Module 1: Pharmacodynamics PDF

MODULE 1: PHARMACODYNAMICS Pharmacodynamics What do drugs do in the body What is a drug The pharmacological principles that describe drug effects on “a chemical substance of known structure, other than a nutrient or an the body, explaining both...

MODULE 1: PHARMACODYNAMICS Pharmacodynamics What do drugs do in the body What is a drug The pharmacological principles that describe drug effects on “a chemical substance of known structure, other than a nutrient or an the body, explaining both mechanism of action and dose– essential dietary ingredient*, which, when administered to a living response relationship organism, produces a biological effect” Drug origins Synthetic à Aspirin Genetically engineered à parathyroid Phytochemical à morphine from opium hormone poppy Anti-inflammatory Used to treat hypoparathyroidism Poppies are picked to make alkaloids Was originally found in animal kingdom but made where there is lack of parathyroid Also used to make medicine to treat synthetically now for time/cost efficiency hormone causing hypercalcemia opioid addiction Drug interaction with molecular targets Receptors - biological macromolecules that recognises and responds to endogenous chemical signals or exogenous drugs o Agonist à ligand activates receptor o Antagonist àligand binds but doesn’t activate Ligand gated - Tube -like macromolecule with protein subunits that pass through plasma membrane ion channels - Ligand binds to extracellular or in channel or intracellular à ionotropic - Binding alters conductance of ions through channel - E.g. nicotinic acetylcholine transporter o Acetylcholine binds to α subunits ➔ Na+ channel opens ➔ Na+ entry ➔ ap G-protein - Mostly on plasma membrane coupled - Has 7 transmembrane regions à - Extracellular region = ligand binding metabotropic - G-protein = α and βγ subunits à not covalently linked - Effector = enzymes, ion channels, transporters or gene transport regulators - E.g. muscarinic acetylcholine receptors Kinase linked - Transmembrane receptors with enzymatic cytosolic domains - Tyrosine-kinase is largest - Usually large dimeric peptides - E.g. targets for growth factors, cytokines and hormones like insulin - Ligand indued activation à dimerization of receptors à transphosphorylation of tyrosine residues Nuclear - Monomeric proteins - Normally expressed in nucleus but can also be in cytosol - E.g. steroid hormone receptors - Ligand binding à conformation change of receptors à nucleus à receptor-ligand dimer binds to DNA à alters transcription rate à modulates protein expression Ion channels - Allow passage of particular ions Ligand gated - Also a type of receptor Voltage gated E.g. Nifedipine à L-type Voltage operated calcium channel (VOCC) blocker - Ca+ channels important for contraction of smooth muscle cells and blood vessels - Increased Ca+ influx causes more Ca+ release from SERCA pumps Nifedipine àBlocks calcium channels = prevents release of Calcium = reduces blood pressure  Enzymes - Also blocked when treating hypertension - E.g. RAS blocker o ANG-2 = vasoconstriction = increases blood pressure o Enalapril = prevents conversion of ANG1 to ANG2 by blocking angiotensin converting enzyme in lungs Transporters - Allows passage of some ions and small molecules - Has recognition sites - E.g. selective serotonin reuptake inhibitors à fluoxetine, sertraline, citalopram o Used to treat depression and anxiety o Patients have less serotonin = re-uptake inhibitors block re-uptake = serotonin stays in synapse longer and prolong its effect Drug selectivity factors - Rarely tissue/target selective à many tissue/receptor targets - Usefulness of drug directly proportional to binding site selectivity à less selective = more adverse - Lack of selectivity à increase risk of adverse effects Adverse effects from poor selectivity Relative selectivity inducing Dose-control adverse effects - Some drugs selective at low dose = but still chance of adverse effect - Indicates dose is high for specific patient and concentration in circulation is causing adverse effects Drug affinity to two targets Use/develop selective drugs àDrug with only one target Drug is tissue non-selective Change administration - Drugs used to target lungs may effect heart when taken orally à use inhalation Drug binding - Factors that increase binding o Increase drug concentration o Increase receptor concentration - What determines binding o Receptor concentration [R]total o R total = R + LR o Equilibrium direction depends on: § K1 = association complex § K-1 = disassociation complex Affinity - Measure of attraction of ligand for biological target à strength of binding - KD is ligand concentration = where half of receptors is occupied o High KD = low affinity à needs lots of drug to reach KD - High affinity ligand o Rapid binding for long time o Results in à many bound targets at lower concentration compared to others with low affinity Efficacy - Ability of ligand to initiate cellular effect once bound to target Agonist Partial Agonist Antagonist Full activation Submaximal (partial) activation No activation Affinity + + + Efficacy ++ + -  Drugs that target β1-adrenoceptors - β1-adrenoceptors found in sympathetic nervous system, heart (SA/AV node, ventricles) - When