BIO200 Introduction to Pharmacology Lecture 5 PDF

BIO200- Introduction to Pharmacology Lecture 5 Physiology of Receptors Dr. Nagham Abdalahad January 21st 2025 Readings for lectures 5-8 Katzung, Chapter 1, pharmacodynamics part only...

BIO200- Introduction to Pharmacology Lecture 5 Physiology of Receptors Dr. Nagham Abdalahad January 21st 2025 Readings for lectures 5-8 Katzung, Chapter 1, pharmacodynamics part only Chapter 2 1  This Week’s Contents Tuesday January 21st Lecture 5- Pharmacodynamic I Thursday January 23rd Lecture 6- Pharmacodynamic II Friday January 23rd Tutorial 3- Drug Discovery 2  Pharmacology Pharmacodynamics = what the DRUG does to the BODY Determines how drug is classified (ex./ irreversible vs. reversible) Helps determine if drug is best for specific disease Pharmacokinetics = what the BODY does to the DRUG Governs how drug is absorbed, distributed, metabolized, and eliminated from body Important when determining kind of drug & administration 3  Pharmacodynamics Principles Drug interacts with target, or receptor TARGET DRUG Effect (protein, DNA, etc.) EFFECTOR MECHANISM: drug alters cell communication Effector = functional role; communicates effect of DRUG:TARGET interaction to the cell Orphan Receptors : unknown ligands = potential drug discoveries 4  Pharmacodynamics Principles Types of effector systems: DRUG Binds to Regulatory Proteins Enzymes Structural proteins Transport proteins https://www.researchgate.net/figure/Classification-of- https://en.wikipedia.org/wiki/Cytoskeleton membrane-transport-proteins-into-either-a-carrier-left- https://www.futurelearn.com/courses/bioche or-channel_fig1_321151168 mistry/0/steps/15299 https://en.wikipedia.org/wiki/Regulation_of_gene _expression 5  Drug-Target/Receptor Interactions Drug binding to protein target = conformational change Affects protein SHAPE Alters protein FUNCTION (example: if target is enzyme) Drug binding can cause effect directly or indirectly The lock and Key relation INDIRECT EFFECT DIRECT EFFECT Fast (ex./ enzyme) or slow (ex./ gene regulation) response Receptors will decide what the drug does! Selectivity Duration of drug/target interaction depends on the type of bonds 6  Model of Drug-Target Interactions Protein targets bind to LIGANDS 2 conformation of R No effect Targets exist in two states: Inactive = Ri → not stimulated by ligand Active = Ra → stimulated by ligand Both forms are always in equilibrium Constitutive activity = mostly in Ra, in absence of ligand Drugs will bind better to one form or the other → shifts equilibrium! (Katzung, Fig. 1-3) Ex./ D – Ri binding = stabilizes the inactive target form Inert binding site = drug binding to non-regulatory target; no effect on biology (ex./ plasma albumin) = no change in its biological function Can affect distribution of drug in circulation (PK) 7  Drug-Target Interactions Hyperbolic curve Emax* C E = ---------------- C + EC50 (Katzung, Fig. 2-1) Effect increases with the increase of the dose Emax = The maximum response that can be produced by a drug EC50 = The concentration of drug that produces 50% of the maximum response 8  Drug-Target Interactions Very similar to the Mass Action Law Hyperbolic curve Effect increases with the increase of the dose concentration of free drug when receptors are 50% bound Fraction of free receptors decreases with increasing drug (or ligand), until saturation occurs (Bmax) Kd = Equilibrium dissociation constant = Free unbound drug concentration of free drug (mol/L) when receptors are 50% bound D bound to R Bmax * C B = ---------------- It describes the affinity of the R to the D C + Kd Low Kd = high affinity High Kd = Low affinity (Katzung, Fig. 2-1) 9  Drug-Target Interactions Curves can also be plotted as response vs. logarithm of [DRUG] Log scale = small changes in the concentration is all it requires to make a big change in effect This expands the scale of the Maximum effect conc. Axis at low conc. Where the effect is changing rapidly and compress it at higher conc. When the effect is changing slowly (Katzung Fig. 2-2) 10  Drug-Target/Receptor Interactions 2 major types of drug / target interactions or COUPLING Occupancy-response