pharmacokinetic & pharmacodynamic

8/18/2019 Pharmacokinetic & Pharmacodynamic

1/77

1

INTRODUCING

PHARMACOKINETICS ANDPHARMACODYNAMICS

Kinanti Narulita DPharmacology Department

FACULTY OF MEDICINE – UNISSULA


2/77

2

LEARNING OUTCOMES

Define and discuss pharmacokinetic factorsDiscuss the factors that affect absorption,

distribution, metabolism and excretion-howthey affect drug therapyDefine and discuss pharmacodynamicmechanisms of drug actionsApply pharmacokinetic andpharmacodynamic concepts to patientscenarios.


3/77

PHARMACOKINETIC


4/77

4

PHARMACOKINETICS :CONSIDERING SUCH TERMS AS

Route Absorption

DistributionProtein BindingHepatic Metabolism

Metabolic productsRenal ExcretionHalf-life

Toxicity


5/77

Route : oral, parenteral, inhalation, rectal,transdermal, injection.

Absorption entry into body-acidity and solubility.

First-pass-metabolic change due to liver enzymes :patients with liver disease poor metabolism toxicity.Distribution extent of protein binding important as

only free (unbound) drug can have effect. Penicillin ishighly protein bound. Two drug co-administered,degree of protein binding can be altered, displaced?Toxicity?Excretion removal or clearance of drug from body.Half-life how long does it take the plasmaconcentration of drugs to go down to 50%.Toxicity consider the pharmacological routes toadverse drug effects.

5


6/77

PHARMACOKINETIC

Pharmacokinetics is what the body does tothe drugs (THE BODIES RESPONSE TOMEDICATION) , pharmacokinetics refers to thehandling of a drug within the body.For almost all drugs the magnitude ofpharmacological effect depends on itsconcentration at its site of action.To achieve the pharmacological responsedesired, the drug must first be in an availableand suitable form and then administrated by an

appropriate route. 6


7/77

7

DistributionMetabolism

Excretion

Absorption


8/77

8

Absorption

Route

EnteralParenteral

IVTopical

transdermal inhalationoral sublingual

Distribution

Systemic circulation

Absorption Absorption


9/77

9

ABSORPTION

Process of drug movement from theadministration site to the systemic circulation.The amount and rate of absorption are determinedby several factors :

Drug characteristics that affect absorption /physical nature of the dosage form : molecularweight, ionization, solubility, & formulation


10/77

Disintegration and dissolution of the releaseddrug into the correct part of the GI tract is

required for the drug to be absorbed. Drugs inliquid dose form require no disintigration andoften dissolution are already accomplished andtherefore absorb more rapidly with faster effects.

10

ABSORPTION


11/77

Food effect on some drugs affects thebioavailability.

GI motility effects the thorough mixing in the GItract which increases the efficacy in which thedrug makes contact with surfaces that areavailable to engage absorption.

Drug absorption is mainly in the upper smallintestine that is facilitated by the large surfacearea of villi and the rich blood supply.

11

ABSORPTION


12/77


13/77

13

ABSORPTION

KEYNOTE Factors affecting drugabsorption related to patients :

Route of administrationGastric or intestinal pHContents / composition of GI tract

Presence or absence of food in thestomachMesenteric blood flow

Concurrent administration with other drugs


14/77

14

BIOAVAILABILITY

“Bioavailability is the proportion of the administereddose that reaches the systemic circulation. ” = refersto the amount and the rate of appearance of thedrug in the blood after administration in its initial

dose form.Orally administered drug bioavailability is directlyrelated to the individual solubility in body fluids.

Poor solubility = low bioavailability

To become affective i.e. produce a therapeuticeffect, a drug must reach an adequate concentrationin the blood. Drugs administered by the IV route arebioavailable in 100% of cases as it is administered

directly into the blood.


15/77

15

BIOAVAILABILITY

Some drugs with the same active principle, made bydifferent manufacturers may differ in thebioavailability, dependant on the degree of

compression or nature of excipients (addedsubstances), that may affect the disintigration anddissolution of the drug.Drugs licensed for use in the UK (including parallel

imports) the manufacturing processes are controlledto ensure bioavailability across drug production isconsistent.Brand vs generic prescribing . Bioequivalenceshould be similar with a few exceptions.


16/77

Time to Peak Concentration

010

20

30

40

50

6070

80

90

100

0 5 10 20 30 60 120 180

minutes

c o n c e n

t r a

t i o n

IV

Oral

Rectal


17/77

17

EFFECT OF FOOD ON THEABSORPTION OF DRUGSBioavailability of some drugs is affected by thepresence of food. E.g : penicillin, erythromycin,rifampicin, thyroxine.Some drugs are taken before meals to allowtime for drug to act before food is taken.Gastric irritation can be caused by drugs takenon an empty stomach.


