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Pharmacodynamics• Detailed mechanism of action by which

drugs produce drug produce theirbiochemical and physiological effect

• Dose response relationship; relationshipbetween drug concentration and magnitudeof drug effect

• Provides scientific basis for the selectionand use of drugs to counteract specificpathophysiologic mechanisms in particulardisease

59-291 Section 1, Lecture 7

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Nature of drug receptors

• Drugs produce their effects by interacting ofreceptors

• Most ligands bind to protein receptors,which are embedded in the membrane

• Some agents act directly to on DNA ormembrane lipids

3Cyclophosphamide and doxorubicinNucleic acids

Alcohol and amphotericin BMembrane lipids

Other macromolecules

Amitriptyline, cocaine, and fluoxetineNeurotransmitter transporters

Furosemide and hydrochlorothiazideIon transporters

Lidocaine, quinidine, and verapamilIon channels

Membrane transport proteins

AllopurinolXanthine oxidase

DigoxinNa+,K+-adenosine triphosphatase

PhenelzineMonoamine oxidase

IndinavirHuman immunodeficiency virus (HIV) protease

CiprofloxacinDNA topoisomerase

Acyclovir and zidovudineDNA polymerase

Aspirin and celecoxibCyclooxygenase

Donepezil and physostigmineCholinesterase

AcetazolamideCarbonic anhydrase

Enzymes

Cortisol, estradiol, and tamoxifenSteroid receptors

Morphine and codeineOpioid receptors

TubocurarineNicotinic receptors

Atropine and bethanecholMuscarinic receptors

Tegaserod, ondansetron, and sumatriptan Insulin5-Hydroxytryptamine (serotonin) receptors Insulinreceptors

Cimetidine and diphenhydramineHistamine receptors

Epinephrine and propranololAdrenergic receptors

Hormone and Neurotransmitter Receptors

Examples of Drugs that BindReceptorTypes of Drug Receptors

Table 3-1 Drug Receptors

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Types of drug receptors• G-protein coupled receptors (GPCR)

– Guanine nucleotide binding protein (G protein)• Extracellular/transmembrane domain binds to ligand• Intracellular domain binds to effector molecules (G

protein)

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Types of drug receptors• G-protein coupled receptors (GPCR)

– Guanine nucleotide binding protein (G protein)• Enzymes

– Competitive and noncompetitive inhibitors

• Membrane transport proteins– Ligand and voltage-gated ion channels– Neurotransmitter transporters

• Membrane lipids and phospholipids– Anesthetics and alcohol

• Steroid hormone receptors– Intracellular proteins, translocate to nucleus

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A small # of drugs produce their physiological effect withoutinteracting with receptors. Examples:

Drugs that bind to enzymes interfere with the normal activity of theenzyme in one of 2 ways

Competitive-

Non-competitive-

Drugs can also bind to membrane transport proteins (competitivelyand non-competitively) and inhibit their function.

Some drugs can also bind to membrane lipids and DNA in order toproduce their action.

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Drug receptor interactions are very specific. They form ionic,hydrophobic and H-bonds with their receptor. The receptor bindingsite recognizes the 3-D shape of their ligands.

L-isoproterenol binds to a β-adrenergic receptorwith higher affinity than its mirror image D-isoproterenol.

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The non-covalent interactions are reversible as a result drugsdissociate from their receptors as their concentration in the plasmadecreases.

Affinity- is the tendency of a drug to combine with its receptor

[D] + [R] [D-R] Effect

Law of mass action: the # of R occupied by D depends on the [D]

And the K D - the ratio of drug receptor dissociation k2 and associationk1 rate

K D= k2/ k1

The lower the K D higher the affinity. This occurs if the associationrate constant k1 >> (much greater than) k2 .

k1

k2

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KD= the concentration of drug required to saturate 50% of thereceptors

Most effective drugs have KDs in the micromolar (10-6) to nanomolar(10-9) range.

Signal transduction: the process where the binding of a drug to itsreceptor initiates a cascade of biochemical events that result in thephysiological effect.

Membrane receptors are coupled to with a G-protein, an ion channelor an enzyme

For example G proteins:

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Gαs = Stimulatory; increase adenylate cyclase (AC) activityGαi = Inhibitory ; decrease AC activityGαq= activate phospholipase C >> formation of Inositol triphosphate(IP3) and diacylglycerol from (DAG) from membrane phospholipids

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Efficacy or Intrinsic activity- the ability of a drug to initiate a cellulareffect

Agonist- drug has both receptor affinity and intrinsic activity

Antagonist- drug has receptor affinity only.

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3 Types of Agonists

Full- max physiologicalresponse

Partial- sub maximalphysiological response

In the presence of a fullagonist a partialagonist behaves like anantagonist.

Inverse agonist-decreases the rate ofsignal transduction

Antagonists bind to receptorbinding-site and prevent theaction of agonists and inverseagonists.

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Practice Questions

• Which of the following drug is moreeffective if they are administered with thesame dose? Why?

• Drug A with KD = 3x10-10

• Drug B with KD = 2x10-5

• Drug A, because it has a lower KD

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• How does a Gαq increase IP3? How doesIP3 function in the cells

• Activates phospholipase C• IP3 releases calcium from intracellular

storage sites and augment calcium-inducedprocesses such as muscle contraction