PHRM20001 NOTES PART 1 Lecture 1 History of Pharmacology- Key Principles Hippocrates (5 th century BCE):... benefit my patients according to my greatest ability and judgment, and I will do no harm or injustice to them... Risk vs Reward balance between patient benefit and potential side effects (try to have minimal side effects) Paracelsus (16 th Century): All things (drugs) are poison, and nothing is without poison; only the dose permits something not to be poisonous. Dose determines effect selectivity issues à one particular concentration of a drug can make the drug be selective in producing it s actions but if you are given a higher dose then you see target effect s happening (i.e. starts effecting other pathways of the body that you don t want to influence and can produce adverse effects) Erlich (20 th Century):... for chemotherapy the principle is true that corpora non agunt nisi fixata (substances do not act unless bound). Drugs bind molecular targets What Makes a Safe and Effective Drug? Pharmacodynamics How to drug is affecting the system? Target Drug must: Be at an effective concentration Bind Have an effect Be selective Pharmacokinetics How the body react to the drug Get there Drug must be: Absorbed Distributed Reach an effective concentration Get out of there Drug is: Some metabolised (liver commonly) Some Excreted (urine/faeces commonly) STRONG INTERPLAY BETWEEN PHARMARCODYNAMICS AND PHARMACOKINETICS What is a drug? Chemical that affects physiological function in a specific way 1. Present in the body» Used for cellular communication o Hormones, Neurotransmitters, Second messengers o Antibodies, genes i.e. Adrenaline: from Adrenal gland - anaphylactic shock 2. Not normally found in body Synthetic or naturally occurring Therapeutic agent I.e. Atropine: from Atropa Belladonna - dilated pupils (attractive!) = Deadly Nightshade - dry mouth, photophobia, hallucinations, death!
What we will cover in this subject Drug Targets. What are they and how do we decide which is best? How drugs exert their actions (both beneficial and toxic)... binding, affinity, potency, efficacy How does the body deal with drugs? ADME How do we find new drugs? Lessons from the past and from new technologies Currently used drugs... how do they act, how are they regulated and what are their problems? Toxic effects of drugs... How can they be avoided and can they be harnessed for good? Lecture 2 - Drug Targets Common drug targets include: Ion channels Carrier molecules l Enzymes Cell receptors DNA - exception Numerous drugs bind to binding s and prodices an effect Drug Targets - Ion Channels allow passage of ions into cells allows to control the electrochemical gradient open Ca 2+ blocked Ca 2+ Ca 2+ entry = contraction reduced contraction Drugs block or modulate channel opening l o nifedipine blocks Ca 2+ channels à Ca 2+ can t get into the cell reduced blood vessel constriction reduced blood pressure Drug Targets - Carrier Molecules Transport of molecules across lipid membranes (also found in blood brain barrier) molecule molecule activation removal from site of action = inactivation drug blocks removal of molecule
Drugs block or utilise carriers o fluoxetine - blocks serotonin uptake into nerves prolongs serotonin action used for depression Drug Targets - Enzymes substrate product substrate Enzyme product drug = inhibitor Drugs may inhibit enzymes o aspirin inhibits cyclooxygenase (COX) o inhibits cyclo-oxygenase (COX) o reduced synthesis of mediators of pain / fever / inflammation Prodrug Active drug produced Drugs may use enzymes o L-dopa uses dopa decarboxylase increased synthesis of dopamine used for Parkinson s disease False substrate Abnormal metabolite produced Abnormal metabolite hijacks the normal pathway à prevents process Drugs may use enzymes o Fluorouracil replaces uracil as an intermediate in purine biosynthesis. DNA synthesis inhibited preventing cell division. Drug Targets - Receptors recognition sites for molecules (selectivity no drug has one action à depends on concentration of drug) Drugs activate or block receptors o Morphine (agonist) - activates opioid receptors used for pain o Naloxone (antagonist) - blocks opioid receptors used for heroin overdose no efficacy A receptor is a biological macromolecule or complex that binds another molecule and initiates or modulates signalling or effector activity within a cell. Located in plasma membrane or cell cytoplasm Ligands (neurotransmitter, hormone, pharmaceutical drug or toxin) bind to binding sites (binding site doesn t necessarily have to be a drug target but it can also be binding s) A ligand that binds to a receptor and activates it is an agonist. A ligand that binds to a receptor without activating it will act as an antagonist.
