Principles of Drug Action

Size: px

Start display at page:

Download "Principles of Drug Action"

Sylvia Casey
5 years ago
Views:

1 Principles of Drug Action How Do Drugs Work? Drugs (usually small molecules) bind to proteins (large molecules) or nucleic acids (only a few) Drug target = binding site of drug (RICE) o Receptors o Ion channels o Carrier molecules/transporters o Enzymes Drugs alter protein function by: o Agonism/activation (+) o Modulation (+/-) o Antagonism/blockage/inhibition (-) Receptors Receptors = protein molecules that enable extracellular molecules to alter intracellular cellular events Agonists = bind to (occupy) the receptor, activating it to produce a direct or indirect (transduction) response Antagonists = bind to (occupy) the receptor but do NOT activate it Four main types: o Ligand-gated ion channels (ionotropic) eg: nachr o G-protein coupled eg: machr o Kinase-linked o Nuclear Ion Channels Ion channels = allow ions (eg: Na +, Ca 2+, K + ) to cross membranes. May be voltage-gated or ligand-gated (also a type of receptor) Blockers = prevent ions from passing through channel Modulators = increase or decrease the opening probability of the channel (but do not block) How Drugs Work: Examples Drugs agonize (activate) receptors. Example: salbutamol- β 2 agonist used in asthma to relax bronchial smooth muscle and oppose bronchoconstriction Drugs antagonize receptor. Example: atenolol- β 2 agonist which antagonizes the action of NA, decreasing heart rate and reducing blood pressure Drugs block ion channels. Example: lignocaine- blocks Na + channel to prevent the transduction of pain signals across nerve cells (local anesthesia) Drugs inhibit enzymes. Example: asprin- inhibits enzyme cyclooxygenase, which prevents prostaglandin production, causing analgesia and reducing inflammation Drugs inhibit transporters. Example: fluoxetine- inhibits serotonin/5ht uptake into nerve cells in the CNS, increasing synaptic concs of 5HT (used to treat depression)

2 Autonomic Terminology Cholinergic = nerve ending (synapse) in which ACh is the main neurotransmitter Adrenergic = nerve ending (synapse) in which NA is the main neurotransmitter NMJ = neuro-muscular junction- synapse between somatic nerve and skeletal muscle NEJ = neuro-effector junction- synapse between autonomic nerve and smooth muscle Cholinesterases and Inhibitors Background ACh facilitates neurotransmission in both the PNS (autonomic- SNS, PNS, ENS and somatic) and CNS Blockade of ACh transmission is lethal, causing cognitive, autonomic and neuromuscular dysfunction Acetylcholine-esterase (AChE): o Hydrolyzes and inactivates ACh! choline + acetic acid o Regulates synapse conc o Extracellular and membrane-bound (whereas most enzymes are intracellular) Anticholinesterases (AChE inhibitors): o Block the activity of AChEs enhance cholinergic transmission o Classed by their duration of action- short, medium, long o Reversible anti-aches are used clinically, while irreversible are used as insecticides and nerve gasses Examples: Uses of AChE Inhibitors To treat dementia and Alzheimer s disease (eg: tacrine) To reverse the action of neuromuscular blocking drugs (eg: vecronium- NMJ is the synapse between somatic nerves and skeletal muscle- drug blocks post-synaptic nicotinic receptors to prevent ACh transmission) when the effects of drug are no longer required (eg: neostigmine) To test for (eg: edrophonium) or treat myasthenia gravis (eg: neostigmine) As pesticides and in the treatment of head lice (eg: malathion) As war gasses (eg: sarin) The Cholinergic Synapse (nicotinic and muscarinic) Synthesis: o Synthesized at the nerve terminal by enzyme choline-acetyltransferase (CAT) o Choline + Acetyl-CoA! ACh + CoA Storage: o Stored in vesicles at nerve terminal o Vesicle transport mediated by vacht Release: o Stimulation of presynaptic ACh receptor causes Ca influx (depolarization) o Vesicles exocytose with terminal membrane, releasing ACh into synapse o Suxamethonium- agonist that irreversibly binds to nachr, preventing ACh from binding (depolarizing blocking agent) Metabolism: o AChE breaks down ACh! choline + acetic acid o Choline transported back into nerve terminal to be recycled

3 Anti-Cholinesterases NB: ACh can be catalyzed by both AChE and butyrylcholinesterase (BuChE)- a soluble enzyme found in plasma- each is named after their preferred substrate AChE BuAChE Distribution Limited: MNJ and neuronal synapse Substrate Specificity Narrow: ACh and methacholine Function Hydrolyzes and terminates action of ACh at synapse Widespread: liver, skin, brain, GI smooth muscle, plasma (soluble form) Broad: BuCh, ACh, suxamethonium Physiological function unclear: keeps ACh levels low. Pharmacologically used to metabolize some drugs AChE Structure Substrate binding: ACh binds to the enzyme via two major sub-sites (pockets) o The catalytic (esteratic) site Catalytic tri-ad (glutamic acid, histidine, serine) o The peripheral Anionic site (PAS) Ionic interaction between quaternary N+ ion and acidic glutamic residue (-) Cation-π interaction between quaternary N+ ion and the π-cloud of aromatic amino acid residues (Phe, Trp) AChE Mechanism of Action Acylation o Glu acid depolarizes the NH of histidine side chain, making the other N (with free e) more basic (ie: more ability to remove electrons) o The histidine N deprotonates the serine OH!O - o The deprotonated O - will neucleophilically attack the carbonyl C atom on ACh o Serine O has formed a covalent bond with the ACh carbonyl C o Protonated N gives H to bound ACh, releasing choline molecule o Serine is left acylated Deacylation o Glu acid depolarizes the NH of histidine side chain, making the other N (with free e) more basic (ie: more ability to remove electrons) o Histidine N deprotonates a H 2 O molecule! OH - o OH - attacks carbonyl C atom of acylated serine! tetrahedral intermediate o Acetic acid is release and enzyme is returned to original conformation

