Pharmacology drugs receptors 10 PDF

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Pharmacology – Drug targets 10.10.2019 LO: -Pharmacodynamics -human proteins as main targets of drugs; cellular communication -physiology of common drug targets: receptors, enzymes, ion channels, transporters -variation in responses to drugs: tolerance and withdrawal Drug: An exogenous ligand that generates a physiological response Ligand: Something that binds to a biological target Endogenous ligand: A natural chemical produced by the body to bind to the biological target Pharmacodynamics: The Biochemical interaction by which a drug causes its effects -cellular biological, physiological and clinical effects Protein drug targets: -MOST happens on receptors (ligand gated ion channel, GPCR) -the rest is transporter, enzymes (29%, the most), ion channels (8%) -1044 target known human proteins -435 different therapeutic proteins Most prescribed drugs

Other drug targets: -pathogens, fungi, parasites (antibiotics) -dietary supplements -direct DNA interaction -amino acids -chemical messengers (eg antibody drugs) Specificity and selectivity Specific ligands are more effective at a target than others (>100 times more potent) Selective ligands – mild-moderate greater effectiveness at a target than others Non-selective ligands – minimal difference in effectiveness between multiple targets Drugs physiology Organisms > organs > tissues > cells > molecules (drugs) *small level of physiology changes can make a massive difference in higher level Molecules > cells -signal comes in to receptor -activate the enzyme, then starts of several intracellular signaling cascade, then 2 nd messenger -generate responses In the pp slide, there are 3 responses generated (A, B, C effects) [A can be phosphorylation – form of signaling B is a signal in the nucleus (change of expression protein within cell) C is some effects outside of the same cell, which affects the other cells] *When we want one of the effects, we may not want the other two. This is known as side effects – potentially harmful to patients* Cells > organs -drug target present in other cells (same or different organ) -drug affects other targets (same or different organ) -eg same receptor in the heart also present in kidney -drugs may not be specific to the receptors, causing side effects physiology of common drug targets: receptors, enzymes, ion channels, transporters Receptors: -detecting cellular communication -endocrine, paracrine, juxtactine, autocrine

-4 superfamilites: GPCR, Ligand-gated ion channels, kinase linked receptors, nuclear receptors GPCR: -largest receptor family -ligand-activated receptors-linked to intracellular effectors – G-proteins -activate enzymatic signaling cascade – metabotropic, SLOW (seconds – minutes) Gs proteins -stimulate adenylate cyclase (increase Camp/PKA) -GTP > GDP, binding to Alpha subunit in the G protein -this causes the G protein dissociates from GPCR into Alpha and Beta subunit -then the Alpha subunit binds to the adenylate cyclase, which catalising the reaction from ATP to cAMP -cAMP then activates the protein kinase A (PKA), which then phosphorylates other target (sometimes some other proteins membranes, sometimes intracellular cascade) Gi proteins -inhibit adenylate cyclase (decreases cAMP/PKA) -signalling molecule binds to GPCR -G protein dissociates into Alpha and Beta subunits -when the Alpha subunit binds to the adenylate cyclase, it inhibits the adenylate cyclase to convert ATP to cAMP, so it reduces the activity of PKA -works opposite to the Gs protein Gq proteins -activate phospholipase C (increases PKC and Ca2+) -similar steps as above, but adenylate cyclase is substituted by PLC -the PLC releases DAG and IP3 Examples of GPCR: Muscarinic acetylcholine receptors -CNS, lungs, GI tract Adrenergic receptors – heart, vasculature, lungs, CNS Histamine receptors – heart, vasculature, GI tract, nociception Prostaglandin receptors – inflammation, GI tract, CNS Opioid receptors – nociception, GI tract, CNS

