pharmacodynamics eng

8/13/2019 Pharmacodynamics Eng

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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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2004-2005

Response

Dose

Full agonist

Partial agonist

Agonist Dose Response Curves


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2004-2005

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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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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2004-2005

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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2004-2005

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

pharmacodynamics eng

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