adrenaline/noradrenaline bind à increases heart rate and blood pressure Isoprenaline à Agonist Pindolol à Partial agonist Metoprolol à Antagonist Non-selective β1-adrenoceptor agonist Is an agonist but decreased blood Beta-blocker Binds to multiple receptors including β2- pressure as well Selective to β1-adrenoceptors adrenoceptors It outcompetes noradrenaline to Inhibits ability for noradrenaline to bind to Has similar effect as noradrenaline = increase HR and activate fully by partially activating receptors so heart rate doesn’t increase contractions receptors Used for anti-hypertension Used for patients with heart block or arrythmia Not used in Australia anymore Drug dose relationship - Very high dose = makes drugs non-selective = effects receptors it’s not supposed to - Curves o X-axis = ligand concentration o Y-axis = effect as % of maximum effect it can produce Emax Maximum effect of drug in given system Same ligand can have different effect on different systems Potency Drug concentration needed to produce intended effect Usually measured at 50% of maximum effect EC50 Potency of drug at 50% of maximum effect High EC50 = low potency = more drug needed Agonist vs Partial Agonist - Agonists have higher efficacy than partial agonists - Because agonists can occupy less that 50% of receptors illicit maximum response - But partial agonist needs to occupy more than 50% or all receptors to illicit same response o EC50 ≥ KD → no spare receptors Benefits of partial agonist Salbutamol à β2-adrenoceptor agonists = Sumatriptan à 5-HT1A receptors - Used to dilate airways in asthma - Used for migraine - Preferred over full agonist because it can cause desensitization of receptors - It constricts blood vessels associated with migraines by overstimulating and fewer receptors will be left without constricting blood vessels in the heart which - So partial agonists can be used for long term treatment prevents heart attachs Antagonists - interferes with interactions of agonist and receptor proteins or molecules Types of antagonists Receptor Agonist Reversible Competitive Naloxone à Agonist + competitive antagonist binding site - reversible binding that competitive opioid = ↓potency of agonist without doesn’t stabilise the receptor affecting efficacy conformation - used for opioid Concentration of agonist required - of the receptor à receptor overdose to produce 50% response will be stays in inactive - outcompetes increased conformation blocks opioid ligands But if enough agonist is added, agonist from binding can still reach Emax - doesn’t effect number of receptor à binds/unbinds Irreversible Non-competitive Omeprazole à proton Binding to agonist site: - can’t be outcompeted pump inhibitor - Agonist + competitive - binds irreversibly to agonist Used for heart burn to antagonist: ↓potency of binding site covalently or decrease acid agonist & ↓ efficacy with high affinity concentration - More agonist needed  Binds to proton pumps and makes them internalised. Receptor is recycled and new one will come up so doesn’t have permanent effect Allosteric Reversible Non-competitive allosteric Binding allosteric site site binds reversibly and irreversibly - Agonist + competitive Irreversible to allosteric site antagonist: ↓potency of agonist (not necessarily) & ↓ efficacy - Potency can be same - Efficacy can decrease Non- Chemical Inactivates agonist by modification or Protamine à for heparin receptor sequestering before agonist can bind to - Heparin given as anti-coagulant receptor - Thins blood Non-competitive antagonist Protamine breaks it down Functional AKA physiological antagonist Omeprazole à against histamine Causes response that is opposite to agonist - Used for heart burn without targeting the same receptors - Histamine is à expressed in parietal cells of stomach lining that binds to receptor to Non-competitive increase acid secretion - Omeprazole will bind with proton pump and reduce its actions so histamine will still function but acid production reduces elsewhere Partial agonist - partial agonist can function as an antagonist in the presence of a full agonist - binds to same site as agonist so it outcompetes full activation of agonist receptors à competitive antagonism - Agonist + partial agonist: ↓potency of agonist without affecting efficacy - If you treat patient with partial agonist in absence of full agonist = functions as normal agonist - E.g. Pindolol à β2-adrenoceptor partial agonist MODULE 2: PHARMACOLOGY ANS Targeting ANS Pro Cons Wide therapeutic opportunity Potential for adverse effects Neuron - Dendrites = receive synaptic input - Soma = housekeeping à protein synthesis and processing - Axon = action potential conductance - Pre-synaptic terminal = converts electrical signal (AP) into chemical (neurotransmitters) Processing CNS Peripheral 1. CNS receives and integrates information - Brainà Anything external to from internal/external environment via meninges dura mater afferent sensory neurons - Spinal cord - Cranial nerves à 2. CNS integrates information and à cervical, most responds to maintain homeostasis via thoracic, - Spinal nerves à all efferent motor sensory neurons and PNS lumbar, sacral - Peripheral ganglia - Sensory receptors 3. Tissue respond to feedback loop by CNS