PHRM20001: Pharmacology - How Drugs Work!

Size: px

Start display at page:

Download "PHRM20001: Pharmacology - How Drugs Work!"

Hillary Martin
5 years ago
Views:

1 PHRM20001: Pharmacology - How Drugs Work Drug: a chemical that affects physiological function in a specific way. Endogenous substances: hormones, neurotransmitters, antibodies, genes. Exogenous substances: natural or synthetic therapeutic agents. Safe and Effective Drugs: Must be absorbed and distributed so that they reach their target at an effective concentration Elicit an effect once bound to a target Act selectively upon the desired target Are eliminated by liver metabolism or excretion Pharmacodynamics: the effects of drugs and the mechanism of their action. Concerns site of action, selectivity, potency and efficacy. Pharmacokinetics: the movement of drugs within the body. Concerns administration, absorption, distribution and elimination. Drug Targets Ion Channels: allow passage of ions into cells Carrier Molecules: transport of molecules across lipid membranes Enzymes: catalyse the synthesis/breakdown of molecules : selective recognition sites for molecules Drugs block or modulate channel opening Nifedipine: blocks Cα2+ channels - reduced blood vessel constriction - reduced blood pressure Drugs block or utilise carriers Fluoxetine: blocks serotonin uptake into nerves - prolongs serotonin action - treatment for depression Drugs may inhibit or utilise enzymes: Aspirin (inhibitor): inhibits cyclo-oxygenase - reduced synthesis of pain/fever/inflammation mediators L-Dopa (prodrug): utilises dopa decarboxylase - increases synthesis of dopamine - treatment for Parkinson s disease Fluorouracil (false substrate): replaces Uracil in purine biosynthesis - DNA synthesis and cell division inhibited Drugs activate or block receptors: Morphine (agonist): activates opioid receptors - alleviates pain Naloxone (antagonist): block opioid receptors - treatment for heroin overdose

2 Receptor Families Ligand-Gated Ion Channels G-Protein Coupled Tyrosine Kinase - Ionotropic receptors located in the plasma membrane - Ligand binding stimulates channel opening and ion flow - Ligand dissociation mediates channel closure Nicotinic receptor: - Acetylcholine agonist binds to α subunits - Na + channel opens - Na + influx stimulates contraction - Agonist binds to a cell-surface serpenting (7-segment) receptor - G-proteins link receptor to effector ion channels or enzymes - Activity of second messengers (induced by the effector) cause cellular modulation - Signal Amplification occurs when G-proteins remain associated with the effector or post second-messenger generation Gs: stimulates production of camp Gi: inhibits production of camp Gq: stimulates phospholipase C to produce IP3 and DAG - Agonist binds to extracellular domain of a transmembrane protein - Binding activates enzymatic activity in the protein s cytoplasmic domain Growth Factor : - Agonist binding causes receptor dimerisation - Activation of tyrosine kinase in the cytoplasmic domain leads to phosphorylation of substrates regulating cell growth Cytoplasmic Nuclear - Lipid-soluble signaling molecules enter cell - Ligand binds to and activates intracellular receptor - Drug-receptor complex enters nucleus and binds to DNA to induce or repress genes - Slow onset but long-lasting Glucocorticoid Receptor: activation inhibits synthesis of cyclooxygenase Mass Action: the rate of a chemical reaction is proportional to the concentrations of the reactants. Forward Rate: [D][R]k+1 Backward Rate: [DR]k-1 Dissociation Constant: KD = k-1 / k+1 Measure of affinity Low KD = high pkd = high affinity 50% receptors occupied KD = [D] logec50, EC50 and pec50: concentration of drug required to elicit a 50% response in the absence of inhibitor. Measures of potency

