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Introduction to Pharmacology
Pharmacology is the study of substances that interact with living systems through chemical processes.
Medical pharmacology is the science of substances used to prevent, diagnose, and treat disease.
Toxicology is the branch of pharmacology that deals with the undesirable effects of chemicals on living systems.
History of Pharmacology
Prehistoric people recognized the beneficial or toxic effects of many plant and animal materials.
Early written records list remedies, some of which are still recognized as useful drugs today.
Materia Medica, the science of drug preparation and medical uses of drugs, developed as the precursor to pharmacology.
François Magendie and Claude Bernard developed the methods of experimental physiology and pharmacology.
Advances in chemistry and physiology laid the foundation for understanding how drugs work at the organ and tissue levels.
Pharmacogenomics
Pharmacogenomics is the relation of an individual's genetic makeup to their response to specific drugs.
Small interfering RNAs (siRNAs) and micro-RNAs (miRNAs) are investigated as therapeutic agents.
Antisense oligonucleotides (ANOs) can interfere with the readout of genes and the transcription of RNA.
General Principles of Pharmacology
All substances can be toxic under certain circumstances, depending on the usage of the drug.
Chemicals in botanicals are no different from chemicals in manufactured drugs, except for the greater proportion of impurities in botanicals.
Dietary supplements and therapies promoted as health-enhancing should meet the same standards of efficacy and safety as conventional drugs and medical therapies.
General Principles of Pharmacology
A drug is any substance that brings about a change in biologic function through its chemical actions.
Receptors are target molecules that drugs interact with.
Agonists activate receptors, while antagonists inhibit receptors.
Xenobiotics are chemicals that are not synthesized in the body.
Poisons are drugs that have almost exclusively harmful effects.
Toxins are poisons of biologic origin, synthesized by plants or animals.
Nature of Drugs
Drugs vary in size and molecular weight.
Drugs must be convertible to polar compounds for easy excretion.
Drugs with a molecular weight <100 are rarely selective in their action.
Drugs with a molecular weight >1000 are poorly absorbed and poorly distributed.
Drug-Receptor Bonds
Drug-receptor bonds can be covalent, electrostatic (ionic, hydrogen, van der Waals), or hydrophobic.
The strength of bonds determines the reversibility of the drug's effect.
Pralidoxime cannot reverse insecticide poisoning if the bonds formed by the poison have aged and become covalent.
Atropine is given in insecticide poisoning to alleviate symptoms.
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Pharmacodynamic Principles
Receptors are specific molecules in a biologic system with which drugs interact to produce changes in the function of the system.
Receptors must be selective in their ligand-binding characteristics.
Receptors must be modified when they bind an agonist to bring about functional change.
Receptors are mostly proteins.
Graded Dose-Response Relationship
The graded dose-response relationship graph shows the response of a particular receptor-effector system measured against increasing drug concentrations.
The graph yields a sigmoid curve when plotted on a semilogarithmic axis.
Efficacy (Emax) and potency are derived from this curve.
Binding affinity is the fraction of receptors bound by a drug plotted against the log of the drug concentration.
The smaller the Kd (concentration required to bind 50% of receptors), the greater the affinity of a drug for its receptor.
Emax is the maximal effect achievable with increasing concentration of a drug.
EC50 is the concentration of the drug where half of the maximal effect is achieved.
Bmax is the maximum percentage of receptors with increasing concentration of the drug.
Kd is the concentration where 50% of receptors are occupied.
Quantal Dose-Response Relationship
The quantal dose-response relationship determines the minimum dose required to produce a specified response in each member of a population.
The quantal dose-response curve shows the fraction of the population that responds at each dose against the log of the dose administered.
Median effective (ED50), median toxic (TD50), and median lethal (LD50) doses are derived from this curve.
No attempt is made to determine the maximal effect.
Therapeutic Index
The therapeutic index is a measure of the safety of a drug.
It is the ratio of the median toxic dose (TD50) to the median effective dose (ED50).
A higher therapeutic index indicates a safer drug.
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Potency
Denotes the amount of drug needed to produce a given effect.
Determined mainly by the affinity of the receptor to the drug.
Measurement:
In graded dose-response curve, it is the dose required to produce 50% of the maximal effect.
In quantal dose-response curve, three potency variables are measurable:
ED50
TD50
LD50
Spare Receptors
Receptors that do not bind to the drug when the drug concentration is sufficient to produce maximal effect.
Present when Kd50 (50% receptors are occupied) is greater than EC50 (50% max effect achieved).
