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Flashcards in Pharmacodynamics Deck (76):
1

Drug

Any substance that when administered to a living organisms produces a biological affect

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Pharmacology

Study of how function of living systems is affected by chemical agents

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Pharmacokinetics

Study of absorption, distribution, metabolism, and a excretion of drug

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Pharmacodynamics

Study of effects of drugs and their mechanisms of action

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Toxicology

Study of adverse effects of drugs.

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Drug receptor

Component of organism with which the drug interacts. Sometimes called drug target.

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What types of ion channels can drugs act upon?

Voltage gate and ligand gated

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For ligand gated channels, what is an example of ligands?

Neurotransmitters (acetylcholine) or an intracellular mediator (cAMP and second messengers)

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What two drugs classes act by altering the conductance of ion channels?

Local anesthetic and benzodiazepines

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How do local anesthetics work?

Block voltage gated sodium channels in neurons that transmit pain information from the periphery to the CNS. this prevents action potential propagation and pain perception.

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How do benzodiazepines work?

Bind to the GABAa receptor in neuronal membranes in the CNS. GABAa functions as a chloride ion channel and is activated by GABA (inhibitory neurotransmitter). This enhances the ability of GABA to open the chloride channel, hyperpolarizing the neuron.

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On which receptor do most prescription drugs act?

G protein linked receptors

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Albuterol

Beta-2 agonist use for asthma

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Propranolol

A beta antagonist used for hypertension

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Bethanechol

Muscarinic (acetylcholine receptor) agonist used for atonic bladder

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Ipratropium

Muscarinic antagonist used for asthma

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what are the three components of G protein linked receptors?

Cell surface receptor, G protein, effector (enzyme or an ion channel)

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G protein effectors

G proteins can either directly control ion channels or they can interact with enzymes which leads to the production of second messengers

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What are the most frequent target enzymes for G proteins?

Adenylyl cyclase and phospholipase C

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What was Gs do?

Increase adenylyl cyclase

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What does Gi do?

Decrease adenylyl cyclase and open potassium channels by decreasing cAMP

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What does Gq do?

Increases the amount of phospholipase C

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What does IP3 do?

releases calcium from the ER, which allows calcium to control many enzymes

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What are some calcium meditated responses?

Smooth muscle contraction, increased force of contraction of cardiac muscle, secretion from exocrine glands, neurotransmitter release, hormone release

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What are the ligand regulated transmembrane enzymes?

Tyrosine kinase, serine/threonine kinase, and guanylyl cyclase

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What are the receptors for tyrosine kinase?

Insulin receptor, epidermal growth factor receptor, platelet derived growth factor, and nerve growth factor receptor

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What can gain of function mutations in tyrosine kinase receptors cause?

Cancer, because tyrosine kinase receptors play an important role in cellular growth and differentiation

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Imatinib

Tyrosine kinase inhibitor that is effective for leukemia

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Cytokine Receptors

Respond to peptide ligand like growth hormone, prolactin, erythropoietin, and interferons. Have no intrinsic enzymatic activity. Bind to an intracellular tyrosine kinase from the Janus-kinase (JAK) family.

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What usually makes up intracellular receptors?

Nuclear receptors, enzymes, structural proteins

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Nuclear Receptors

Ligand activated transcription factors, contain binding sites for ligands and DNA. Regulate the expression of genes. May be in the nucleus or the cytoplasm.

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Statins

Drugs that act on enzyme receptors-specifically the HMG-CoA receptor that is used in the rate limiting step for cholesterol synthesis. This leads to less intracellular cholesterol, leading to LDL up regulation and LDL clearance in the blood.

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Vinca Alkaloids

Drug that acts on structural proteins. It binds to tublin and prevents the polymerization of tublin to microtubules which leads to there being a lack of cell division. Cells are arrested in metaphase. Cancer drug.

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ACE

Extracellular enzyme that converts angiotensin I to angiotensin II (which is a potent vasoconstrictor)

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Transporters

Membrane transported are targets for many psychiatric drugs.

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SSRIs

Selective serotonin reuptake inhibitors that act by blocking serotonin reuptake.

