Lect 4

• Pharmacodynamics is the relationship between drug concentration and intensity of action at the receptor level.
• Different types of drug targets include enzymes, carriers, ion channels, and receptors.
• The selective interaction of a drug molecule with its target must result in a response, which is like a lock and key.
• Drug responses reflect the interaction of drugs with their targets.
• Enzymes, carriers, ion channels, and receptors are the four types of protein targeted by drugs.
• Cyclooxygenases are the target site for NSAIDs, and their inhibition leads to the suppression of proinflammatory prostaglandins.
• Acetylcholinesterase (metabolizes acetylcholine), is a target site for cholinesterase inhibitors such as neostigmine and physostigmine.
• Antibiotics may act by inhibiting enzymes involved in cell wall biosynthesis, nucleic acid metabolism and repair, or protein synthesis.
• Non-steroidal anti-inflammatory drugs (NSAIDs) block the cyclooxygenase-1 and -2 and stop thereby the synthesis of prostaglandins.
• Cyclooxygenase-1 and -2 are also known as COX-1 and COX-2.
• Coxibs are selective cyclooxygenase inhibitors.
• Potency does not reflect how effective a drug is.
• Noncompetitive Antagonist Antagonist Agonist potency Agonist efficacy Competitive Decreases No change Noncompetitive No change DecreasesDrug Specificity The drug - receptor interaction is responsible for the specificity of drug action.
• If the drug concentration is increased several targets may be involved simultaneously.
• The P athophysiologic Basis of Dr ug T herapy Fourth edition Edited by David E Golan, Ehrin J Armstrong, and April W Armstrong 2017 Elsevier Saunders.
• A drug may be specific at a low concentration if it activates only one type of target (enzyme, receptor, etc).
• Specificity is unusual.
• Most drugs can display activity towards a variety of receptors.
• Each drug has its own E max and EC 50.
• Increasing the dose of a drug when the response is submaximal will enhance the therapeutic effect.
• Veterinary Pharmacology and Therapeutics Tenth edition Edited by Jim E Riviere and Mark G Papich 2018 Wiley.
• Potency is an expression of the activity of a drug in terms of the concentration of the drug required to produce a defined effect.
• Increasing the dose of a drug when the response is maximal will not improve the therapeutic effect but may elicit toxic effects.
• Efficacy (E max) gives information on the maximum reachable effect of a drug.
• Acetylcholine (ACh) is broken down into acetic acid and choline by Acetylcholinesterase (AChE).
• The primary role of AChE is to terminate neuronal transmission and signaling between synapses to prevent ACh dispersal and activation of nearby receptors.
• Membrane transport proteins are target sites for many drugs.
• The Na+/K+/2Cl- symport in the nephron is the site of action of furosemide and other diuretics such as torsemide.
• The effect is the observed effect; Emax is the maximal possible effect; kd is the equilibrium constant of dissociation (a parameter measuring affinity) and Drug is the drug concentration.
• The β2 AR is linked to a stimulatory guanine-nucleotide-binding protein (Gs).
• Cell Signalling involves G-Protein coupled Receptors (GPCRs), Phospholipase C, and Second messengers such as Diacylglycerol (DAG) and Inositol triphosphate (IP3).
• The drug has to occupy all receptor to achieve a maximal effect (Emax) and the response is terminated when the drug dissociates from the receptor.
• Response is proportional to the number of activated receptors.
• Occupancy theory was the first model proposed by Clark in 1923.
• Drugs mimic or prevent the actions of endogenous ligands.
• In occupancy theory, the more receptors occupied by a drug the greater the response.
• Occupancy Theory (Graded Activation Model) was confirmed in a limited number of cases.
• Albuterol, a bronchodilator, produces its effect through interaction with β2 receptors (β2 AR) located in the plasma membrane of airway smooth muscle cells.
• Drug receptor theories consist of a collection of evolving models that permit qualitative and quantitative description of the relationship between drug concentration and their effect.
• cAMP activates the protein kinase A (PKA) which leads to smooth muscle cell relaxation in the airways.