18/77

18

FIRST PASS EFFECT

Drugs that are absorbed via the GIT arecirculated to the liver first via

the hepatic portal veinLiver then acts as a filterOnly part of the drug is

circulated systemicallyThe combination of

processes is termed

the ‘First Pass’ effect

http://www.nurse-prescriber.co.uk/education/visual_lib/pp18.jpghttp://www.nurse-prescriber.co.uk/education/visual_lib/pp18.jpg


19/77

All drugs taken orally that are absorbed pass bythe hepatic portal vein. This is a defencemechanism to detoxify substances coming into

the body.The liver protects the body from systemicallycirculating toxins that are absorbed via the GIT by

filtering drugs through a range of detoxificationmechanisms seeking for natural toxins. As a result only part of the administered drugreaches the systemic circulation via the hepaticartery.

19

FIRST PASS EFFECT


20/77

20

Distribution

Factors affecting

Absorption Metabolism

Low albumin Problems with:Heart

CirculationDiabetes

Bound drugs are pharmacologically inactive because the drug-

protein complex is unable to cross cell membranes.


21/77

Membrane permeabilitycross membranes to site of action

Plasma protein bindingbound drugs do not cross membranesmalnutrition = albumin = free drug

Lipophilicity of druglipophilic drugs accumulate in adipose tissue

Volume of distribution

DISTRIBUTION


22/77

22


23/77

Low Affinity, high capacity binding Proteins : Albumin (e.g. phenytoin) 1-acid glycoprotein (cationic lidocaine)Lipoproteins

Specific binding Proteins (high affinity lowcapacity) : cortisol binding globulin, thyroidbinding globulin

PLASMA PROTEINS


24/77

Protein Berat Molekul

(Da)Konsentrasi

(g/L)Obat yangmengikat

Albumin 65,000 3.5 –5.0 Acid drugs (large variety ofdrug)

α1 - acidglycoprotein

44,000 0.04 – 0.1 Basic drug : propranolol,imipramine and lidocaine.

Globulins : corticosteroids.

Lipoproteins 200,000 – 3,400,000 .003-.007 Basic lipophilic drug :chlorpromazine

α1 globulin

α2 globulin

59000

13400

.015-.06 Steroid, thyroxine,Cynocobalamine,

Vit. A,D,E,K

IKATAN OBAT – PROTEINPLASMA


25/77

PENYAKIT DANPROTEIN BINDING

Protein Binding (Ikatan Obat – Protein) Menurun Pada Kondisi :

PENYAKIT LIVER PENYAKIT RENAL

DapsoneDiazepamMorphinePhenytoinPrednisoloneQuinidineTolbutamideTriamterene

Barbiturates SalicylatesCardiac Glycosides SulfonamidesChlordiazepoxide TriamtereneClofibrateDiazepamDiazoxideFurosemideMorphinePhenylbutazone

Phenytoin


26/77

Beberapa obat mampuberikatan dgn HAS lebih satubinding site :- Flucoxacillin, flurbiprofen,

ketoprofen, tamoxifen dandicoumarol berikatan dgn2 binding site

- Indomethacin berikatan

dengan 3 binding site. AAG mempunyai kapasitasterbatas. AAG hanyamempunyai binding site 1untuk lidocaine.

Site 1

Site 2

Site 3

site4

DRUG BINDING SITEON HSA

Warferinbinding

site

Diazapambinding

site

Digitoxinbinding site

Tamoxifenbinding site

HSA


27/77

27

METABOLISM

Drugs are metabolised in the liver, lungs, kidneys,blood and intestines.In order for drugs to pass across the lipid cellmembrane they must be lipophilic. Lipophilic

means fat soluble. Hydrophilic means watersoluble.The higher the solubility in lipids compared towater, the more rapid the tissue entry.

Metabolic rate determines the duration of theaction of the drugs.The primary metabolic site is the liver. If enzymefunction is inadequate the metabolic effect can becompromised and cause toxicity.


28/77

Eg : liver disease, very young and very old whohave diminished hepatic microsomal enzymeactivity.

Body works to convert drugs to less active formsand increase water solubility (hydrophilic thanlipophilic) to enhance elimination / excretion.

The speed with which a drug is metabolised willdetermine the duration of the action of the drug.This in turn will determine how often the drug isadministered.