Ligand-gated ion channels: -ligand binds to receptor -channel opens, allowing ion movement across membrane – ionotropic -VERY fast, Neurotransmission Examples ligand-gated ion channels: Nicotinic acetylcholine receptors – CNS, peripheral nerves, NMJ NMDA glutamate receptors – CNS GABAa receptors -CNS P2X receptors – ligand purines (ATP), CNS, peripheral nerves, blood cells Enzyme-linked and nuclear receptors -activated by signaling molecules, cytokines, hormones -regulate cell processes and gene expression -slow induction of effects, very LONG lasting effects (gene regulation) -enzyme-linked eg receptor tyrosine kinase (RTK), receptor serine/threonine kinase (RSTK) Kinase-linked receptors -large & heterogenous family Activation protein phosphorylation > gene transcription > protein synthesis > growth factors are common ligands Nuclear receptors -in nucleus or cytoplasm -regulate gene transcription -hormones and steroids target nuclear receptors -can recognize foreign molecules and initiate metabolic processes Receptor subtype Muscarinic acetylcholine receptors: M1, M2, M3, M4, M5 -monomeric GPCRs -M1,3,5: Gq-linked; M2,4: Gi-linked Nicotinic acetylcholine receptors: -pentameric ligand gated ion channels: autonomic ganglia, CNS and NMJ Enzymes -regulation of metabolism key to physiology (feedback, modulation (+/-), inhibition

and activation) -intracellular and intercellular signaling: gene activation / suppression -important to pharmacokinetics – drug metabolism Ion channels -selective either cations (K+, Na+, Ca2+) and anions (Cl-) Cation channels can be selective for a specific ion, if non-specific, permeable to all three Eg ligand-gated channels, leak channels, voltage-gated channels Voltage-gated ion channels example – voltage-gated sodium channel -Na+ channel closed at normal membrane potential (-70mV) -membrane depolarization (-40mV) causes Na+ channel to open Local anaesthetics: -binds to the VG Na+ channels -block inside of channel pore, prevent Na+ flux Transporters: -are proteins that move ions and small molecules across the membrane -may use electrochemical gradient / ATP hydrolysis (energy dependent) -eg symphorters (co-transport), antiporters (exchange) Selective Serotonin Reuptake Inhibitors: -targets to Serotonin transporter (SERT) -5-HT is reuptaken by presynaptic cell and astrocytes -effects: increases the concentration of 5-HT at synapse, increases 5-HT receptor activity Pharmacodynamic variations: -genetics, ageing disease tolerance, other drugs

Homeostasis – the body tries to maintain a constant environment -drugs affect natural equilibrium Tolerance: the drug may become less effective (“refractory”) Withdrawal: remove a drug, may cause a reverse rebound since the body needs adjustment to the new baseline Desensitisation: -reduction of activity of a receptor to the drug -receptor desensitization may be acute, rapid and transient – tachyphylaxis -may be long-term, caused by chronic administration, based on tolerance Protein modification and inhibition -B2 adrenoreceptor, causing kinase activity, then resulting in phosphorylation on its self, leads to G protein dissociates in the GPCR (alpha unit and beta unit) -When B-agonist binds to the receptor, the shape of the receptor has a conformational changes, so there will not be any intracellular activity -this prevents overactivity of beta receptor -in conclusion, there are two ways: phosphorylation and other protein modifications and inhibitory products Expression: -Opioid binds to opioid receptor, this causes the opioid receptor is withdrawn from the membrane by endocytosis -this decreases expression of target (eg opioid)

-tolerance exists due to increased expression of proteins mediating opposite activity can also occur Other examples of tolerance: -increases in opposite activity Eg increased in excitatory signaling with CNS depressants -Pharmacokinetic Eg altered ADME, eg induction of liver enzymes -drug resistance Eg developed mechanisms of drug inactivation eg antibiotics -behavioural Eg learning how to handle drug (eg alcohol) Withdrawal – corticosteroids -presence of corticosteroids activates adrenal hypothalamic pituitary system (HPS axis) feedback to suppress endogenous cortisol production -removal of corticosteroids may lead to cortisol deficit *Hypothalamus produces CRH> anterior pituitary releases ACTH > adrenal gland releases cortisol, which targets tissues throughout body -there is negative feedback of cortisol to anterior pituitary and hypothalamus -when drugs are removed, the body hence will not produce enough cortisol...