Pharmacology PDF

Lec 1 Pharmacology: the study of the interaction between chemicals and living systems. Pharmacology subdivisions: ⁃ Pharmacokinetics: What the body does to the drug “ADME”. ⁃ Pharmacodynamics: What the drug does to the body “mech of action” ⁃ Pharamcotherapeutics: th...

Lec 1 Pharmacology: the study of the interaction between chemicals and living systems. Pharmacology subdivisions: ⁃ Pharmacokinetics: What the body does to the drug “ADME”. ⁃ Pharmacodynamics: What the drug does to the body “mech of action” ⁃ Pharamcotherapeutics: the use of drugs prevention, diagnosis, and treatment of disease. ⁃ Toxicology: the undesirable effects of drugs. Drug development criteria: Must be safe, effective in humans. Drugs must undergo animal testing (preclinical phase), and right after it manufacturer must submit an Investigational New Drug Exemption (IND) application. IND approval —> drug undergoes the 4 clinical trial phases The 4 phases: Phase I: studies safety + PKs in a small group of normal people (not patients). Phase II: studies efficacy in a small group of patients. Phase III: similar to II but a lot larger scale testing, using control drugs. Phase IV: Post-marketing surveillance for long-term effects. ANS importance: Regulates functions that are not under conscious control Eg: Blood pressure, heart rate, etc.. Sympathetic nervous system Parasympathetic nervous system Origin Thoracolumbar part of spinal cord Cranial nerve Preganglionic neurons Short path Long path Postganglionic neurons Long and terminate Short, near the targer Receptors Adrenergic (alpha & beta), and Cholinergic receptors (muscarinic dopamine & nicotinic) Functions Fight or ight Rest and digest Major neurotransmitters Norepinephrine Acetylcholine fl Lec 2 Direct acting: Choline esters, Cholinomimetic, Parasympathomimetic 1. Acetylcholine ⁃ kinetics: not absorbed orally, acid labile, doesn’t pass BBB (no CNS effects), rapidly hydrolyzed —> short duration ⁃ MOA: direct equal affinity stimulation of M + N, M is dominant at normal doses because it’s more sensitive. Actions of Ach: 1. CVS: ⁃ Heart (M2): ↓ Heart rate (bradycardia) → ↓ Cardiac Output ⁃ Blood vessels (M3): vasodilatation → ↓ peripheral resistance (PR) → ↓ Blood pressure 2. Smooth muscle (M3) ⁃ respiratory system: Bronchoconstriction → ↑ secretions → mucosal congestion ⁃ GIT & Urinary tract: ↑ motility → ↑ evacuation ⁃ Uterus: Contraction of non pregnant uterus. 3. Eyes: ⁃ Contraction of constrictor muscle → miosis & widening of filtration angle ⁃ Spasm of the ciliary muscle → opening of the Canal of Schlemm ⁃ Both ↑ drainage of aqueous humor to ↓ Intraocular pressure (IOP) - ↑ lacrimal secretions 4. Exocrine glands: (M3) ⁃ ↑ secretions for: lachrymal, salivary, nasopharyngeal, gastric acid, pancreatic and sweat glands. Nicotinic actions of Ach: Do not appear unless M receptor is blocked by atropine. Then, large dose of Ach is injected → Ach acts on N receptors in: ⁃ Parasympathetic ganglia: ↑ Ach release →effect blocked by atropine ⁃ Sympathetic ganglia → ↑ Noradrenaline (NA) release → ↑ adrenoceptors ⁃ Adrenal medulla → ↑ release of Ach into circulation → ↑ adrenoceptors ↑ Adrenoceptors = ↑ BP (Ach reversal) Ach in CNS controls: cognition, memory, motor control and vomiting reflex. Brain: Muscarinic receptors > Nicotinic Receptors Spinal cord: Nicotinic Receptors > Muscarinic receptors Cholin esters: Mathacholine - Carbachol - Bethanechol - kinetics; more absorbed orally than Ach, longer duration, more specific in action Structure-Activity ⁃ β -methylation: ↑ muscarinic and ↓ nicotinic ⁃ Carbamylation: protects from hydrolysis → longer duration Therapeutic uses: - Methacholine: Paroxysmal atrial tachycardia, Urinary retention, Raynaud's disease ⁃ Bethanechol: gastric atony, non-obstructive paralytic ileus and urinary retention. ⁃ Carbachol: glaucoma locally ADRs: Flush, sweating, GI cramps, bronchospasm, salivary hypersecretion, urinary urgency, bradycardia, hypotension. Contraindications: Intestinal/urinary mechanical obstruction, Asthma, COPD, CHD, hypotension, hyperthyroidism Cholinomimetic alkaloids (Pilocarpine): ⁃ Kinetics: absorbed orally, pass BBB (CNS access), partial agonist ⁃ Action: only muscarinic, on eyes & exocrine glands ⁃ ADRs: Blurred vision, excessive salivation, sweating, bronchospasms and hypotension. ⁃ Uses: 1. Topical (eye drops/ lotion) ⁃ Glaucoma: ↓ IOP ⁃ Prevent the mydriatic effect of atropine. ⁃ Promotion of hair growth: ↑ blood supply 2. Systemically (oral tabs) ⁃ Xerostomia secondary to conditions ⁃ Diaphoretic ⁃ Antidote for anticholinergic drugs poisoning Synthetic cholinomimetics 1. Cevimeline: full agonist effect for M3 ⁃ Use: Xerostomia, lesser side effects that pilocarpine ⁃ ADRs: Nausea, vomiting, diarrhea (NVD), excessive secretions, blurred vision ⁃ Contraindications: Asthma and glaucoma 2. Varenicline: partial agonist on nicotinic receptors ⁃ Use: smoking cessation therapy. Prevents rewarding and withdrawal effects of nicotine.  