28

METABOLISM


29/77

Cytochrome P450 systemLocated within the endoplasmic reticulumof hepatocytesThrough electron transport chain, a drugbound to the CYP450 system undergoesoxidation or reduction

Enzyme inductionDrug interactions

PHASE 1 REACTIONS


30/77

HydrolysisOxidation

ReductionDemethylationMethylation

Alcohol dehydrogenase metabolism

PHASE 1 REACTIONS


31/77

Polar group is conjugated to the drugResults in increased polarity of the drug

Types of reactionsGlycine conjugationGlucuronide conjugation

Sulfate conjugation

PHASE 2 REACTIONS


32/77

Pulmonary = expired in the airBile = excreted in feces

enterohepatic circulationRenal

glomerular filtration

tubular reabsorptiontubular secretion

EXCRETION / EXCRETION


33/77

33


Drugs are primarily excreted by the kidneysIn order for drugs to be excreted they need to

become hydrophilicExcretion of drugs can be affected by theurinary pH

How the drug is excreted can influenceprescribing decisionsThe excretion rate varies from hours to weeksand on the condition of the kidneys


34/77

Aging patient with reduced renal capacitymore prone to build up (toxicity) of drugs

excreted renally, more of problem with drugsnarrow therapeutic range e. g digoxin. somebeta blockers (celiprolol, sotaolol) etc.Excretion and prescribing influence. Egampicillin is excreted in high concentrationsin bile, so is a good chioce for biliary tractinfection.

34



35/77

When lipid soluble drugs pass through thekidneys they are re-absorbed in the distal

tubule and return to the plasma. In order tobe excreted they need to become morehydrophilic. This occurs in the Bowman’s capsule, converted to less active metabolitesmore easily excreted.

35



36/77

Steady State : the amount of drugadministered is equal to the amount of drug

eliminated within one dosing interval resultingin a plateau or constant serum drug level.Drugs with short half-life reach steady state

rapidly; drugs with long half-life take days toweeks to reach steady state.



37/77

37

HALF LIFE OF DRUGS

Drug excretion is commonly expressed in termsof half life (t1/2)This is the time required for the concentration of

the drug in the plasma to decrease by one-halfof it’s initial valueDrug half life is variable and can be long or shortSubsequent doses are given to raise theconcentration levels to a peakIn theory, the optimal dosage interval betweendrug administration is equal to the half-life ofthe drug


38/77

Eg. half life of drugs – aspirin 6 hours,metronidazole 9 hours, digoxin 36 hours.Half-life is affected by :

Short half life : extensive tissue uptake, rapidmetabolism, rapid excretion.Long half life : extensive protein binding, slow

metabolism, poor excretion.Concentration falls after metabolism andexcretion. If dose interval is too long, effect is notachieved, too short an interval leads to toxicity.

38

HALF LIFE OF DRUGS


39/77

39

LOADING DOSES

Are used when the medical conditiondemands high concentrations very quickly

This is achieved by an initial dose that istwice the maintenance doseExample :

Acute infections : use stat dose ofantibiotic, 2 times the next dose.Digoxin loading dose.


40/77

Loading dosesallow rapidachievement of

therapeutic serumlevelsSame loading doseused regardless ofmetabolism /eliminationdysfunction

0

5

10

15

20

25

30

35

40

w/ bolus

w/o

bolus

LOADING DOSES


41/77

Renal Disease : same hepatic metabolism,same / increased volume of distribution andprolonged elimination dosing intervalHepatic Disease : same renal elimination,same / increased volume of distribution, slowerrate of enzyme metabolism dosage,

dosing intervalCystic Fibrosis Patients : increasedmetabolism / elimination, and larger volume ofdistribution dosage, dosage interval

SPECIAL PATIENTPOPULATIONS


42/77

PHARMACODYNAMIC


43/77

43

PHARMACODYNAMICS

Pharmacodynamics : study of the biochemicaland physiologic processes underlying drug action

what the drug does to the body or mode of

action of drugs in the body , ideally including howdrugs exert their effect at a general , cellular levelor the molecular mechanism by which the drugacts.

