Pharmacology Unit One Lange

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Pharmacology

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Study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes

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Medical Pharmacology

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science of substances used to prevent, diagnose, and treat disease

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Toxicology

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Branch of pharmacology that deals with the undesireable effects of chemicals on living systems, from individual cells, to humans, to complex ecosystems

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Materia Medica

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17th century science of drug prep and medical use of drugs, precursor to modern pharmacology

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Experimental Physiology and Pharmacology

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methods created by Francois Magendie and Charles Bernard in th 18th and 19th century

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Controlled Clinical Trial

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only around past 60 or so years, able to verify drug claims and efficacy

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Receptor

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the component of a cell or organism that interacts with a drug and initiates the chain of events leading to the drug's observed effects

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pharmacogenomics
aka
pharmacogenetics

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study of the genetic variations that cause differences in drug response among individuals or populations

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Knock Out Gene Therapy

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Gene therapy developed in which gene for receptor or ligand is knocked out so the gene for an anomaly is absent or non-functional

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Agonist

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drug molecule that binds to a receptor and acts as an activator either directly or indirectly

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Antagonist

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drug molecule that acts as inhibitor by binding with the receptor and compete with or prevent binding with other molecules

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Chemical Antagonist

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drug molecules that interact directly with other drugs

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Osmotic Agent

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drugs that interact almost exclusively with water molecules

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Hormones

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Drugs Synthesized by body

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Xenobiotics

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Drugs not synthesized by body Greek "xenos" meaning stranger

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Poisons

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Drugs that have almost an exclusively harmful effect usually inorganic

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Toxins

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Poisons of organic origin, i.e. synthesized by plants or animals

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5 factors that make action of drug effective

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1. Physical Nature of Drug
2. Size of Drug
3. Drug Reactivity and Receptor Bands
4. Drug Shape
5. Rational Drug Design

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1. Physical Nature of Drugs

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1.may be gas, liquid, solid which helps to determine route of administration
2.may be organic or inorganic
3. organic drugs may be acid or base which affects degree of ionization

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2. Drug Size

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Usually have mw of 100-1000. any smaller may not be effective any larger drug will not readily diffuse into compartments of body

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3. Drug Reactivity and Drug Receptor Bonds

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1. Covalent bond very strong
2. Electrostatic weaker but much more common
3. Hydrophobic weakest important in lipid- soluble drugs

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4. Drug Shape

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Shape of molecule must be such as to bind with receptor. Chiral(non-superimposable mirror images) molecules produce an effecttive enantiomer and a less effective one. Racemic solutions have equal amounts of each enantiomers.

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5 Rational Drug Design

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Implies the ability to predict the appropriate molecular structure of a drug on the basis of information about it biological receptors.

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Pharmacodynamics

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The study of the action or effects of drugs on living organisms.

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Pharmacokinetics

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The process by which adrug is absorbed, distributed, metabolized, and eliminated by the body

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Allosteric drugs

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Drugs that bind to a receptor molecule but do not prevent binding of an agonist. May enhance or inhibit action of agonist

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Full Agonist

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bind (have affinity for) and activate a receptor, displaying full efficacy at that receptor. One example of a drug that acts as a full agonist is isoproterenol which mimics the action of adrenaline at β adrenoreceptors. Another example is morphine, which mimics the actions of endorphins at μ-opioid receptors throughout the central nervous system

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Partial Agonist

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(such as buspirone, aripiprazole, buprenorphine, or norclozapine) also bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. One study of benzodiazepine active sedative hypnotics found that partial agonists have just under half the strength of full agonists.[2] Partial agonists such as abecarnil have demonstrated a reduced rate and reduced severity of dependence and withdrawal syndromes.

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Inverse Agonist

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is an agent which binds to the same receptor binding-site as an agonist for that receptor and reverses constitutive activity of receptors. Inverse agonists exert the opposite pharmacological effect of a receptor agonist

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Intrinsic Efficacy

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refers to the ability of a drug-receptor complex to produce a functional response.

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Affinity

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which is a measure of the ability of the drug to bind to its molecular target,

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Neutral Antagonism

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fixing the amounts of the agonist and antagonist so that no drug effects can be realized.

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Receptors must do two things in order to function as a receptor:

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1. be selective in choosing ligand in which to bind.
2. upon binding to ligand it must change the function in such a way as to alter the function of the biologic system.

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Prodrug

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is a pharmacological substance (drug) that is administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolised in vivo into an active metabolite. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and excretion (ADME) optimization. Prodrugs are usually designed to improve oral bioavailability, with poor absorption from the gastrointestinal tract usually being the limiting factor.

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Phases of the journey drug takes through body

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1. Absorption = from the site of administration to the systemic circulation
2. Distribution = from the systemic circulation to the site of action
3. Metabolism (AKA biotransformation) = after leaving the site of action it goes to the liver where it is broken down and inactivated.
4. Elimination (AKA excretion) = from the site where broken down to out of the body.

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Mechanisms of Permeation of drugs

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1. Aqueous Diffusion(passive)
2. Lipid Diffusion(passive)
3. Special Carrier proteins
4. endocytosis(cell engulfs drug and then vesicle membrane is broken down by cytosol) and exocytosis (responsible for releasing substances from cell)

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Fick's Law of Diffusion

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Discusses the passive flux of molecules down a concentration gradient

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Henderson-Hasselbalch Equation

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describes the derivation of pH as a measure of acidity (using pKa, the acid dissociation constant) in biological and chemical systems. The equation is also useful for estimating the pH of a buffer solution and finding the equilibrium pH in acid-base reactions (it is widely used to calculate isoelectric point of the proteins).

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What does ph have to do with distribution?