3 Concentration: amount in a given volume/ at a molecular target Dose: amount administered - determines effect In vitro, dose approximates concentration In vivo, does not approximate concentration due to pharmacokinetic processes: Adsorption, distribution, metabolism and excretion alter concentration. Affinity: molecular attraction to the receptor Both agonists and antagonists have affinity Constant for specific drug-receptor combinations Differs when different drugs bind the same receptor Potency: amount of drug needed for effect Clinically useful drugs exert their desired effects at low doses The higher the dose, the higher the probability of other (unwanted) actions Depends on both affinity and efficacy of the drug as well as number of available receptors in the tissue Efficacy: the ability of a drug to activate the receptor Maximal responses differ when different drugs act on the same receptor Efficacy is a combination of receptor number and stimulus-response coupling Agonists: drugs which bind and activate receptors to elicit a response. Mimic activity of nerve activation/na and ACh in the peripheral nervous system Potency measured by how much drug required to elicit response Full agonists: elicit a maximal response, higher efficacy. Not all receptors occupied for maximal response - have a receptor reserve. Partial agonists: do not elicit a maximal response, lower efficacy. All receptors occupied for maximum response Maximum response less than that for full agonist Antagonists: drugs which bind receptors but do not activate them. Block nerve-evoked responses /NA and ACh in the peripheral nervous system Potency defined by ability to inhibit agonist responses Response only elicited when an endogenous agonist is present Only agonists exhibit efficacy (activation) by blocking receptor activation Response only elicited when an endogenous agonist is present No efficacy in vitvo Clinical Efficacy: efficacy of a drug in vivo with a measurable potency

4 Gaddum s Equation: Gives the proportional occupancy of a receptor by agonist in the presence of both agonist and antagonist. Antagonist Affinity and Potency: Dissociation constant (KD / KB) can be derived from: Direct binding assays using labelled drugs Schild Plots/Concentration Ratios: Plot of the relative shift of the agonist curve against antagonist concentration pα2 Value: the negative logarithm of the concentration of antagonist required to cause a two-fold rightward shift of the agonist concentration-response curve An indication of antagonist potency pα2 approximates pkb Effect of Increasing Surmountable Antagonist Concentration: Parallel, rightward shift observed Reduces potency: higher concentration of agonist needed to exert the same response Surmountable as the maximum response is unchanged by the antagonist A specific antagonist will exhibit similar effects on full and partial agonists for a given receptor Effect of Increasing Insurmountable Antagonist Concentration: Rightward shift is not parallel Reduces potency: higher concentration of agonist needed to exert the same response Insurmountable as the maximum response is depressed by the antagonist Maximum collapses immediately if there are no spare receptors A specific antagonist will exhibit different effects on full and partial agonists for a given receptor Competitive Insurmountable Antagonism: agonist and antagonist bind to the same site Pattern of antagonism determined by: Association/dissociation constants Relative concentrations of agonist and antagonist Duration of exposure to antagonist Binding of antagonist is slowly reversible or irreversible High affinity, strong binding Decreases the number of receptors available for agonist binding

5 Chemical Transmission in the Post-Ganglionic Autonomic Nervous System Organ/Tissue Parasympathetic: ACh acting on muscarinic receptors Sympathetic: NA acting on α- and β- adrenoceptors Heart Decreased heart rate Increased heart rate Gastrointestinal Tract Increased activity Decreased activity Pupil Constriction Dilation Arteries ---- Constriction Glands Secretion ---- Bronchi Constriction Dilation Opposing responses facilitates drug therapy as selectivity issues are alleviated Adrenergic Pharmacology: Mediated by adrenaline and noradrenaline Chatecolamines: contain both catechol (C6H6(OH)2) and amine (NH2) groups Chatecolamine Synthesis: Tyrosine taken up into sympathetic neurons by specialised transporters Tyrosine hydroxylase converts tyrosine to L-DOPA DOPA decarboxylase converts L-DOPA to Dopamine In dopaminergic neurons, pathway terminates here Dopamine packaged into synaptic vesicles Dopamine β-hydroxylase converts dopamine to noradrenaline In adrenals, noradrenaline is converted to adrenaline by the action of Phenylethanolamine-N- methyl transferase (PNMT). Chatecolamine Release: Action potential depolarises neuron Cα2 + influx triggers packaging of neurotransmitters into synaptic vesicles Fusion of vesicular membrane with pre-synaptic terminals Exocytotic release into synapse Chatecholamine Inactivation: Neuronal Uptake 1: high affinity, major re-uptake mechanism Free noradrenaline transported into pre-junctional neuron Repackaging into vesicles Degradation by monoamine oxidase to metabolites (re-uptake dependent) Inhibited by cocaine Extraneuronal Uptake 1: low affinity, secondary re-uptake mechanism Free noradrenaline transported into effector tissues Inhibits continual stimulation of adrenoceptors by noradrenaline on the given neuron Catechol-O-Methyl Transferase (COMT): Degradation in pre-synaptic neurons and effector tissues

PHRM20001 NOTES PART 1 Lecture 1 History of Pharmacology- Key Principles

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