Lec 3 Cholinergic Drugs (Indirect Acting) Cholinesterase: a family of enzymes that catalyze the hydrolysis of Acetylcholine into choline + acetic acid and terminate its action, a reaction necessary to allow a cholinergic neuron to rest Anticholinesterase: cholinesterase inhibitors Inhibit the cholinesterase from breaking down Ach → increase both the level and duration of Ach Mode of action: 1. Reversible: are competitive or noncompetitive, have therapeutic applications 2. Irreversible: are associated with toxic effects Reversible anticholinesterase drugs - Role: plays in the pharmacological manipulation of the enzyme activity, and has various functional groups. - Application: in the diagnostic and/or treatment of various diseases. - MOA: - Carbamates: Carbamylate the esteratic site of the enzyme, thus blocking the entry of Ach before slowly dissociating. - Edrophonium: binds to the anionic site and dissociates rapidly. Drug Uses A. Alcohols (Edrophonium) Myasthenia gravis B. Carbamates Neostigmine Myasthenia gravis Physostigmine Glaucoma Physostigmine vs Neostigmine Physostigmine Neostigmine Source Natural alkaloid Synthetic Chemistry Tertiary amine Quaternary ammonium Kinetics Well absorbed orally, passes poorly absorbed orally, doesn’t BBB, slowly hydrolyzed pass BBB, passes placental barrier, short duration Actions - Non speci c muscarinic and - Nicotinic: at NMJ, has direct nicotinic, and CNS. stimulation of skeletal muscles - Locally: on eyes - Muscarinic: ↑GIT + UT motility fi  Physostigmine Neostigmine Uses - locally: on the eyes for - urinary retention + paralytic glaucoma ileus (NEVER obstructive) - Systemic: in the treatment of - Myasthenia gravis atropine poisoning - Antidot for NM blocker - Cobra envenomation Physostigmine Neostigmine Substitute Rivastigmine Pyridostigmine Uses Management of Alzheimer Treatment of myasthenia gravis disease Toxicity Acute cholinergic syndrome, crisis, or toxidrome. Other Uses: - Pyridostigmine: used as a prophylactic agent against nerve gas exposure - Edrophonium: used in differential diagnosis and management of acute myasthenic crisis Myasthenia gravis: Myasthenia Gravis (MG) is an autoimmune disease of the neuromuscular junction (NMJ), where antibodies attack nicotinic motor (Nm) receptors due to thymus hyperplasia (thymoma), reducing the number of receptors. Signs and symptoms: Muscular weakness and rapid fatiguability, ptosis, loss of facial expressions, difficulty with speech, chewing, swallowing, shortness of breath. Diagnosis: Edrophonium test → improvement of muscle weakness (it has “Anticholinesterase drug effect”) Anticholinesterase as Treatment: they inhibit the breakdown of Ach, increasing Ach levels around muscle cells which helps counteract the effects of antibodies that reduce Ach receptors. Treatment of MG: 1- Anticholinesterases - Pyridostigmine: ↑ Ach availability at the NMJ→ improves muscle weakness - Neostigmine: with atropine added to abolish its unwanted muscarinic effects 2- Ephedrine or caffeine → enhance Neuromuscular transmission (NMT). 3- Immunosuppressants 4- Thymectomy Irreversible anticholinesterase drugs: A- Organophosphates: - Drugs for glaucoma - Insecticides - Nerve gases for warfare B. Carbamates - Insecticides MOA: They bind to the enzyme’s catalytic site, phosphorylating it and forming a permanent bond after a period of time that cant be reversed, a process called “aging.” This prevents the enzyme from binding to Ach, and recovery depends on the synthesis of new enzyme. (Carbamates do not age.) Organophosphate Poisoning (Acute cholinergic syndrome, toxidrome, crisis) - Muscarinic effects: (DUMBBELS): Diaphoresis, Urination, Miosis, Bradycardia, Bronchospasms, Emesis, Lacrimation, and Salivation. - Nicotinic effects: Stimulation followed by depression - Skeletal muscles: Twitches