Receptor nomenclature Receptors often named for earliest known activator o muscarinic receptors are activated by muscarine o nicotinic receptors are activated by nicotine Receptors are also named for cognate hormone or neurotransmitter o Muscarinic and nicotinic receptors are acetylcholine (ACh) receptors o Adrenoceptors are activated by adrenaline and noradrenaline o Angiotensin receptors are activated by angiotensin Receptor classes Muscarinic and nicotinic receptors are separate classes of ACh receptors Alpha-adrenoceptors and beta-adrenoceptors are separate classes of adrenoceptors Receptor subclasses based on pharmacology and distribution in body Alpha different drugs bind to each of these o alpha 1 on blood vessels (predominantly found in blood vessels) o alpha 2 on nerve terminals (predominantly found in nerve terminals)l Beta o Beta 1 in heart o Beta 2 in airways, some blood vessels l selective agonist/antagonist and/or molecular cloning can identify subtypes Receptor Families dit, Ionotropic vs Metabotropic receptors agonist binds directly to and directly regulates the opening of an ion channel = ionotropic agonist binding triggers a series of intracellular events that produce second messengers to indirectly produce cellular responses = metabotropic Ligand-gated channel agonist binds directly to and directly regulates the opening of an ion channel = ligand-gated ion channel Ionotropic receptor/ very fast/ Conformational change
e.g. nicotinic receptor (5 subunits α2βγδ) located on skeletal muscle (neuromuscular junction) agonist = acetylcholine (ACh) ACh binds to subunits à Na + channel opens à Na + entry stimulates contraction Ligand-gated ion channel Kinase-linked receptors intrinsic enzymatic activity in receptors transmembrane receptors Takes some time to occur but may produce more prolonged effects compared to ligand-gated channels Kinases can be in the membrane or can recruit them from the cytoplasm of the cell agonist binds to extracellular domain of a transmembrane this activates enzymatic activity of the s cytoplasmic domain e.g. growth factor receptors o o agonist binding causes receptor dimerisation (compound formed by 2 similar molecules) activation of tyrosine kinase (cytoplasmic domain) phosphorylates substrates that regulate cell growth Nuclear receptors Lipid-soluble chemical signal enters cell Ligand binds to and activates intracellular receptor Receptor may regulate gene transcription Drug-receptor complex enters nucleus and binds to DNA to induce or repress genes Slow onset - synthesis takes hours Effect lasts for days - slow turnover e.g. glucocorticoid receptor activation inhibits synthesis of cyclo-oxygenase Nuclear receptors glucocorticoid growth factor Gene transcription P -Y Y- P Protein phosphorylation Nucleus nucleus DNA GR transcription cytoplasm mrna translation
G- coupled receptors (GPCR) Largest receptor family Takes longer than ligand-gated channelsl Agonist binds to a cell-surface receptor consisting of 7 transmembrane segments (serpentine receptor) o Linked to an effector by a G- effector may be an ion channel effector may be an enzyme e.g. muscarinic ACh receptor, adrenoceptors GPCRs activate a particular G- l That G- is then able to selectively interact with the effector (e.g. ion channel or enzyme) A number of different G-s exist Changes the activity of 2 nd messenger that causes cellular modulation Extracellular binding site and intracellular segment (interacts with G s) Agonist binds to a receptor causing a conformational change in the effector (i.e. ion channel) which allows the G to interact with it This changes the permeability of the ion channel to ions (influx of efflux) Agonist G Ion channel Agonist binds to a receptor causing a conformational change in the effector (i.e. enzyme) which allows the G to interact with it This alters the activity of the enzyme causing the production of second messengers Second messengers cause a number of cellular effects) Agonist G Enzyme G coupled receptors examples G S = stimulatory stimulates the Adenylate-cyclase 2 nd messenger G s Adenylate Cyclase GTP camp ATP Cellular effects
G i = inhibitory inhibits the function of Adenylate-cyclase GTP Gi Adenylate Cyclase camp ATP G q coupled to phospholipase C Generation of two 2 nd messengers Cellular effects Phospholipase C Gq GTP IP 3 & DAG PIP 2 Signal amplification Can use small concentrations of a drug (low doses) to produce a good effect Single agonist-receptor complex can activate multiple G- molecules G- can remain associated with the effector for long enough to produce many 2 nd messenger molecules Amplification also occurs post 2 nd messenger generation before the final cellular response occurs Drug-receptor interactions molecular shape & properties of drug determine degree of binding covalent irreversible (bad for drugs? à Good and bad) STRONG bonds electrostatic o ionic > hydrogen bonds > van der Waals hydrophobic o lipid soluble drugs with lipid membranes Lecture 3 How do drugs act? for chemotherapy the principle is true that corpora non agunt nisi fixata. Ehrlich, 1913 Drugs do not act unless bound Enzymes Carrier molecules Ion channels Receptors DNA The power of attraction Receptors Bind endogenous and exogenous chemicals Alter cell function in a specific way o can influence enzymes, ion channels, carriers Cellular effects PIP 2 = Phosphatidylinositol (4,5) bisphosphate IP 3 = Inositol (1,4,5) trisphosphate DAG = Diacylglycerol