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59-291 Section 1, Lecture 7
Pharmacodynamics
• Detailed mechanism of action by which
drugs produce drug produce their
biochemical and physiological effect
• Dose response relationship; relationship
between drug concentration and magnitude
of drug effect
• Provides scientific basis for the selection
and use of drugs to counteract specific
pathophysiologic mechanisms in particular
disease
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Nature of drug receptors
• Drugs produce their effects by interacting of
receptors
• Most ligands bind to protein receptors,
which are embedded in the membrane
• Some agents act directly to on DNA or
membrane lipids
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Table 3-1 Drug Receptors
Types of Drug Receptors
Examples of Drugs that Bind
Receptor
Hormone and Neurotransmitter Receptors
Adrenergic receptors
Epinephrine and propranolol
Histamine receptors
Cimetidine and diphenhydramine
5-Hydroxytryptamine (serotonin) receptors Insulin
receptors
Tegaserod, ondansetron, and sumatriptan Insulin
Muscarinic receptors
Atropine and bethanechol
Nicotinic receptors
Tubocurarine
Opioid receptors
Morphine and codeine
Steroid receptors
Cortisol, estradiol, and tamoxifen
Enzymes
Carbonic anhydrase
Acetazolamide
Cholinesterase
Donepezil and physostigmine
Cyclooxygenase
Aspirin and celecoxib
DNA polymerase
Acyclovir and zidovudine
DNA topoisomerase
Ciprofloxacin
Human immunodeficiency virus (HIV) protease
Indinavir
Monoamine oxidase
Phenelzine
Na+,K+-adenosine triphosphatase
Digoxin
Xanthine oxidase
Allopurinol
Membrane transport proteins
Ion channels
Lidocaine, quinidine, and verapamil
Ion transporters
Furosemide and hydrochlorothiazide
Neurotransmitter transporters
Amitriptyline, cocaine, and fluoxetine
Other macromolecules
Membrane lipids
Alcohol and amphotericin B
Nucleic acids
Cyclophosphamide and doxorubicin
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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 without
interacting with receptors. Examples:
Drugs that bind to enzymes interfere with the normal activity of the
enzyme in one of 2 ways
CompetitiveNon-competitiveDrugs can also bind to membrane transport proteins (competitively
and non-competitively) and inhibit their function.
Some drugs can also bind to membrane lipids and DNA in order to
produce their action.
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Drug receptor interactions are very specific. They form ionic,
hydrophobic and H-bonds with their receptor. The receptor binding
site recognizes the 3-D shape of their ligands.
L-isoproterenol binds to a β-adrenergic receptor
with higher affinity than its mirror image Disoproterenol.
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The non-covalent interactions are reversible as a result drugs
dissociate from their receptors as their concentration in the plasma
decreases.
Affinity- is the tendency of a drug to combine with its receptor
k1
[D] + [R]
[D-R]
Effect
k2
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 association
k1 rate
K D= k2/ k1
The lower the K D higher the affinity. This occurs if the association
rate constant k1 >> (much greater than) k2 .
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KD= the concentration of drug required to saturate 50% of the
receptors
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 its
receptor initiates a cascade of biochemical events that result in the
physiological effect.
Membrane receptors are coupled to with a G-protein, an ion channel
or an enzyme
For example G proteins:
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Gαs = Stimulatory; increase adenylate cyclase (AC) activity
Gαi = Inhibitory ; decrease AC activity
Gαq= 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 cellular
effect
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 physiological
response
Partial- sub maximal
physiological response
In the presence of a full
agonist a partial
agonist behaves like an
antagonist.
Inverse agonistdecreases the rate of
signal transduction
Antagonists bind to receptor
binding-site and prevent the
action of agonists and inverse
agonists.
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Practice Questions
• Which of the following drug is more
effective if they are administered with the
same 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 does
IP3 function in the cells
• Activates phospholipase C
• IP3 releases calcium from intracellular
storage sites and augment calcium-induced
processes such as muscle contraction
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