Increase sensitivity to agonist because the likelihood of drug receptor interaction increases directly proportional to the number of receptors available.
Factors Affecting Dose-Response Curves
Full Agonists:
Capable of fully activating the effector system when it binds to the receptor.
High affinity for the activated receptor conformation.
Sufficiently high concentrations result in all the receptors achieving the activated state.
Partial Agonist:
Produces less than the full effect, even when it has saturated the receptors.
In the presence of an agonist, a partial agonist acts as an inhibitor/antagonist.
Inverse Agonist:
Drug has a much stronger affinity for the Ri conformation than the Ra state and stabilizes a large fraction in the Ri-D complex.
Activation of these agonists leads to mass inhibition.
The drug will reduce any constitutive activity, resulting in effects opposite of the effects produced by the full agonist.
Antagonist:
Do not provoke a biological response by themselves upon binding to a receptor.
Blocks or dampens drug response in the presence of an agonist.
Classification of Antagonists:
Competitive or Reversible Antagonist:
Binds to receptors in a reversible way without activating the effector system.
Shifts the dose response curve (DRC) to the right (increased ED50) but same maximal effect is reached.
Effects overcome by adding more agonist (surmountable).
Non-competitive or Irreversible Antagonist:
Causes downward shift of the DRC.
No horizontal shift of DRC (ED50 unchanged) unless spare receptors are present.
Not overcome by adding more agonist (insurmountable).
Physiologic Antagonist:
Binds to a different receptor, producing an effect opposite to that produced by the drug it is antagonizing.
Chemical Antagonist:
Receptors are not involved.
Interact directly with the drug being antagonized to remove it or to prevent it from reaching its target.
Allosteric Antagonist:
Binds to a different binding site that forms a conformational change in the receptor preventing the agonist from binding.
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Signaling Mechanisms and Drug Actions
Intracellular Receptor:
Crosses the plasma membrane and acts on the intracellular receptor.
Enzyme
Regulator of gene transcription
Transmembrane Receptor:
The signal binds to the extracellular domain of a transmembrane protein, thereby activating the enzymatic activity of its cytoplasmic domain.
Enzyme-Linked Receptor:
Have extracellular binding sites where ligand or typically hormone or growth factor can attach and thus activate enzymatic activity inside the cell.
Most enzyme-linked receptors are of tyrosine kinase.
Ligand-Gated Ion Channel:
Signal binds to and directly regulates the opening of an ion channel.
G-Protein Coupled Receptors:
Alpha 1 and 2 receptor.
The signal binds to a cell-surface receptor linked to an effector enzyme by a G protein.
Also called as 7-transmembrane.
Ligand binds to receptor.
GDP becomes GTP.
Alpha is removed from the G-protein coupling.
Requirements for Adenylyl Cyclase
Alpha should meet GTP
Three Types of G Protein
Gs:
Stimulative G protein that activates the enzyme called ADENYLYL CYCLASE.
Adenylyl cyclase then produces cyclic AMP which is a very important secondary messenger.
Gi:
Inhibitory G protein that inhibits ADENYLYL CYCLASE, thus lowers the level of cAMP in the cell.
Gq:
Contraction due to calcium.
Activates a class of enzyme called phospholipases C (PLC).
PLC produces two secondary messengers called diacylglycerol (DAG) and inositol triphosphate (IP3).
DAG: leads to different responses through activation of protein kinases.
IP3: produces various responses by mediating intracellular release of calcium.
G-protein coupled receptors, as well as enzyme-linked receptors, have the ability to amplify signals that they receive.
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Variations in Drug Response
Tolerance:
Continuous activation may lead to depletion of essential substrates.
Reversed by repletion of missing substrates.
Example: depletion of thiol cofactors in nitroglycerin tolerance, reversible with administration of glutathione.
Down Regulation:
Long-term reduction in receptor number due to continuous exposure to agonist.
Upregulation:
Occurs when receptor activation is blocked for prolonged periods.
Tachyphylaxis:
Responsiveness diminishes rapidly after administration of a drug.
Slight delay after first intake.
Frequent or continuous exposure to agonists often results in short-term diminution of the receptor response.
Examples of drugs that display tachyphylaxis: Metoclopramide, Nitroglycerin, Ephedrine, Nicotine, Dobutamine, Hydralazine, LSD, Desmopressin, Calcitonin.
Idiosyncratic Drug Response:
One that is infrequently observed in most patients.
Example: aplastic anemia with chloramphenicol, cataracts