U1 P4 Summary (Jenan) PDF

Lecture1: Autonomic nervous system (Nasir) Located in the cranial cavity Located in the vertebral cavity Peripheral nervous system - PNS:  Afferent n...

Lecture1: Autonomic nervous system (Nasir) Located in the cranial cavity Located in the vertebral cavity Peripheral nervous system - PNS:  Afferent neurons = into the CNS  Efferent neurons = out of the CNS  (12 pairs of cranial nerves and 31 pairs of spinal nerves) which serve as linkage between the CNS and the body Autonomic nervous system  Controls involuntary structures: smooth and cardiac muscles, glands  Controlled by: brain stem, limbic system and frontal lobes (by the hypothalamus)  Function: maintain homeostasis of the internal environment along with the Endocrine system  Has 2 neuron chain Sympathetic (fight or flight)  Also called thoracolumbar (T1-L2)  Activates adrenal medulla to release norepinephrine and epinephrine  Stimulate activities of the effect or organs (except digestive organs)  Functions for intense skeletal muscle activity  Activated in stressful situations  Axon: highly branched and affect many organs  Divided into: 1. Alpha  contraction of smooth muscle 2. Beta 1  metabolic functions 3. Beta 2  relaxation of smooth muscle Parasympathetic (rest and digest)  Also called Craniosacral (S2-S4)  Functions for maintenance  Activated in calm and rest situations  Inhibit activities of the effect or organs (except digestive organs)  Axon: few branches and has localized effect  Uses a neurotransmitter called acetylcholine  Divided into: 1. Nicotinic  we use an ion channel 2. Muscarinic  we use G-protein receptor  Divided into: Cranial outflow:  III 3 {Oculomotor} - pupils constrict  VII 7 {Facial} - tears, nasal mucus, saliva  IX 9 {Glossopharyngeal} – parotid salivary gland  X 10 (Vagus) – visceral organs of thorax & abdomen: (stimulates digestive glands, increases motility of smooth muscle of digestive tract, decreases heart rate, bronchial constriction) Sacral outflow (S2-4):  Form pelvic splanchnic nerves  Supply 2nd half of large intestine  Supply all the pelvic (genitourinary) organ  Enteric Nervous System {ENS}  Located within the wall of the digestive tract, from the Oesophagus to anus  Divided into: 1. Myenteric plexus {of Auerbach}  located between longitudinal and circular muscle. 2. Submucosal plexus {of Meissner}  located between circular muscle and luminal mucosa Preganglionic neurons  Originate in the brain or spinal cord  Short sympathetic and long parasympathetic Postganglionic neurons  Originate in the ganglion located outside the CNS  Long sympathetic and short parasympathetic Sympathetic system: postganglionic cell bodies  Paravertebral ganglia  located at the sides of vertebrae and united by preganglionic into sympathetic system (preganglionic are thoracolumbar) (postganglionic are cervical to coccyx)  Prevertebral (preaortic)ganglia  located at the anterior to abdominal aorta, in plexuses surrounding its major branches (preganglionic reach preventable ganglia via abdominopelvic splanchnic nerves) Autonomic Plexuses  Cardiac plexus  heart  Pulmonary plexus  bronchial tree  Celiac plexus  largest. stomach, spleen, pancreas, liver, gallbladder, adrenal medullae  Superior mesenteric plexus  small intestine and proximal colon  Inferior mesenteric plexus  distal colon and rectum  Hypogastric plexus  urinary bladder and genital organs  Renal plexus  kidneys and ureters  Autonomic reflexes  Baroreceptor reflex : control of blood pressure  Micturition (urination) reflex : Emptying bladder  Gastrointestinal reflexes Adrenal medulla  Large sympathetic ganglion  Release epinephrine (80%), norepinephrine (20%)  Chromaffin Cells  cells with granules or vesicles containing adrenaline or noradrenaline and they are the secretory cells of the adrenal medulla Amygdala  Behavioural awareness areas and is believed to make the person’s behavioral response appropriate for each occasion  Main limbic region for emotions  It can trigger a fear response even after the trauma is over  Receives neuronal signals from  all portions of the limbic system, neocortex of the temporal and from the auditory and visual association areas  Transmits signals back into the same cortical area  into the hippocampus, septum, thalamus, and especially the hypothalamus Somatic nervous system  One neuron chain  Somatic motor neurons don’t have ganglia  Controls voluntary structures: skeletal muscles  Somatic pain  pain in visceral organs  Lecture2: Enzyme inhibition (Sameh) Enzymes  Enzymes acts on the substrates  