relationship Indirect = Enzymes Direct = ion channels The biologic response may reach the Effect depends on how many drug maximum before full saturation molecule binds to how many receptors 11 Occupancy-Response Relationship Hyperbolic curve Effect increases Fraction of free receptors decreases with increasing drug with the increase until saturation occurs (Bmax) of the dose (Katzung, Fig. 2-1) Maximum response may occur without maximum occupancy of the receptors Kd and EC50 are not always the same Very important when determining the drug dose Free unbound drug D bound to R B C ------------ = ---------------- Total no. of R Bmax C + Kd 12  Agonists AGONIST = looks like, binds like, acts like endogenous ligand; activates target pathway Full agonist (activates ~all targets; shifts eq. to saturate all receptors pool Ra–D) Ex./ Acetylcholine (ACh) & Benthanechol (Katzung, Fig. 1-3) Muscarinic Parasympathetic receptors used to treat urinary retention (difficulty urinating), contracting the bladder smooth which may occur after surgery, after delivering a baby, muscle (detrusor) and relaxing and in other situations. the bladder outlet during micturition 13  Special Type of Agonists Some Agonists don’t mimic structure of endogenous ligand Activates target pathway by Inhibiting negative regulators of that endogenous pathway Ex./ Acetylcholine (ACh) & Acetylcholinesterase One possible treatment: inhibit ACE Increases activity of endogenous ACh Acetylcholinesterase (ACE) Sometimes this is more selective than direct agonists (natural biological pathway enhanced) 14  Antagonists ANTAGONIST = (may) look like, bind like, but prevents activity of endogenous ligand; inhibits target pathway Bind to the receptors but do not activate them Competitive Antagonist Compete with endogenous ligand to bind to same pocket They do not have any effect if there is no endogenous agonist 15  Antagonists Competitive Antagonist Higher concentration of agonist will overcome the antagonist effect Propranolol is Beta blocker( competitive inhibitor of B- receptors) that reduces blood pressure 16  Antagonists Higher conc. Of agonist can overcome the antagonist Competitive Antagonist Shift to the right Higher conc. of agonist is needed to produce same effect (Katzung, Fig. 2-3) Receptor-Effector Coupling and Spare Receptors Decreases effect of agonist Shifts agonist effect curve to the RIGHT Increase in EC50 of agonist (ligand) Need higher [ligand/agonist] to have same effect on target Maximum effect Number of available targets (receptors) that can bind Spare receptors Number of effectors (response pathways) associated with receptors → COUPLING (Katzung Fig. 2-2) 18  Antagonists Example Atropine : Uses: decreases saliva production during surgery ACh vs. Atropine 19 Competitive Antagonist - Inhibitor  Caffeine: an Antagonistic Drug Inhibitory neurotransmitter competitive antagonist Produced in brain Binds to all adenosine Longer time awake: more receptors produced Same affinity as adenosine Binds to cell surface Blocks adenosine action receptors; induces calming effects & sleep Drowsiness Decreased heart rate “Calm” feeling Alertness Over time: brain responds by increasing the # of adenosine receptors (how?) Increased heart rate Up-regulation of adenosine receptors “Agitated” feeling Coffee drinkers = need a lot more coffee to have the same effect! 20 Journal of Alzheimer’s Disease 2010, 20, S3-S15  Antagonists Non- competitive antagonist Bind to the receptor and deactivate it. Irreversible antagonist covalent bound to the receptor – Pheochromocytoma and alpha antagonist drugs ( Phenoxybenzamine) 21  Antagonists Competitive antagonist Non- competitive antagonist Higher conc. Of agonist can overcome the antagonist Higher conc. Of agonist cannot overcome the antagonist Shift to the right Higher conc. of agonist is Irreversible antagonist needed to produce same effect Of the agonist stays the same Never reach the max effect no matter how we increase the agonist dose. 22 (Katzung, Fig. 2-3)  Allosteric Regulators Allosteric drug = binds to alternative pocket (~far away) Enhances (allosteric agonist) Inhibits (allosteric antagonist) (Katzung, Fig. 1-2) 23