Principles of Pharmacology 1 Lecture Notes PDF

Principles of Pharmacology 1 Introduction to Pharmacology, focusing on receptors, transmitters and drug actions Dr Vassilis Beglopoulos Slides by Dr Chris Smith  The need for receptors Signal molecule Signalling molecules or hormones in the...

Principles of Pharmacology 1 Introduction to Pharmacology, focusing on receptors, transmitters and drug actions Dr Vassilis Beglopoulos Slides by Dr Chris Smith  The need for receptors Signal molecule Signalling molecules or hormones in the blood can reach a large no of Receptor different cells – No specificity Target However - not all cells respond to proteins circulating chemicals – Specificity provided by only specific cells having receptors for that chemical Intracellular signal “a cell cannot respond to a chemical molecules signal if the cell lacks the appropriate receptor proteins for that signal” Silverthorn Response  3 of 27 The receptor concept – Langley and Ehrlich Chemicals produce their effects by combining with specific receptor sites in cells The response is a function of the number of occupied receptors The lock and key hypothesis – chemical specificity – Affinity – the “strength” of the drug receptor interaction Receptors Proteins Have binding site – “Receptive to ligand” – Has affinity to ligand Receptor locations Four types of receptors Transmitters Hormones Neurotransmitters Also – Local signalling molecules – Autocoids – Neuropeptides – Neuromodulators – Cytokines Hormones Released from one cell into extracellular space/circulation to travel to new site of action where they provoke a specific response  Neurotransmitter Synthesised in the presynaptic neurone and stored in vesicles Exocytosis triggered upon Ca++ influx Diffusion through synaptic cleft Bind to post-synaptic receptors triggering a response Neurotransmitter uptake/break down to terminate transmission  The synapse http://blog.nervousencounter.com/?p=215 Neurotransmitter release Exocytosis: Process by which vesicles release their contents Bear et al., Neuroscience Exploring the Brain, 3rd ed  Neurotransmitter release http://www.intechopen.com/source/html/37703/media/image3.jpeg Neurotransmitter recovery and degradation – Diffusion: Away from the synapse – Reuptake: Neurotransmitter re-enters presynaptic axon terminal – Enzymatic degradation: inside terminal cytosol or synaptic cleft Neurotransmitters Acetylecholine Monoamines – Noradrenaline, dopamine, 5-HT Amino acids – Glutamate, GABA Neuropeptides – Endorphins Purines – ATP Soluble gases – Nitric oxide (not nitrous oxide!) Amino acids Certain amino acids are neuroactive and function as neurotransmitters – GABA – Glutamate The major inhibitory and excitatory neurotransmitter respectively in the CNS – GABA accounts for 40% of inhibitory transmission – GLU accounts for 50% of excitatory transmission Recall… …the distinction the between a hormone and a neurotransmitter Neurotransmitter – Synthesised and stored in nerve terminal and released into the extracellular space to act on adjacent neurones Hormone – Synthesised and stored in one organ and is released into the blood to have an affect on another organ  Hormone or neurotransmitter? Adrenaline is important hormone – Released into the blood Increases heart rate, force of contraction Dilates bronchi Mobilises glucose (inhibit insulin release) – Fight or flight Noradrenaline is important neurotransmitter Types of receptors based on ligand Cholinoceptors (muscarinic and nicotinic) Adrenoceptors (α and β) Histamine (H1, H2 AND H3) Dopamine (D1, D2 etc..) Insulin Steroids Etc., etc. (100+ different types) Types of receptors Cholinoceptors (_______ and _______) ____________ (α and β) ____________ (H1, H2 and H3) Dopamine (D1, D2 etc..) 5-HT (5-HT1, 5-HT2, 5-HT3…) Insulin Steroids Etc. etc. (100+ different types) Acetylecholine receptors Divided into nicotinic (nAChR) and muscarinic (mAChR) subtypes depending on activity to selective drug mAChr nAChR G-protein coupled receptor Ligand gated ion channel 5 subtypes (M1 – M5) permeable to Na+ ions Excitatory M1, M3 and M5 excitatory M2 and M4 inhibitory Nicotinic ACh receptors nAChR = pentameric – 5 subunits Each subunit termed either α, β, γ, δ or ε Each subunit spans the membrane four times Variations in subunits confers specificity between neuronal and muscle nAChRs Glutamate receptors Both ionotropic and metabotropic GLU receptors exist Ionotropic named after selective ligands (like ACh receptors) – AMPA – NMDA – Kainate Ionotropic receptors open cation channel GABA receptors GABAA – Ionotropic – ligand gated ion channel – Chloride channel GABAB – Metabotropic – GPCR – Ultimately inhibit voltage gated Ca++ channels and open K+ channels  G protein coupled receptors An extremely large group of receptors – visual pigments, odorant receptors, monoamine receptors, peptide receptors etc etc – Specific examples are muscarinic, alpha/beta Via activation of transducer proteins: guanine nucleotide binding proteins (G proteins) Common structural motifs Single polypeptide chain 7 hydrophobic (transmembrane) regions Extracellular N-terminus Intracellular C-terminus – Size of the N- and C-termini and the various loops differ enormously – Confers site specificity, different subtypes and involvement of varied second messenger systems to be possible G protein coupled receptors G protein coupled receptors Signal Transduction Mechanism Receptor activated G protein – A family of proteins that bind guanosine triphosphate - G T P G Protein-GDP + GTP G Protein-GTP + GDP Receptor Inactive Active G Protein-dependent signal transduction Active G Protein interacts with yet another protein: Ion Channel or Enzyme. Ion Channel – Mechanism is the influx of an ion eg Na+, Ca++ Enzyme – Produces a substance that serves as a relay in the signal transduction mechanism called: Second Messenger or Intracellular Messenger By far the largest category Ligands acting on receptors Agonist Cellular response Antagonist No effect Agonists / Antagonists Pharmacological agonist Combines with a receptor and produces a response – has affinity and efficacy Pharmacological antagonist Combines with a receptor, does not produce a response, but prevents the action of an agonist – has affinity but no efficacy  Acting on ion channels Permeation blockers blocked eg local anaesthetics block Na+ channels modulators Increased/decreased opening probability eg barbiturates and benzodiazepines  Acting on enzymes Substrate Normal reaction, normal metabolite produced Inhibitor Normal reaction inhibited eg aspirin inhibits COX False Abnormal metabolite substrate produced Prodrug Active drug produced Acting on transporters Normal transport Transport Inhibitor or blocked Eg prozac False Unnatural compound substrate accumulated Types of drug action Transport systems (5%) Enzymes (15%) Microbes (40%) Cellular Receptors (40%) Others (less than 1%) Genetic transplants (0.00000000001%) Recap Drugs acting on specific proteins on cell membranes called receptors Drugs that block the action of specific enzymes Drugs that inhibit cell transport mechanisms Drugs that act on ion channels Drugs that act on invading organisms Drugs with a non-specific action