enzyme changes its shape  decrease energy  to form a product Michaelis-Menten Equation  Describes how reaction velocity varies with [S]  Km (Michelis constant)  [S] at half Vmax (1/2 Vmax)  High Km – low affinity and vice versa  Velocity is proportional to enzyme concentration Line weaver-Burk Plot (double reciprocal plot)  When it is difficult to determine Vmax (1/v against 1/[S])  Hyperbolic curve  straight line, which intercepts the x-axis at - 1/Km and the y-axis at 1/Vmax Types of enzymes inhibitors  Molecules & factors that interact with the enzyme, and prevent (block) it from working Nonspecific inhibitor: Irreversible: effects all enzymes Inhibitor combine with the functional groups of the Specific inhibitor: amino acids in the active site single enzyme covalently or non-covalently 1) Competitive Reversible: 2) Non-competitive Inhibitor can dissociate from 3) Uncompetitive the enzyme  Competitive inhibition  Binds at the same binding site  Blocks the substrate action  It has less potent  It is reversible (increasing the concentration of the substrate can reverse the inhibitor effect)  Km increases  Vmax unchanged Non-competitive Inhibition  Binds at different binding site to the allosteric site  Lowers the affinity of the substrate to the binding site without blocking it  Cannot be reversed  Formation of both E-I and EIS  Km unchanged  Vmax decrease BAL (British Anti-lewisite; Dimercaprol) Antidote for heavy metals poisoning Cyanide Inhibits cytochrome oxidase Iodoacetate Would inhibit enzymes (Glyceraldehyde 3P dehydrogenase) Fluoride Will remove magnesium and manganese ions Uncompetitive Inhibition  Binds only to the ES complex, not to free enzyme  Cause structural distortion of the active site so it becomes inactive  Can’t be reversed  Bind at different binding site  Example: placental alkaline phosphatase inhibited by phenylalanine Irreversible Inhibition  Inhibitor combine with the functional groups of the amino acids in the active site covalent or non-covalent bond  Slow dissociation of EI complex  Examples: poisons such as Iodoacetate, OP poisoning and oxidizing agents  Km unchanged  Vmax decrease  Regulation of Enzyme Activity  Protein modification  chemical group is covalently added  Feedback inhibition  Proenzymes  inactive form of enzyme which can be activated by removing a small part on their polypeptide chain Cholinesterase  In the nervous systems  Signals carried by acetylcholine (cholinergic neurotransmitter)  signals are discontinued by acetylcholinesterase which breaks down the acetylcholine into choline and acetic acid  Types of cholinesterase: 1. Acetylcholinesterase (AChE), choline esterase I, erythrocyte cholinesterase, RBC cholinesterase, acetylcholine acetylhydrolase  neural synapses, neuromuscular junctions and RBC membranes 2. Butyrylcholinesterase (BChE), choline esterase II, pseudocholinesterase, plasma cholinesterase  produced in the liver and found in the blood plasma Anticholinesterases (cholinesterase inhibitors)  Block hydrolysis of acetylcholine  (Parathion inhibits the action of the enzyme acetylcholinesterase leading to accumulation of Ach)  Used as a smart drugs (paralysis during anesthesia, myasthenia gravis, glaucoma, Alzheimer’s disease)  2 types of acetylcholinesterase inhibitors: 1. Reversible  do not covalently modify acetylcholinesterase (combine with a residue of serine in the active site). Produce effects of moderate duration : E.g., carbamates, acridine 2. Irreversible  organophosphates (phosphorylates the serine residue in the active site); produce effects of long duration (pesticide, nerve gas Sarin) Lecture3: Principles of management of organophosphate poisoning (Kannan) Organophosphate compounds Drug:  Ecothiophate Pesticides:  Parathion  Malathion Nerve gases:  Sarin  Soman  Tabun Clinical features of organophosphate poisoning Principles of management of organophosphate poisoning (Airway, Breathing, Circulation, Drugs)  Measures to prevent/reduce absorption (Transdermal/Oral ingestion) 1. Wash with soap and water and remove clothes 2. Gastric lavage 3. Activated charcoal  adsorption  Anti-muscarinic drug  Atropine sulphate – 2 to 3 mg IV stat followed by 1-2 mg q10-15 minutes until adequate atropinisation  Cholinesterase re-activators  pralidoxime - Immediate administration is recommended due to “Aging” of the enzyme  Acetylcholine in the Central Nervous System (CNS)  Op poisoning  Convulsions  Benzodiazepines – Lorazepam, diazepam  Comatose and shallow respiration Management of ephedrine overdose Increase the heart rate Strengthen the force of the heart beat Lecture4: Autonomic pharmacology (Yasin) Autonomic neurotransmitter Autonomic receptors  Ach (cholinergic) receptors: 1. Muscarinic  postganglionic parasympathetic 2. Nicotine  (Nn: preganglionic sympathetic and parasympathetic) (Nm: neuromuscular junction)  NEN (adrenergic) receptor  postganglionic sympathetic How does the body get rid of Ach and NEN?  