4 AChE Inhibitors Mechanism of Action Short-medium duration (reversible): Long duration (irreversible): Classification and Use of ChE Inhibitors Drug Duration of Main Site of Notes Action Action Edrophonium Short NMJ Diagnosis of myasthenia gravis Neostigmine Medium NMJ Treatment of mg and reversal of competitive NMJ block Tacrine Medium CNS Alzheimer s disease (limited effectiveness) Malathion Long - Insecticide and head lice Sarine Long NMJ + P Nerve gas (eg: Tokyo 1995) Organophosphorous Compounds History of Organophosphorous (OP) Compounds Initial development: o First developed in Germany during WW1 o Developed as pesticides (due to shortage of nicotine) o Tabun (GA) also developed at the same time o Not used in warfare due to concerns of retaliation Increasing OP pesticide use across world- less stable in environment than organochlorines Begun to be used as nerve agents (highly poisonous chemicals that work by preventing the nervous system from working properly)- used in: o Iran-Iraq war o Tokyo terrorist attack (1995)- 12 dead, 6000 exposed o Syria (2013)

5 OP Compounds- a diverse group Over 100 members All bind to AChE- either reversible or irreversible Pro-poison (thion) or active (oxon) Different kinetics (fat solubility and clearance affecting half-life) Different propensity to age Neuropathic? (peripheral and CNS- multiple mechanisms) Toxicology Ops inhibit various esterase enzymes in the body- AChE inhibition is the most important for inducing acute effects ACh transmission is significant in: o PNS (eg: glands) o SNS (eg: adrenal medulla, sweat glands, blood vessels) o Somatic NS (eg: skeletal muscle) AChE is important for normal communication between nerves and other nerves, glands, muscles, etc (turns off ACh transmission) AChE inhibition increases ACh transmission Variation in Onset: Thion or Oxon? Some OPs are pro-poisons- ie: converted by hepatic metabolism (CYP 450s) into their active form Rats and insects are much more efficient metabolizers than humans (kg/kg basis) when sprayed with pesticides, they rapidly convert the chemical into the active poison form, whilst humans (due to slow metabolism) are relatively protected (NB: variation between humans in metabolism rate) Variation in Offset: Diethyl or Dimethyl? Chemical structure: either diethyl 2x(O-CH 2 -CH 3 ) or dimethyl 2x(O-CH 3 ) group bound to phosphate (others too) OPs phosphorylate and inactive AChEs Aging = a process that occurs after initial binding when the OP loses one of their alkyl groups (diethyl/dimethyl) and forms a permanent bond with AChE (ie: irreversible binding)- rate of aging differs between compounds

6 Toxicity from OP Compounds: Cholinergic Syndrome Stages: (1) Acute cholinergic crisis: Occurs within seconds (warfare agents) or 1-2 hrs (pesticides) post exposure Involves: wet, weak and slow o Wet: sweating, tears, rhinorrhea (runny nose), urination, diarrhea, vomiting, increased bronchial secretions, bradycardia (slow heart rate), salivation o Weak: muscle weakness with fasciculation (spontaneous muscle contraction) o Slow: CNS effects- reduced LOC and seizures Main cause of death in acute exposures Responds to atropine (2) Intermediate syndrome (myasthenia): Occurs 1-4 days post exposure and lasts 5-18 days Involves weakness and respiratory failure Tolerance of ACh overstimulation! failure of NMJ No proven antidote (3) OP induced delayed polyneuropathy: Occurs 1-3 weeks post exposure Involves weakness of feet, legs, hands and forearms Damage to neurons (unable to communicate with each other) No antidote Treatment Atropine: o Muscarinic antagonist used to block ACh at mus receptors o Unsure of how much ACh is present small dose given and then increased until effect is observed (2, 4, 6, 8, 16mg) o Aims to reverse initial cholinergic crisis- eg: poor air entry into lungs (bronchospasm and bronchorrhea)! clear lungs, excessive sweating! dry axillae, bradycardia! increased heart rate Oximes: o Aims to re-inactivate enzyme back into pro-poison form o Effectiveness depends on type- diethyls reactive well, dimethyls do not Amino Acid Neurotransmitters: GABA and Glycine Excitatory and Inhibitory Neurotransmission Resting state of a neuron: membrane potential ~ 60mV Excitation = on switch o Influx of Na + ions causes depolarization o Membrane potential changes to more positive values- ON SWITCH Inhibition = off switch o Influx of Cl - ions causes hyperpolarization o Efflux of K + ions also causes hyperpolarization o Membrane potential changes to more negative values- less likely to be activated-

A nerve cell fires an AP when it is depolarised. Module 1. Lecture 2- Principles of Drug Action

A nerve cell fires an AP when it is depolarised. Module 1. Lecture 2- Principles of Drug Action PCOL2012 Notes Module 1-Principles of Drug Action in the Nervous System... 2 Module 2-Drug Abuse, addiction and analgesia... 24 Module 3-Drug Treatment of Allergies and GI Disorders... 48 Module 4-Introduction