and hyper-reflexia - CNS effects: Excitation, convulsions followed by respiratory depression - Death may occur due to respiratory failure, neuromuscular weakness, excessive respiratory secretions, and pneumonia Treatment of Organophosphates Poisoning 1- Atropine: Blocks muscarinic effects: given as IV bolus then repeated every 5-10 minutes until the patient is fully atropinized. Patient should be kept atropinized for at least 48 hours 2- Cholinesterase regenerators (Oximes): To control nicotinic effects (should be used in the early stage) - Pralidoxime (PAM): It does not pass BBB, hence regenerates the enzyme only peripherally. - Diacetylmonoxime (DAM): can cross the BBB, so regenerates some of the CNS enzymes. 3- Diazepam to control convulsions and other central symptoms MOA: Organophosphates bind covalently to cholinesterase, permanently inactivating it. If pralidoxime (PAM) is given before the organophosphates age (lose an alkyl group), it can remove them from cholinesterase. Lec 4 Anticholinergic drugs (Parasympathetic depressants, Parasympatholytics) A-Natural alkaloids B-Semisynthetic/Synthetic atropine substitutes. 1. Atropine Pharmacokinetics: Well absorbed orally, pass BBB, distributed to all tissues, 70% metabolized by hepatic atropine esterase and 30% is excreted unchanged Actions: 1. CVS - Heart: tachycardia, ↑ AV conduction velocity - Blood vessels: toxic dose → cutaneous vasodilatation + atropine flush - Blood pressure: no major effect 2. Smooth muscle (blocks M3) ⁃ respiratory system: bronchodilation, ↓ bronchi secretion, ↑ depth and rate of respiration - GIT & urinary tract: ↓ tone and motility of the wall + ↑ tone of sphincters → constipation & urinary retention 3. Exocrine glands: It reduces all exocrine secretions Sweat → hyperpyrexia (hot dry skin) Salivary → dry mouth (xerostomia) Lachrymal → dry eyes (xerophthalmia) Decrease gastric, and bronchial secretions 4. Eyes: Paralysis of the constrictor pupillae muscle & ciliary muscle → ↑ IOP, acute glaucoma. Inhibition of lachrymation 5. CNS - CNS stimulant effect: Restlessness, Bradycardia, Stimulates respiration - Antiemetic effect: by blocking M1 receptors in the vomiting center - Antiparkinsonian effect: blocks M1 receptors in basal ganglia → relieves tremors of Parkinson disease Uses of atropine: 1. Injections A. Pre-anesthesia IM: - reduces salivary, bronchial, and gastric secretions to prevent suffocation + stress- induced gastric secretion - Protect against vagally-induced bradycardia - blocks unwanted muscarinic effects B. Vasovagal attack C. Heart block D. Antidote for cholinergic poisoning: with oximes to block muscarinic + nicotinic effects 2. Tablets: Used in Colic, Vomiting, Diarrhea, Bronchial asthma 3. Eye drops: Used as mydriatic in eye examination ADRs of Atropine ⁃ ANS: Dry mouth, tachycardia, blurred vision, acute glaucoma, urine retention ⁃ CNS: Cognitive impairment ⁃ Toxicity: Fever, skin flushing, restlessness, hallucination ⁃ Contraindication: Glaucoma, BPH, paralytic ileus, and cognitive defects 2. Hyoscine: like atropine but - has shorter duration ⁃ anticholinergics effects are more prominent on exocrine glands and eye ⁃ Sedation, Hypnosis, Hallucinations and short-term memory loss ⁃ has an anti-motion sickness effect Uses: ⁃ Antispasmodic: used in intestinal colic ⁃ Pre-anesthetic medication: used in trauma surgery, it decreases awareness and recall of events associated with surgery ⁃ Inflammation of Inner-Ear: Motion sickness and Meniere's disease ⁃ Mydriatic eye drops 3. Semisynthetic and Synthetic Atropine substitutes 1- Bronchodilators ⁃ Drugs: Ipratropium ⁃ Used in asthma and COPD 2- GI Antispasmodics ⁃ Drugs: Mebeverine ⁃ Used for treatment of Irritable Bowel Syndrome (IBS) with diarrhea 3- Urinary Antispasmodics ⁃ Drugs: Tolterodine ⁃ Used to treat urinary incontinence and urgency associated with overactive bladder 4- Antisecretory Agents ⁃ Drugs: Telenzepine ⁃ Used to reduce gastric acid secretion in peptic ulcer disease 5- Anti-Parkinson Drugs ⁃ Drugs: Biperiden ⁃ Used to relieve tremors associated with Parkinson disease 6- Antiperspirants ⁃ Drugs: Glycopyrrolate ⁃ Used to manage hyper-hidrosis 7- Topical Mydriatics ⁃ Drugs: Homatropine Glycopyrrolate: a synthetic quaternary amine with no CNS effects Uses; ⁃ Pre-operative medication ⁃ to prevent its unwanted muscarinic effects ⁃ treat hyper-hidrosis Made by: Rmeez & Sarah Best wishes