Mechanism of drug action Drug-receptor interaction

EfficacySafety profile


44/77

Understanding the pharmacodynamics ofdrugs will enable you to predict drug

interactions and toxicities.The pharmacology of a drug is not alwaysknown-but where it is, it would be nice if youhad a handle on how the drugs you will beprescribing exert their effect

44

PHARMACODYNAMICS


45/77

45

ReceptorsReceptors-agonist, partialagonist and antagonist

Ion channels

Ion channels-gating ofintracellular ionsEnzymes

Enzymes-drugs act to inhibit or

potentiateCarrier molecules

Carrier molecules-allowmolecules not lipid soluble to

cross cell membrane

CONSIDERING


46/77

46

CONSIDERING

ChemotherapyChemotherapeutic agents

Drug tolerance / dependenceEffects of pathological state and biologicalvariability


47/77

47

TYPES OF RECEPTORS

G-protein-couple receptors. G protein receptorswork in seconds, e.g. muscarinic ACh receptors,adrenoceptors, histamine receptors. Proteins or

glycoproteins :Present on cell surface, on an organelle within thecell, or in the cytoplasmFinite number of receptors in a given cell

Kinase linked receptors. Kinase (enzyme) linkedreceptors can take hours, e.g. Insulin, Growth factor.Nuclear intracellullar receptors, e.g. steroid, thyroidhormone.

http://www.nurse-prescriber.co.uk/education/visual_lib/pp20.jpg


48/77

48

http://www.nurse-prescriber.co.uk/education/visual_lib/pp20.jpghttp://www.nurse-prescriber.co.uk/education/visual_lib/pp20.jpg


49/77

Action occurs when drug binds to receptor andthis action may be :

Ion channel is opened or closedSecond messenger is activated :

cAMP, cGMP, Ca ++, inositol phosphates,etc.Initiates a series of chemical reactions

Normal cellular function is physically inhibitedCellular function is “turned on”

DRUG RECEPTORS


50/77

AffinityRefers to the strength of binding between adrug and receptorNumber of occupied receptors is a functionof a balance between bound and free drug

DRUG RECEPTORS


51/77

51

RECEPTORSReceptors are a target molecule thata drug molecule has to combine withto produce a specific effectReceptors must be compatible –like 2pieces of a jigsaw e.g.neurotransmission

Main types of action at receptor :

Receptor agonistsReceptor antagonists


52/77

AGONISTDrugs which alter the physiology of a cell by

binding to plasma membrane or intracellularreceptors.Full agonist is isoproterenol , which mimicsthe action of adrenaline at β -adrenoreceptors . Morphine , which mimicsthe actions of endorphins at μ -opioidreceptors throughout the CNS.

DRUG RECEPTORS


53/77

PARTIAL AGONIST A drug which does not produce maximaleffect even when all of the receptors areoccupied. E.g : Clomiphene & Tamoxifen

partial agonist at estrogen receptor.

Buprenorphine partial agonist at μ -opioid receptors throughout the CNS.

DRUG RECEPTORS


54/77

ANTAGONISTSInhibit or block responses caused by

agonists. Physiological antagonist =opposing physiological actions , but actat different receptors. They are sometimescalled blockers ; examples include : α -blockers, β -blockers, CCB .

DRUG RECEPTORS


55/77

COMPETITIVE ANTAGONISTCompetes with an agonist for receptors. Highdoses of an agonist can generally overcomeantagonist.Naloxone is used to reverse opioid overdose caused by heroin / morphine .

Flumazenil vs benzodiazepines.Competitive antagonists combine with thesame receptor as an endogenous agonist(e.g . ranitidine at histamine H2-receptors ).

DRUG RECEPTORS


56/77

NONCOMPETITIVE ANTAGONISTBinds to a site other than the agonist-bindingdomain. Induces a conformation change in the

receptor such that the agonist no longer“recognizes” the agonist binding site. High dosesof an agonist do not overcome the antagonist inthis situation.

Histamine ↓ arterial pressure through vaso-dilatation at the H1 receptor, while adrenaline ↑ arterial pressure through vasoconstrictionmediated by α -adrenergic receptor activation.

DRUG RECEPTORS


57/77

IRREVERSIBLE ANTAGONISTBind permanently to the receptor binding site

by forming a covalent bond to the active site/ just by binding so tightly, therefore they cannot be overcome with agonis.Irreversible enzyme inhibitors that actsimilarly are clinically used and include drugssuch aspirin, omeprazol and monoamineoxidase inhibitors .

DRUG RECEPTORS


58/77

58

Drugs act to affect cellular gating mechanismin cell wall. Ligand-gated ion channels work inmilliseconds e.g GABA benzodiazepines,Nicotinic Ach.Some ion channels are gated by receptor(open only when receptor is occupied by an

agonist) while other are voltage-gated-drugasaffect the permage or flow of for example,potassioum, sodium or calcium in and out ofthe cell.

