PHRM246 Study Notes - Pharmacodynamics (2020) PDF

**[PHARMACODYNAMICS]** Pharmacodynamics deals with the effects of drugs on biologic systems. The effects of most drugs result from their interaction with macromolecular components of the organism. The interaction results in biochemical and physiological changes that are characteristic of the respon...

**[PHARMACODYNAMICS]** Pharmacodynamics deals with the effects of drugs on biologic systems. The effects of most drugs result from their interaction with macromolecular components of the organism. The interaction results in biochemical and physiological changes that are characteristic of the response to the drug Most drugs exert their effects by interacting with receptors present on the cell surface or intracellular. The formation of the drug-receptor complex leads to a biologic response, and the magnitude of **the response is proportional to the number of drug-receptor complexes.** Drug + Receptor ↔ Drug-Receptor complex → Biologic effect receptor%20and%20ligand *[a) Receptors]* Receptors are the specific molecules in a biologic system with which drugs interact to produce changes in the function of the system. ***Receptors must be selective***; ***Receptors must be modifiable***. The interaction of a drug with its receptor is the fundamental event that initiates the action of the drug. Drugs that bind to physiological receptors and mimic the regulatory effects of the endogenous signaling compounds are *agonists.* Other drugs (*antagonists*) bind to receptors without regulatory effect, but their binding blocks the binding of the endogenous agonist. Antagonists may still produce effects by inhibiting the action of an agonist. Agents that are **only partly as effective as agonists no matter the amount employed are *partial agonists.*** *[b) Receptor families]* A receptor is any biologic molecule to which a drug binds and produces a measurable response 4 main receptor families: ***i) Ligand-gated ion channels*** Many drugs can mimic or block the actions of endogenous ligands that regulate flow of ions through plasma membrane channels. Natural ligands are ***acetylcholine, serotonin, GABA and glutamate***. Each of their receptors **transmits its signal across the plasma membrane by increasing transmembrane conductance of the relevant ion and thereby altering the electrical potential across the membrane**. The response to these receptors is very rapid.  *ii) G protein-coupled receptors* Many extracellular ligands act by **increasing the intracellular concentrations of second messengers**. Extracellular ligand binds to cell-surface receptor. The **receptor triggers the activation of a G protein located on the cytoplasmic face of the plasma membrane.** The **activated G protein the changes the activity of the effector element, usually an enzyme or ion channel.** Second messengers include *adenylyl cyclase and phospholipase C* GPCR-Zyklus *Activity:* Watch the video posted on the Moodle session for this week, and complete each step of the process in the figure above: 1: \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ 2: \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ 3. \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ 4: \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ 5: \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ 6: \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ ***iii) Enzyme-linked receptors*** **Binding of a ligand to an extracellular domain activates or inhibits the cytosolic enzyme activity.**  ***iv) Intracellular receptors*** **Receptor is entirely intracellular**. Ligand *[must diffuse into the cell to interact with the receptor]*. The receptor becomes activated because of the dissociation of a small repressor peptide. The activated ligand-receptor complex migrates to the nucleus where it binds to specific DNA sequences, resulting in the regulation of gene expression. Because gene expression -- and therefore, protein synthesis -- is modified, cellular responses are not observed until considerable time has elapsed and the duration of response is much greater than other receptor families. The time course of activation of these receptors are therefore much longer than other mechanisms. steroid-receptors ***v) Spare receptors*** A characteristic of many receptors is their **ability to amplify signal transduction and intensity**. A single ligand/receptor complex can interact with many G proteins, thereby multiplying the original signal many-fold. The activated G protein persists for a longer duration than the original ligand/receptor complex, also multiplying the signal. **Because of this amplification, only a fraction of the total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell.** Systems that exhibit this behaviour are said to have spare receptors e.g*[. insulin receptors]*. ***Spare receptors are said to exist if the maximal drug response (E~max~) is obtained at less than maximal occupation of the receptors ((B~max~).*** This can be determined by comparing EC~50~ with K~d~ - if the EC~50~ is less than the K~d~ spare receptors exist. *vi) Desensitization of receptors* Repeated or continuous administration of an agonist may lead to changes in the responsiveness of the receptor, **especially the response of G-coupled receptors.** To prevent potential damage to the cell, **several mechanisms have evolved to protect a cell from excessive stimulation**. When repeated administration of a drug results in diminished effect, the phenomenon is called **tachyphylaxis.