pharmacodynamics eng
TRANSCRIPT
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Metabolism (Biotransformation)
Effects
Transformation to less active metabolite/s
Formation of active metabolite /PRODRUG/
Transformation to more active metabolite/s
Enhancement of solubility
Liver = primary site
Liver disease
Slows metabolism
Prolongs effects
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Hepatic First-Pass Metabolism
Affects orally administered drugs
Metabolism of drug by liver before drug
reaches systemic circulation
Drug absorbed into portal circulation, must
pass through liver to reach systemic
circulation
May reduce availability of drug
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Liver
First passmetabolismthrough liver viahepatic portalvein
Metabolism of drugsby liver enzymes
Excretion of metabolites andintact drugs in urine
Kidney
Orally ingesteddrugs
hepatic vein
Pharmaco-dynamic
activity inbody
Parenteral / IVdrugs etc.
Renal artery
GIT
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First - pass metabolism
Cytochrome P450 (microsomal) enzymes are a large
family of enzymes found in the liver that are part of the
bodys defence mechanism against toxic substances
The body treats drugs as foreign, potentially toxic
substances Microsomal enzymes change drugs by biochemical
reactions.
There are several families of these enzymes, the most
clinically significant being CYP1, CYP2 and CYP3 (CYP =
CYtochrome P450).
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First - pass metabolism
The various cytochromes have specific
affinities for particular drugs.
This is why there is so much variation in themetabolism of drugshalf life etc.
The products of drug metabolism, the
metabolites, are generally excreted via the
kidney in the urine although some are
excreted via the bile duct in the faeces
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Elimination
Urine, Bile,
Exhaled air, Breast milk,
Sweat,
Feces and saliva
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Elimination
Kidneys = primary site Mechanisms dependent upon:
Passive glomerular filtration
Active tubular transport
Tubular secretion
Partial reabsorption
Hemodialysis
Renal disease
Slows excretion
Prolongs effects
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Elimination of the drugs
Tubular
secretionGlomerular
filtration
Tubular reabsorption
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Glomerular filtration
Small
Protein-freeHydro-, lipophilic drugs
C-pl
P-osm.blood
GBFR
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Tubular reabsorption
Lipophilic
Ph >7, ROH
Ph< 7, HA
Passive diffusion
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Tubular secretion
Active transport
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A patient has overdosed on phenobartital. Phenobarbital is an
acid. If we alkalinalize the urine by giving bicarbonate what will
happen to the phenobarbital molecules as they are filtered
through the renal tubules?
They will ionize...
Urine pH and Elimination
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Non-ionized
HA H++ A-
How will this affect phenobarbital
reabsorption by the kidney?
Decreased reabso rpt ion
Increased el imination
Ionized
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Clearance
Clearance is a volume of plasmafrom which drug is completely
removed in a measure of time i.e.clearance characterizes the speed ofdrug elimination from the body.
There are total (TC), renal (RC) andorgan(OC) clearances.
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Clearance
TC = RC + OC RC = (Cm*Vm)/Cp, Cmurine
concentration of the drug
Cp- plasma
concentration of the drug
Vmvolume ofthe urine excreted in a measure of
time.
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Biological Half-life (t 1/2)
Unit of the time during which drug dose is
reduced in a twice
Shorter t1/2
may need more frequent doses
Hepatic disease may increase t1/2
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A drug has a half life of 10 seconds. You give a
patient a dose of 6mg. After 30 seconds howmuch of the drug remains?
Time Amount
0 sec 6 mg
10 sec 3 mg
20 sec 1.5 mg
30 sec 0.75 mg
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Maintaining drug levels in the
body
Maximum safeconcentration
Minimum effectiveconcentration
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Pharmacodynamics
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Site of
ActionDosage Effects
Plasma
Concen.
Pharmacokinetics Pharmacodynamics
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Drug Receptors and Pharmacodynamics
(how drugs work on the body)
The action of a drug on the body,
including receptor interactions, dose-response phenomena, and
mechanisms of therapeutic and toxic
action.
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Mechanism of Action
A drug may produce its effect through:
Receptor mediated action.
Non-receptor mediated action.
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Non-Receptor Mediated Mechanisms
Drugs act on enzymes:
Nitric oxide (NO) penetrates the cell membrane stimulatingcytoplasmic guanylyl cyclase enzyme leading to increase ofintracellular cGMP.
Digitalis inhibits Na+/ K+ATPase enzyme.
Drugs Act on Plasma Membrane:
Polymixins and amphotricin B increase the permeability ofbacterial plasma membrane.