ION CHANNELS


59/77

59

Drugs acting at ion channels include :Benzodiazepines that act at GABA

(gamma amino butyric acid receptor)chloride channel return over excitablereceptor to constitutive (normal) level ofactivationCalcium channel blockers prevent diffusionof calcium through cell membraneNicorandil acts at potassium channels

ION CHANNELS


60/77

60

Another examples of this drugs :Loop diuretics which inhibit sodium,

potassium and chlorine passage in the lopof Henle Another example omeprazole inhibitsproton pump in the gastric mucosaTricyclics inhibit noradrenaline uptake

ION CHANNELS


61/77

61

Carrier molecules allow transport of smallorganic molecules that are too polar – notsufficiently lipid soluble to penetrate cellmembranes on their own. Drugs act oncarrier transporters which allow molecules

eg. glucose and amino acids.

CARRIER MOLECULES


62/77

62

ENZYME INHIBITORS

An enzyme is a protein that can promote oraccelerate a biochemical reaction with asubstrateWhen the enzyme mistakes the drug for asubstrate, a drug-enzyme interaction occursThis interaction could increase or decreasethe rate of the biochemical reaction


63/77

Many drugs target enzymes acting as falsesubstrates to competitively inhibit eitherreversibly e.g.neostigmine or irreversibly e.g

AspirinSimvastatin inhibits HMG CoA REDUCTASE

63

ENZYME INHIBITORS



64/77

64



65/77

CHEMOTHERAPEUTIC


66/77

66

CHEMOTHERAPEUTICAGENTS

Cytotoxic drugs act by interfering with cellgrowth and division at different stages of the

cycle Anti-infective drugs

CHEMOTHERAPEUTIC


67/77

Examples :Folic acid is required for DNA synthesis.Methotrexate inhibits the formation of folicacid.Penicillins and cephalosporins inhibitsynthesis of bacterial cell walls.

Nyastatin acts by increasing the permeabilityof of cell membranes of invading organisms.Erythromycin inhibits bacterial protein

synthesis.67


Bacterial Cell


68/77

68

Cell wall

Cell membraneDNA

C l a

s s

1 r e

a c t i o

n s

C l a

s s

2 r e

a c t i o

n s

C l a

s s 3

r e a c t i o

n s

Glucose Precursormolecules

Aminoacids

Nucleotides

ProteinsRNA

DNA

Metabolism of bacterial cell

CHEMOTHERAPEUTIC


69/77

Chemotherapy-exploiting the differencesbetween host and bacteria.

Class 1 reactions are not good targets forchemotherapy no marked difference in theway humans and bacteria obtain energy fromglucose.Class 2 are better targets as some pathwaysconverting precursor molecules to aminoacids occur in bacteria but not in human.

69


CHEMOTHERAPEUTIC


70/77

E.g. man cannot manufacture own folate(needed for DNA synthesis) and needs totake from diet. Bacteria make their own folateand cannot transport into cell fromenvironment.Class 3 reactions are excellent target for

chemotherapy because every cell makes itsown macromolecules, e.g. needed formanufacture of bacterial cell wall, differentfrom human cells. 70



71/77

DEFINITIONS

EFFICACYDegree to which a drug is able to producethe desired response

POTENCY Amount of drug required to produce 50% ofthe maximal response the drug is capableof inducingUsed to compare compounds withinclasses of drugs


72/77

EFFECTIVE CONCENTRATION 50% (ED 50 )Concentration of the drug which induces a specifiedclinical effect in 50% of subjects.

LETHAL DOSE 50% (LD 50 )

Concentration of the drug which induces death in50% of subjects.

THERAPEUTIC INDEXMeasure of the safety of a drug.Calculation : LD 50 /ED 50

MARGIN OF SAFETYMargin between the therapeutic and lethal doses of adrug .

DEFINITIONS

DOSE RESPONSE


73/77

DOSE-RESPONSERELATIONSHIP

Drug induced responses are not an “all ornone” phenomenon.

Increase in dose may :Increase therapeutic responseIncrease risk of toxicity


74/77

PHYSIOLOGICAL


75/77

75

PHYSIOLOGICALVARIABILITY

Reduced hepatic blood flowRenal disease

Potential to reduce the elimination of drugsif eliminated largely by the kidneys. Thiscould lengthen the half life of drugs if the

metabolites are pharmacologically active.Dosage adjustments are required

PHYSIOLOGICAL


76/77

76

PHYSIOLOGICALVARIABILITY

Allergy Allergy incidence is increasing with multiple

drug therapy. Penicillin groups mostcommonly involved.Initial reaction is the formation ofantibodies. Subsequent exposure causeschemicals to be releases e.g. histaminethat causes the allergic response

Decreased plasma proteins


77/77

REMEMBERNo drug produces

a single effect!!!

pharmacokinetic & pharmacodynamic

Documents