** Other types of desensitization occur when receptors are **down-regulated**. Agonist-bound receptors may be **internalized by endocytosis, removing them from further exposure to extracellular molecules**. These receptors may be recycled to the cell surface, restoring sensitivity, or, alternatively, may be further processed and degraded, decreasing the total number of receptors available. *[Activity:]* Indicate to which receptor family each of the receptors below belong to:  \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_ *[c) Graded dose-response relationship]* As the concentration of a drug increases, the magnitude of its pharmacologic effect also increases. The relationship between dose and response is continuous: - \[Drug\] + \[Receptors\] ↔ \[Drug-receptor complex\] When the response of a particular receptor-effector system is measured against increasing concentrations of a drug, the ***graph of the response versus the drug concentration or dose is called a graded dose-response curve*** http://www.cybermedicine2000.com/pharmacology2000/General/Pharmacodynamics/dc\_de%20(Copy%202).gif Plotting the same data on a semi-logarithmic concentration axis usually results in a sigmoid curve: The **efficacy (E~max~)** and **potency (EC~50~ or ED~50~)** parameters are derived from these data: *Potency* **Potency refers to the concentration (EC~50~) or dose (ED~50~) of a drug required to produce 50% of that drug's maximal effect.** ***Potency of a drug depends on the affinity (K~d~) of receptors for binding the drug***. For clinical use, it is important to distinguish between a drug's potency and its efficacy **The clinical effectiveness of a drug depends not on its potency (EC~50~), but on its maximal efficacy and its ability to reach the relevant receptors** ***Efficacy*** Efficacy is the ***greatest effect (E~max~) an agonist can produce if the dose is taken to very high levels..*** Efficacy is determined mainly by the nature of the drug and the receptor and its associated effector system. It **can be measured with a graded dose-response curve but not with a quantal dose-response curve** Partial agonists have *lower efficacy than full agonists.* Efficacy is **dependant on the number of drug-receptor complexes formed**, and the **efficiency of coupling of receptor activation to cellular responses.** **A drug with a greater efficacy is more therapeutically beneficial than one that is more potent.**  *[d) Graded dose-binding relationship & binding affinity]* It is possible to measure the fraction of receptors bound by a drug and, by plotting this fraction against the log of the concentration of the graph, a graph similar to the dose-response curve is obtained. **The concentration of drug required to bind 50% of the receptor sited = K~d~** K~d~ is a **measure of the affinity of a drug molecule for its binding site on the receptor molecule**. ***The smaller the K~d~ the greater the affinity of the drug for its receptor***. If the number of binding sites on each receptor molecule is known, it is [possible to determine the total number of receptors in the system from the B~max.~] *[e) Quantal dose-response relationships]* A graph of the fraction of a population that shows a specified response at progressively increasing doses is a quantal dose-response curve. *f[) Inert binding site]* Inert binding sites are **components of endogenous molecules that bind a drug without initiating events leading to any of the drug's effects**. In some compartments of the body, inert binding sites play an ***important role in buffering the concentration of a drug because bound drug does not contribute directly to the concentration gradient that drives diffusion.*** The 2 most important plasma proteins with significant drug-binding capacity are **albumin and orosomucoid.** *[g) Agonists and partial agonists]* Agonist: - Full agonist - Partial agonist image012 An agonist is a drug capable of fully activating the effector system when it binds to the receptor. **A partial agonist produces less than the full effect**, *even when it has saturated the receptors (intrinsic activity greater than zero, but less than that of a full agonist*). Even if all the receptors are occupied, partial agonists cannot produce an E~max~ of as great a magnitude as a full agonist. Under appropriate conditions, a partial agonist may act as an antagonist or an agonist e.g. the E~max~ of an agonist in the presence of increasing concentrations of a partial agonist will decrease as the number of receptors occupied by the partial agonist, and the E~max~ will decrease until it reaches the E~max~ of a partial agonist  In the presence of a full agonist, **a partial agonist acts as an inhibitor** *[h) Antagonists]* Types of antagonism: - Competitive antagonist - Functional/physiologic antagonism - Non-competitive antagonist - Irreversible antagonist Competitive antagonists are drugs that ***bind to, or very close to, the receptor site in a reversible way without activating the effector system for that receptor*** In the presence of a competitive antagonist, the log dose-response curve is shifted to higher doses, but the same maximal effect is reached. The agonist, if given in a high enough concentration, can displace the antagonist and fully activate the receptors. In contrast, an irreversible antagonist causes a downward shift of the maximum, with no shift on the curve on the dose axis unless spare receptors are present. Unlike the effect of a competitive reversible antagonist, the effects of an [irreversible antagonist] cannot be overcome by adding more agonist Competitive antagonists increase the ED~50~ while irreversible antagonists don't (unless pare receptors are present) *Physiologic antagonists* A physiologic antagonist binds to a different receptor molecule, producing an effect opposite to that of the drug it antagonizes. Thus it is different from pharmacologic antagonists which interacts with the same receptor as the drug it is inhibiting. *Chemical antagonists* A chemical antagonist interacts directly with the drug being antagonized to remove it or to prevent it from reaching its target. A chemical antagonist does not depend on interaction with the agonist's receptor. *[i) Therapeutic index and therapeutic window]* The therapeutic index is the ratio of the dose that produces toxicity (LD~50~) to the dose that produces a clinically desired or effective response (ED~50~), determined from the quantal dose-response curves. *The therapeutic index **represents an estimate of the safety of a drug.*** The **therapeutic window** describes the ***dosage range between the minimum effective therapeutic concentration or dose and the minimum toxic concentration or dose.*** therapeutic-index1