Drugs Act on Subcellular Structures: Erythromycin and chloramphenicol inhibit protein synthesis in
bacteria by binding to 50 S ribosomal subunit. Tetracyclines andaminoglycosides bind 30 S ribosomal subunit.
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Drugs Act by Chemical Action:
Antacids neutralize gastric acid secretion.
Protamine (alkaline & +ve charge) antagonizes heparin(acid & -ve charge).
Drugs Act by Physical Means:
Osmosis e.g. mannitol.
Lubricant e.g. liquid paraffin.
Adsorbent e.g. kaolin and charcoal.
Demulcent e.g. bismuth salt and olive oil.
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Mechanism of Action
Receptor Mediated Action Receptor: receptor is a special molecular component of the cell
(protein macro-molecule or DNA) which is capable of selectivelyrecognizing and binding a drug, hormone, mediator orneurotransmitter, thereby eliciting a cellular response.
Kd = dissociation constant = concentration of drug at 50%binding to the receptors.
)(Re/)(Re)( sponseComplexRDRceptorDDrug Kd
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Dose
R
e
s
p
o
n
s
e
Affinity: it is the ability of a drug to
bind a receptor. It is determined by thedissociation constant (Kd) (the lower
the Kd the higher the affinity).
Intrinsic mimetic activity: it is theability of a drug receptor complex to
produce an effect. Maximal effect
produced if a maximal dose is given. It
is determined by the graded dose-
response curve.
Graded dose-response curve
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General classification of drugs
Agonist = stimulant. Partial agonist.
Antagonist = blocker.
Agonist: a drug has affinity, high efficacy and rapid rate of
association and dissociation with its receptor e.g. adrenaline,morphine and histamine.
Partial agonist: a drug has affinity, weak efficacy and moderateassociation and dissociation. It produces an effect < the fullagonist when it has saturated the receptors. It acts as antagonist
in the presence of full agonist e.g. nalorphine, ergotamine,succinylcholine and oxprenolol.
Antagonist: a ligand having affinity, but no efficacy and slowlyassociated and dissociated from the receptor.
A i t d t i t
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2004-2005
Agonists and antagonists
agonist has affinity plus intrinsic activity
antagonist has affinity but no intrinsic activity
partial agonist has affinity andless intrinsic activity
competitive antagonists can be overcome
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Agonist Drugs
drugs that interact with and activatereceptors; they possess both affinity and
efficacy
two typesFullan agonist with maximal efficacy
Partialan agonist with less then
maximal efficacy
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Response
Dose
Full agonist
Partial agonist
Agonist Dose Response Curves
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Antagonist Drug
Antagonists interact with the receptorbut do NOT change the receptor
they have affinity but NO efficacy
two types
Competitive
Noncompetitive
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Drug
Stimulants
Action of drugs on enzymes
Inhbitors
Activity
Induction
Non specific
Specific
Enzyme Enzyme
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Specific inhibitors
Competitive
Action of drugs on enzymes
Non competitive
Reversible
Irreversible Inhibition
Allosteric centreC
atalytic
cen
tre
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Physiological
Drug
Silent
Receptors
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Recognising domain
Effector domain
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Enzyme receptors
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Tyrosine-kinase receptors
Structure:Receptors exist as individual
polypeptides
Each has an extracellular signal-bindingsite
An intracellular tail with a number of
tyrosines and a single helix spanning themembrane
S gna ng Mec an sms
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S gna ng Mec an smsReceptors located on membrane-spanning
molecules that bind separate intracellular tyrosine
kinase molecules These receptors have extracellular and intracellular domains
and form dimers.
After receptor activation by an appropriate drug, thetyrosine kinase molecules (Janus kinases; JAKs) areactivated, resulting in phosphorylation of "STAT" molecules(signal transducers and activators of transcription).
STAT dimers then travel to the nucleus, where they regulatetranscription.
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2004-2005
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Figure 2-9. Mechanism of activation of the epidermal growth factor
(EGF) receptor, a representative receptor tyrosine kinase.
Copyright 2004 by The McGraw-Hill Companies, Inc. All rights reserved.
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Figure 2-8. Cytokine receptorsCopyright 2004 by The McGraw-Hill Companies, Inc. All rights reserved.
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Examples When insulin, epidermal growth factor (EGF)
and platelet derived growth factor (PDGF) bindtheir surface receptors, a tyrosine-kinase (onthe inner part of the receptor) is activated. This
leads to phosphorylation of certain protein onits tyrosine residue producing the specificcellular function.
