Basic Principles of Pharmacology PDF

Basic Principles of Pharmacology Drug Receptor Binding Pharmacokinetics Pharmacodynamics  Let’s review… Neuropharmacology is the study of drugs interactions with the nervous system Drug is any chemical that interact with a protein or another molecule to cause cellular response...

Basic Principles of Pharmacology Drug Receptor Binding Pharmacokinetics Pharmacodynamics  Let’s review… Neuropharmacology is the study of drugs interactions with the nervous system Drug is any chemical that interact with a protein or another molecule to cause cellular response – Endogenous (made in the body) – Exogenous (delivered to the body) e.g. Poisons (substances with harmful effects, Toxins (poisons of biological source) Receptor is a protein that interact with a molecule and cause a change in downstream signaling pathways  Pharmacology definitions Pharmacokinetics:The study of the effect of the body on the drug Pharmacodynamics: the study of the effect of the drug on the body  Pharmacokinetics (PK) 1. Pharmacokinetics (PK)- absorption, distribution, metabolism, excretion (ADME). – Absorption– oral dosing dependent on GI tract, intravenous dosing not dependent on GI tract but drugs can bind to plasma proteins and not be available for actions. – Bioavailability is fraction of drug that is present in its free form in the blood. Can be influenced by how much gets out of GI tract or how much is bound to plasma protein. – Distribution– how much of the body space can the drug access? Does it gain access to the CNS, is it deposited in fat? – Metabolism-- what happens to the drug after it is distributed? Is it broken down by the liver? How long does this take? What is the half life (the amount of time to break down 50% of the drug)? – Excretion-- how is the drug eliminated? Is it filtered by the kidneys and excreted in urine? Is it eliminated in feces?  Pharmacokinetics (PK) http://optiviabio.com/wp-content/uploads/2014/01/ADME_graphic01112014.jpg  Pharmacokinetics (PK) Routes of administration Oral (aka per os, or PO)– by mouth Parenteral– any other route. Can be: Subcutaneous (subQ, SC)– under the skin Intraperitoneal (IP)– into the abdominal cavity Intravenous (IV)– directly into the venous circulation Intrathecal (IT)– into the CSF in the spinal canal Intracerebroventricular (ICV)– into the ventricles (brain) Intramuscular (IM)– into the muscle  Pharmacokinetics (PK) Cmax Concentration of Drug ½ Cmax Area under the curve: Total exposure of the Drug Tmax T½ Time More Drug in More Drug out than out than in (T ½ is the drug half time)  Pharmacokinetics (PK) Routes of administration 1 1. Inhalation Blood Concentration of Drug 2 2. IV 3. oral 3 Drug half line is identical Time Concentration of the drug 3 2 1 Gut liver vein heart lungs heart artery  Pharmacodynamics 2. Pharmacodynamics (PD)– interaction of drugs with receptors Ligand- a drug, a neurotransmitter, or something that is capable of binding to a receptor. Receptor- typically a protein, but something that a ligand binds to that produces a functional response. NIDA  Pharmacodynamics Types of drugs/ligand Agonist- ligand that causes a response. Increasing concentrations of agonists should cause increasing response. Full agonist- ligand that causes maximal response. Intrinsic activity = 1. Partial agonist- ligand that causes a response less than that of a full agonist. Intrinsic activity between 0 and 1. Antagonist- ligand that does not cause a response. It blocks the response to an agonist. Intrinsic activity = 0. Can be reversible or irreversible. Potency vs Efficacy Efficacy is a measure of the relative maximal response between drugs. Potency is a measure of how much drug is needed to produce a response. A and B are full agonists. C is a partial agonist T. Kenakin  Affinity, Selectivity &Constitutive Activity Affinity is a measure that describes how strong the drug will bind to the receptor Selectivity is a measure of how selective a drug is to bind to receptors Constitutive activity- receptors can be active in the absence of any bound ligand  Dose-response experiments Measures the functional response to a drug/ligand. Can be in vivo, in vitro or ex vivo. X-Y plot where X is the concentration of the drug/ligand and Y is the response. Response might be enzyme activity, accumulation of a 2nd messenger, current, release of a peptide, contraction of muscle… Often called