: cyproheptadine ⇒ Increase appetite - **Second generation** - The most common adverse reaction is headache. ## Histamine H1 Antagonists=H1 receptor blockers ### 1- Histamine - **Adverse Reactions** - **First generation** - Particularly diphenhydramine and promethazine - Receptors - Cholinergic - α-Adrenergic - Serotonin - Histamine H₁ - Histamine H₂ - Effects - Dry mouth - Urinary retention - Sinus tachycardia - Hypotension - Dizziness - Reflex tachycardia - Appetite - Allergic inflammation, itching, sneezing and rhinorrhea - Neurotransmission in the CNS - Sedation - Cognitive and psychomotor performance - Appetite - **Second generation** - All H₁ antihistamines - Particularly promethazine - Particularly cyproheptadine - Adverse Reactions - Drowsiness - Urinary retention - Tachycardia - Hypotension - Vertigo - Dry mouth - Increased appetite ## Histamine H1 Antagonists=H1 receptor blockers ### 1- Therapeutic uses - **First generation** - 1- Allergic and inflammatory conditions (both generations) - controlling the symptoms of allergic inflammation (allergic rhinitis and urticaria, allergic conjunctivitis) - However, the H1-receptor blockers are not indicated in treating bronchial asthma?? - 2. Motion sickness and nausea - Diphenhydramine, cyclizine, meclizine, and promethazine - The antiemetic action of these medications seems to be due to: - their blockade of central H1 and M1 receptors in vestibular pathways and Chemoreceptor trigger zone (CTZ) - 3-Insomnia - Although they are not the medications of choice - But they have strong sedative properties and are used in the treatment of insomnia. - The use of first-generation H1 antihistamines is contraindicated in the treatment of individuals working in jobs in which wakefulness is critical. - The second-generation antihistamines have no value as somnifacients. - **Second generation** ## Histamine H2 Antagonists=H2 receptor blockers ### 1- Histamine - Histamine H2-Receptor Blockers= (H2 antagonists) - Examples: cimetidine, ranitidine, famotidine, and nizatidine - Mechanism of action: block the actions of histamine at H2 receptors in Parietal cells - ⇒↓ gastric acid secretion - Therapeutic uses: inhibitors of gastric acid secretion in the treatment of ulcers and heartburn. ## Biogenic amines ### 2- serotonin (5-HT) - Synthesis of serotonin - Serotonin (5-hydroxytryptamine, 5-HT) is synthesized from the amino acid L-tryptophan - Location of serotonin - Approximately 90% of human body's total serotonin located in GIT (enterochromaffin cells): regulate intestinal motility & secretion. - Actively taken by blood platelet and stored in storage granules (10%)⇒ At injury, platelet release serotonin ⇒ cause Vasoconstriction (VC) and blood clotting (platelet aggregation). - CNS (affect mood, appetite, body temperature regulation, and sleep) - Release of serotonin - serotonin is stored in vesicles and is released by exocytosis of the vesicle. - The activity of serotonin is terminated by uptake into the neuron and platelets. - Metabolism occurs mainly via monoamine oxidase. ## Biogenic amines ### 2- serotonin (5-HT) - There are seven families of 5-HT receptors (5HT₁, 5HT₂,…) ## Biogenic amines ### 2- serotonin (5-HT) - Receptor Type - 5-HT (A, B, C D.E.F) - 5-HT2 (A,B,C) - 5-HT3 - 5-HT4 - Site - CNS - CNS - CNS (im CTZ=vomit-inducing center) - GIT (in myenteric plexus) - CNS - GIT (inc motility) - Cardiac muscle (arrythmia) - Function - Sleep-appetite - body temperature regulation - (5HT-1A) ⇒Dec. anxiety & appetite - (5HT-1D/1B)⇒pain relief - (5HT-1B)>>Vasoconstriction of cerebral BV - 5HT-2A (Platelet) ⇒platelet aggregation (blood clots) - 5HT-2A (CNS) ⇒Hallucination - 5HT-2C (CNS) ⇒ mood, anxiety, appetite - -Induce vomiting - regulate intestinal motility & secretion - regulate intestinal motility & secretion - Drugs - Sumatriptans (5HT-1D/1B Agonist) - Migraine headache - Buspirone: (5HT-1A agonist) - Treatment of Anxiety, weight gain - Olanzapine & Clozapines - (5HT-2A