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Antacids

Not mediated by binding to receptors, but neutralize gastric acid.

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Mesna

Not mediated by binding to receptors. Reacts in bladder with acroleine (a metabolite of the anti cancer drug cyclophosphamide) preventing hemorrhagic cystitis

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Mannitol

Increases the osmolarity of various body fluids. Can promote increase in urine of reduction of cerebral edema

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Cholestyramine, colestipol, and colesevelam

Bind bile acids in the intestinal lumen and prevent their reabsorption. Used to treat hyperlipidemia. Does not bind to receptor.

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Dimercaprol

Chelates heavy metals. Does not bind to a receptor.

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Graded Dose-response Curves

Hyperbolic curve that shows relationship between the drug concentration and effect

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What does a high Kd represent?

Low binding affinity of drug to receptor

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Spare Receptors

Spare receptors can be seen when 50% of the max affect can be achieved by binding with 50% of the available receptors. You have "spares" that aren't being used

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Efficacy

Maximal effect a drug can produce

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Potency

Measure of the concentration or amount of drug necessary to produce and effect of a given magnitude.

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What value determined potency?

EC50

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What value determines efficacy?

Emax

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What determines the clinical effectiveness of a drug?

Maximal efficacy

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Agonist

Drug that binds to and activates a receptor in a way that brings about an effect

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Antagonist

Inhibits the action of an agonist, but has no effect in the absence of the agonist

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Receptor Antagonism

Receptor antagonist binds to the same receptor to which the agonist binds

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Competitive Antagonism

Competitive antagonist bind to the agonist binding site on the receptor, preventing the binding of agonist to the receptor.

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Reversible Competitive Antagonism

Increases the amount of agonist required for a given response. Can be overcome with high concentrations of agonist. Emax remains the same.

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Irreversible Competitive Antagonism

Receptor cannot respond to the binding of an agonist. Emax is reduced, and the antagonism cannot be surmounted by adding more agonist

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Noncompetitive Antagonism

Allosteric antagonism. Antagonist bind to the receptor as a site different from the agonist binding site, reducing the action of the agonist. Insurmountable. Emax is decreased.

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NonReceptor Antagonism

Does not bind to the receptor where the agonist binds, but still inhibits response to agonist.

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Indirect Antagonism

Antagonist binds to a macromolecule in the pathway that links the receptor to the effect

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Physiological Antagonism

One agonist opposes another, but through different receptors. Example of using epinephrine when histamine has increased and there is bronchoconstriction

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Chemical Antagonism

Reacts chemically with an agonist to form an inactive product

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Effect of protamine

Protamine is a protein which is positively charged and counteracts that effects of heparin, a negatively charged anticoagulant

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Full agonist

Produced maximal response

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Partial Agonists

Produce a submaximal response

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Partial Agonist Inhibition

Partial agonist can act as a competitive antagonist in the presence of a full agonist by competing with the full agonist for receptor occupancy, reducing the response to the full agonist

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Inverse Agonist

Reverse the constitutive activity of the receptor.

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Constitutive Agonist

Activity in the absence of an agonist due to a fraction of the receptors being in the active state always

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Drug Selectivity

A drug is selective if there is a10-fold difference between its binding affinity for the first target (therapeutic effects) and its second target (adverse effects)

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Desensitization and tachyphylaxis

Synonymous terms used to describe the diminishing effect of drugs when given continuously or repeatedly

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tolerance

Gradual decrease in responsiveness to a drug, taking weeks or days to develop

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Refractoriness

Loss of therapeutic efficacy

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What can cause rapid desensitization?

Activation of ion channel receptors and G-protein receptors

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Quantal Dose Effect Curves

Plots fraction of the population that responds to a given dose of drug as a function of the drug dose. Defined as present or not present.

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Median Toxic Dose

Dose required to produce a particular toxic effect in 50% of animals

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Median Lethal Dose

The dose required to cause death in 50% of animals

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Therapeutic Index

Ratio of the TD (toxic dose) to the ED50

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The larger the toxic dose...

The safer the drug