T.K
R
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Ion channel coupled receptors
Signaling Mechanisms
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Signaling Mechanisms
Receptors located on membrane ion channels
Receptors that regulate membrane ion channels
may directly cause the opening of an ion channel
Ex: acetylcholine at the nicotinic receptor
Or, modify the ion channel's response to other
agents
Ex: benzodiazepines at the GABA channel.
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Ion channelreceptors
Structure:
Protein pores in
the plasma
membrane
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Figure 2-9. The nicotinic acetylcholine receptor
Copyright 2004 by The McGraw-Hill Companies, Inc. All rights reserved.
G
-
protein coupled
recptors
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p p p
G protein linked receptors
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G protein-linked receptors
Structure:
Single polypeptide
chain threaded
back and forth
resulting in 7
transmembrane
helices
Theres a G
protein attached to
the cytoplasmic
side of themembrane
(functions as a
switch).
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G protein coupled receptors
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G-protein coupled receptors
Gs
Activation of adenilatcyclaseandcAMP/, Ca, PKA
Gi
Inhibition of adenilatcyclaseand
decrease of cAMP/, K
Gq Activation of phospholipase C / IP3, DAG/
Go Closing of Ca channels
Table 2-1. G proteins and their receptors and effectors
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Effector/Signaling PathwayReceptors for:G Protein
Adenylyl cyclase , cAMP
-Adrenergic amines, glucagon,
histamine, serotonin, and many
other hormones
Gs
Several, including:
Adenylyl cyclase , cAMP
Open cardiac K+channels , heart rate
2-Adrenergic amines,
acetylcholine (muscarinic),
opioids, serotonin, and many
others
Gil, Gi2, Gi3
Adenylyl cyclase , cAMP Odorants (olfactory
epithelium) G
olf
Not yet clear Neurotransmitters in brain
(not yet specifically identified) G
o
Phospholipase C, IP3,
diacylglycerol, cytoplasmic Ca2+
Acetylcholine (eg, muscarinic),
bombesin, serotonin (5-HT1C),
and many others
Gq
cGMP phosphodiesterase
(phototransduction)
Photons (rhodopsin and color
opsins in retinal rod and cone
cells)
Gt1, Gt2
Table 2 1. G proteins and their receptors and effectors
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CAM
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Examples
Stimulation of 1 & 2 adrenergic receptorsstimulate Gs increase cAMP.
Stimulation of 1 adrenergic receptors Gq
increase DAG, IP3. Stimulation 2 adrenergic receptors Gi
decrease cAMP.
Receptors regulating DNA transcription
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Receptors regulating DNA transcription
Receptors regulating DNA transcriptio
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p g g p
Drugs actiong on ionic
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Drugs actiong on ionic
channels
Potential dependent
Ionic channels
Drugs acting on genes
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Drugs acting on genes
Inhibition of expression
Switching off of
gene expression
Replacement of the
mutagen gene
Intracellular receptors
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Not all signal receptors are located on the plasma membrane.
Some are proteins located in the cytoplasm or nucleus of targetcells.
The signal molecule must be able to pass through
plasma membrane.
Examples:
~Nitric oxide (NO)
~Steroid (e.g., estradiol, progesterone, testosterone)
and thyroid hormones of animals).
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Second Messengers
Small, nonprotein, water-soluble
molecules or ions
Readily spread throughout the cell
by diffusionTwo most widely used second
messengers are:
1. Cycle AMP
2. Calcium ions Ca2+
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Summary
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Summary
most drugs act through receptors
there are 4 common signal transduction methodsthe interaction between drug and receptor can be
described mathematically and graphically
agonists have both affinity(kd) and intrinsic activity (
)
antagonists have affinity only
antagonists can be competitive (change kd) or
non-competitive (change ) when mixed with agonists
agonists desensitize receptors.
antagonists sensitize receptors.
Receptor Regulation
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Receptor Regulation
Sensitization or Up-regulation
1. Prolonged/continuous use of receptorblocker
2. Inhibition of synthesis or release ofhormone/neurotransmitterDenervation
Desensitization or Down-regulation
1. Prolonged/continuous use of agonist2. Inhibition of degradation or uptake ofagonist
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Effectiveness, toxicity, lethality
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, y, y
ED50 - Median Effective Dose 50; the dose
at which 50 percent of the population or
sample manifests a given effect; used with
quantal dr curves TD50 - Median Toxic Dose 50 - dose at
which 50 percent of the population
manifests a given toxic effect LD50 - Median Lethal Dose 50 - dose which
kills 50 percent of the subjects
Q tifi ti f d f t
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Quantification of drug safety
Therapeutic Index =TD50 or LD50
ED50