Antagonist) - Treatment of Schizophrenia - Lorcaserin :5-HT-2C agonist - a new anti-obesity agent ⇒ food intake and promote fullness - Ondansetron: (5-HT3 Antagonist) - 5-HT3 receptor antagonists are highly effective for the management of chemotherapy-induced nausea and vomiting by blocking the effects of serotonin in the chemoreceptor trigger zone - Cisapride/Mosapride - (5-HT4 agonist) treatment of gastroesophageal reflux disease - Tegaserod (5-HT4 agonist) indicated for - irritable bowel syndrome - Gastrointestinalhypomotility - constipation ## Examples - 5-HT1A agonist - 5-HT1B/1D agonist - 5-HT2A antagonist - 5-HT3 antagonist - 5-HT4 agonist - 5-HT4 agonist ## Peptides ### 1- BRADYKININ - Bradykinin is one of several vasodilator kimims produced from kininogen by a family of enzymes (the kallikreins). - Bradykinin acts through 2 receptors (B1 and B2) - Effects: involved in inflammation and edema, vasodilation, pain transmission, Bronchoconstriction - Bradykinin also plays a role in hereditary angioedema (НАЕ) ## Peptides ### 2- ENDOTHELINS - Endothelins are vasoconstrictors peptide formed in and released by endothelial cells in blood vessels. - Three endothelin peptides (ET-1, ET-2, and ET-3) with minor variations in amino acid sequence have been identified in humans ⇒ that act on Two receptors ETA and ETB. - The ETA receptor appears to be responsible for the vasoconstriction produced by endothelins. - Endothelins may be involved in Idiopathic pulmonary HTN - Ambrisentan= a newer inhibitor of endothelin receptors (used for pulmonary HTN) ## Peptides ### 3- ANGIOTENSIN - Angiotensin I is produced from circulating angiotensinogen by renin, an enzyme released from the kidney. - Angiotensin I is an inactive peptide, is converted into angiotensin II (ANG II, an active peptide, by angiotensin-converting enzyme (ACE). - Angiotensin II acts on Ang type 1 receptor (AT1) - 1- Vasoconstriction - 2-↑ Aldosterone synthesis in the adrenal cortex ⇒ ↑ renal sodium absorption ⇒ ↑ blood volume. - 3- An antihypertensive class of drugs (ACE inhibitors): Can cause life threatening angloedema?? ## Gases ### Nitric Oxide - Nitric oxide (NO) is a gaseous signaling molecule that readily diffuses across cell membranes and regulates a wide range of physiologic and pathophysiologic processes including cardiovascular, inflammatory, and neuronal functions. - Synthesis ⇒ It is generated from l-arginine by nitric oxide synthase (NOS), an enzyme responsible for the synthesis of NO in different tisssues. ## Gases ### nitric oxide synthase (NOS) ### Nitric Oxide - There are three different isozymes of NOS, namely inducible NOS (INOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). - 1- Inducible NO synthase: Is a gene product which is not expressed under basal conditions in most cells. Expression of inducible NO synthase may occur in response to proinflammatory factors such as cytokines - 2- The constitutive forms: which are present under physiological conditions - Endothelial NOS (eNOS) : is constitutively expressed in endothelium. - Neuronal NOS (nNOS). : is constitutively expressed in specific neurons of the brain ## Gases ### Nitric Oxide - NO is a potent vasodilator - NO is the endogenous activator of guanylyl cyclase: an enzyme that convert (GTP⇒ cyclic GMP (cGMP) - Cyclic GMP (cGMP): an important 'second messenger'⇒+PKG ↑activity of myosin light-chain phosphatase (an enzyme that removes phosphate) ⇒ Dephosphorylation of myosin light chain ⇒ Smooth muscle relaxation ⇒ VASODILATION ## Gases ### Nitric Oxide - Epinephrine - B2-adrenoceptor - ATP - Adenylyl cyclase - cAMP - α-adrenoceptor - PIP2 - IP3 - Phospholipase C - Norepinephrine - Nitric oxide - GTP - Guanylyl cyclase - cGMP - Phosphatase - Myosin - Myosin light-chain kinase - Ca2+-calmodulin complex - Sarcoplasmic reticulum - Ca2+ - L-type calcium channel - Ca2+ - Calcium channel blockers - Vascular smooth muscle cell - Actin - Myosin phosphate - Contraction ## Thank you