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Acidic drugs become un-ionized in acidic environments such as the stomach.
Basic drugs become un-ionized in relatively basic environments such as the intestines.
When they lose that ionization or polarity, they become lipid soluble!

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What does ph have to do with elimination?

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if drug is lipid soluble during passage down renal tubule, some if the drug will be reabsorped. If drug is ionized, it will be excreted without reabsorption. i.e. weak acids excreted faster in alkaline urine, and weak bases excreted faster in acidic urine

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Most basic drugs are weak bases that contain what?

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Amine containing molecules
Primary- 1 carbon, 2 hydrogen
Secondary-2 carbon, 1 H
Tertiary-3 carbons
Quaternary-4 carbons

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Prototype drugs

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drugs that typify the most characteristics of a drug group allowing for classification of drug groups

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3 Consequences of the drug receptor concept.

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1. receptors largely determine the quantitative relations between the dose or concentration of drugs and pharmacologic effects.
2.Receptors are responsible for selectivity of action.
3. Receptors mediate the actions of the pharmacologic agonists and antagonists.

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Clearance

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Measure of the ability of the body to eliminate the drug.

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Volume of distribution

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the measure of the apparent space in the body available to contain the drug.
Relates the amount of drug in the body to the concentration of drug in blood.

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Capacity-limited elimination

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Clearance depends on concentration of drug achieved

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Flow-dependent elimination

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Clearance remains constant regardless of concentration achieved.

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Half-life

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is the time required to change the amount of drug in the body by one half during elimination. 94% cleared in 4 half-lifes

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Drug accumulation

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occurs when dosing intervals shorter that four half-lifes

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Bioavailability

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used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%

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3 factors that effect bioavailability

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1. extent of absorption
2. first pass elimination
3. rate of absorption

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first pass elimination

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If a drug is taken into the GI tract, where it enters hepatic circulation through the portal vein, it becomes well-metabolized prior to entering systemic circulation

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Target concentration

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concentration of drug that will produce desired therapeutic effect.

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Loading dose

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initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose.

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Maintenance dose

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the quantity of drug necessary to sustain a normal physiologic state or a desired blood or tissue level of drug.

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Maximum effect

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no matter how high the drug concentration goes, a point will be reached which no further increment in response is achieved.

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biotransformation

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is the chemical modification (or modifications) made by an organism on a chemical compound. It is needed to render nonpolar compounds polar so that they are not reabsorbed in renal tubules and are excreted.

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four types of drug biotransformation

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1. Active Drug to Inactive Metabolite
2. Active Drug to Active Metabolite
3. Inactive Drug to Active Metabolite
4. Active Drug to Toxic Metabolite (biotoxification).

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Phase One Reaction

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Includes oxidative, reductive and hydrolytic reactions.
In these type of reactions, a polar group is either introduced or unmasked, so the drug molecule becomes more water-soluble and can be excreted.
Phase I reactions are Non-synthetic in nature & generally produce a more water soluble & less active metabolite.
The majority of Phase I metabolites are generated by a common hydroxylating enzyme system known as cytochrome P450.

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Phase Two Reaction

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These reactions involve covalent attachment of small polar endogenous molecule such as glucuronic acid, sulfate, or glycine to form water-soluble compounds.
This is also known as a conjugation reaction.
The final compounds have a larger molecular weight.

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Factors effecting Drug Metabolism

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1. individual differences
2. genetic differences
3. diet and environmental factors
4. age and sex
5. drug-drug interactions during metabolism.
6. interactions between drugs and endogenous compounds
7. disease processes that affect metabolism.

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toxicity of drugs

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all drugs are toxic at some dose.

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No effect dose

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maximum dose at which a specific toxic effect is not seen.

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minimum lethal dose

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the smallest dose that is obseerved to kill any experimental animal

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median lethal dose

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dose that kills 50% of experimental animals

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3 confounding factors in clinical trials

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1. The variable natural history of most diseases
2. The presence of other diseases and risk factors.
3. Subject and observer bias and other factors

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Three phases of Clinical Trials

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1. study performed on 20-100 healthy volunteers to determine maximum tolerated dose.
2.drug is studied in pts with target disease to establish efficacy
3. drug is evaluated in lrg numbers of pts to ensure drug meets expectations.

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Adverse Drug Reaction (ADR)

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harmful or unintended response to a drug. 4th leading cause of death.

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Classifications of ADR

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Type A: Augmented pharmacologic effects - dose dependent and predictable
Type B: Bizarre effects (or idiosyncratic) - dose independent and unpredictable
Type C: Chronic effects
Type D: Delayed effects
Type E: End-of-treatment effects
Type F: Failure of therapy

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Orphan Drug

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A pharmaceutical developed to treat a disease that afflicts relatively few people.

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2 Branches of the Nervous System

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1. Central Nervous System (CNS)-consists of brain and spinal cord
2. Peripheral Nervous System (PNS)-consists of neuronal tissues outside the CNS.

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afferent nerve

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carry nerve impulses from receptors or sense organs toward the central nervous system.

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efferent nerve

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otherwise known as motor or effector neurons – carry nerve impulses away from the central nervous system to effectors such as muscles or glands .

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Two subdivisions of efferent nervous system

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Autonomic Nervous System (ANS)
Somatic Nervous system

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Autonomic Nervous System

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involved with activities not under conscious control. visceral functions such as cardiac output, blood flow, digestion and other functions necessary to life

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Somatic Nervous System

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largely concerned with consciously controlled functions such as movement, respiration, and posture.

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2 divisions of the autonomic nervous system

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1. sympathetic(thoracolumbar)-presympathetic ganglionic fibers leave the CNS through the thoracic and lumbarspinal nerves.
2. parasympathetic(craniosacral) parasympathetic ganglionic fibers leave the CNS through the cranial nerves.