concentration-response curves. Dose refers to an in vivo experiment Concentration refers to any experiment in vitro or ex vivo. Shape of dose-response curves Emax is the concentration of ligand that produces a maximal response. EC50 is the concentration of ligand that produces a half-maximal response. Log scale on X axis produces classic sigmoid shaped curve. Types of Antagonists Competetive Non-competetive Competitive receptor antagonists Bind to the same site on the receptor as the agonist. Shift the concentration- response curve to the right so EC50 is higher. Can compete away the effect of the antagonist by adding more agonist. No change in Emax Decrease in potency but not efficacy Non-competitive antagonists Binds to the same site as agonist but is irreversible. Can also bind to a different site- allosteric modulator Prevents the receptor from producing a response. Cannot compete away the effect of the antagonist by adding more agonist. Decreased Emax Decrease in efficacy Allosteric Modulators Allosteric modulators are non-competitive antagonists. But they can also increase the response of the agonist. Allosteric, non-competitive drugs  Antagonist Dose-response curve When agonist given at Emax concentration, increasing concentration of antagonist Agonist-stimulated effect produces decreasing response. IC50 is a measure of the concentration of antagonist required to produce 50% reduction in agonist log [Antagonist] M response.  Inverse Agonists If receptors are constitutively active, inverse agonists can produce a negative response.  Drugs Produce More Than One Effect 100 75 % Response 50 25 0 0.01 0.1 1.0 10.0 100.0 1000.0 Log Morphine (mg/kg)  Drugs Produce More Than One Effect Therapeutic Index “window” 100 LD50 500 = = 250 75 ED50 2 % Response 50 25 0 0.01 0.1 1.0 10.0 100.0 1000.0 ED50 (2mg/kg) LD50 (500mg/kg) Log Morphine (mg/kg)  Radioligand Binding Assays Used to measure the affinity of a ligand for a receptor and other receptor characteristics. Can determine the affinity of drugs for receptors but you cannot tell whether the drugs are agonists or antagonists. Can also determine the total number of available receptors and can compare affinities between ligands.  Law of mass action Binding happens when the ligand and the receptor collide in the right orientation and with enough energy (a reversible process). The association rate is: Number of binding events per unit of time =[Ligand]×[Receptor]×kon. The dissociation rate is: Number of dissociation events per unit time = [ligand×receptor]×koff. After dissociation, the ligand and receptor must be the same as they were before binding. If either the ligand or receptor is changed (chemically), then the binding does not follow the law of mass action. Equilibrium is reached when the rate at which new ligand×receptor complexes are formed equals the rate at which the ligand×receptor complexes dissociate. At equilibrium: Rearrange: Kd is the equilibrium dissociation constant and has units of molarity (M). It is defined as the concentration of ligand required to bind 50% of the receptors. It is an inverse measure of affinity (i.e. smaller Kd means higher affinity).  Fractional occupancy Used to calculate the percentage of receptors bound at any concentration. If Kd = 1 and [Ligand] = 10 X Kd, then fractional occupancy = 10/(10+1) = 10/11 = 0.91 or 91% of the receptors bound.  Saturation Binding Data Left graph is linear x-axis of drug concentration. Right graph is log x-axis of drug concentration (classic sigmoid). Adding more drug results in more binding of ligand to receptor. Kd is concentration of drug where 50% of receptors are bound. Bmax is the maximum binding. Competition Binding Competition curve measures the amount of binding of a radioligand in the presence of increasing concentrations of a non-labeled drug. Start with a the concentration of radioligand that binds 100% of receptors. Add in an unlabeled drug that binds to the same receptor. As more unlabeled drug is added, there should be a decrease in the binding of the radioligand (if they are binding to the same site). Ki is the concentration required to displace 50% of the radioligand.  Fractional Response Equation for fractional response to a drug. Rf is the fractional response for any concentration of agonist and [D] is the concentration of the drug. If the EC50 is 1 nM and you give a dose that is 10 nM what is the fractional response?