Ach  acetylcholinesterase (AchE)  NEN  COMT, MAO, reuptaken back into the nerve ending  Autonomic drug classification  Cholinergic agonist  active parasympathetic by enhancing Ach  Cholinergic antagonist  inactive parasympathetic by suppressing Ach  Adrenergic agonist  active sympathetic by enhancing NEN  Adrenergic antagonist  inactive sympathetic by suppressing NEN Cholinergic parasympathetic agonist (parasymp like effect)  Classified into: 1. Muscarinic 2. Nicotine Cholinergic Examples Action Clinical use agonist Bethanechol Active the GIT/ Constipation and urine retention bladder after surgery Direct-acting Increase salivation Dry mouth (S’jorens syndrome) or (muscarinic) Pilocarpine after head and neck radiotherapy decrease eye Glaucoma (increase eye pressure) pressure Reversible Neostigmine Skeletal muscle Muscle relaxation uses as part of Physostigmine contraction general anesthesia, myasthenia (reversible) gravis Indirect-acting Irreversible Ecothiophate Fatal skeletal muscle (nicotinic) (organophosphates) contraction Nerve gas, pesticide, insecticides Isophlurophate (irreversible) – may cause death  Organophosphate antidotes  atropine, pralidoxime  Cholinergic parasympathetic antagonist (symp like effect) Anti-cholinergic Examples Action Clinical use Increase heart rate (tachycardia) Bradycardia (heart blocker) Atropine Anti-muscarinic Myderiasis (dilate pupils) Miosis (constrict pupils) – myderiatic agents (Muscarinic Ipratropium Bronchodilation Asthma (bronchoconstriction) receptor at Decrease GIT and bladder motility Motion sickness (vomiting, nausea) internal organ) Scopolamine (muscle relaxation) Irritable bowel syndrome Urinary incontinence (unable to control urine) Ganglion blocker Nicotine As a gum or patch-rarely used To quit smoking (Nn) Succinylcholine General anesthesia (patient doesn’t move during Anti-nicotinic Tubocurarine Muscle relaxation the surgery) (Nm) Mivacurium Adrenergic sympathetic agonist (symp like effect) Adrenergic agonist Examples Mechanisms Action Clinical use Vasoconstriction A1-2 Hypotension, shock Epinephrine (adrenaline) (hypertension) B1 Tachycardia Bradycardia (heart failure) B2 Bronchodilation Asthma (bronchoconstriction) Vasoconstriction A1 Hypotension, shock Direct-acting: Dopamine (hypertension) directly bind and B1 Tachycardia Bradycardia (heart failure) activate adrenergic Dobutamine B1 Tachycardia Bradycardia (heart failure) receptor Albuterol B2 Bronchodilation Asthma (bronchoconstriction) Vasoconstriction A1 Hypotension, shock (hypertension) Myderiasis Miosis (constrict pupils) – A1 Phenylephrine (dilate pupils) myderiatic agents Vasoconstriction A1 in nasal arteries Nasal decongestant which decrease congestion 1. Recreational use Indirect-acting: Amphetamine CNS stimulation, 2. ADHD  children have inhibiting NEN Stop NEN wakefulness, low school performance degrading enzyme reuptake euphoria and unable to concentrate and reuptake Cocaine 3. Narcolepsy  sudden sleep Vasoconstriction Mixed: both A1 + enhancing in nasal arteries 1. Nasal decongestant actions Ephedrine NEN release which decrease 2. Recreational use congestion + CNS stimulation  Adrenergic sympathetic antagonist (parasymp like effect) Anti-adrenergic Mechanisms action Clinical use Vasodilation Hypertension (Vasoconstriction) Prazosin A1 urinary sphincter relaxation urinary sphincter contraction Vasodilation Hypertension (Vasoconstriction) Phenoxybenzamine A1-2 (non- selective) urinary sphincter relaxation urinary sphincter contraction Bradycardia Tachycardia Hypotension Hypertension Atenolol B1 (cardio selective) Decrease eye pressure Glaucoma (increase eye pressure) Lower cardiac contractility and None! (bad) cardiac output Bradycardia Tachycardia Hypotension Hypertension Decrease eye pressure Glaucoma (increase eye pressure) Propranolol B1-2 (non-selective) Lower cardiac contractility and None! (bad) cardiac output Bronchoconstriction Bronchodilation (never used in (bronchospasm) asthma) Labetalol + carvedilol A1+B1-2 (A1 blocker) Hypotension Severe hypertension Hypertension in patient with heart Acebutalol /pindolol B1-2 (partial agonist) Less bradycardia failure or bradycardia