Pharmacokinetic, Pharmacodynamic and Clinical · PDF fileภาควิชาเภสัชวิทยา ... Pharmacokinetic process Conditions in which the plasma concentration

Pharmacokinetic, Pharmacodynamicand Clinical Application

ผศ.พญ.สมฤด ฉตรสรเจรญกลภาควชาเภสชวทยา

คณะแพทยศาสตรศรราชพยาบาล

Pharmacology

• Pharmacokinetic : เภสชจลนศาสตร

• Pharmacodynamic : เภสชพลศาสตร

Metabolism & Elimination

Drug concentration in systemic circulation

Dose of drug

administered

Drug concentration at site of action

AbsorptionDistribution

Drug in tissues

Drug metabolized

and excreted

PKs

Pharmacological effect

EfficacyToxicity

Clinical responsePDs

Relationship between Pharmacokinetics and Pharmacodynamics

Pharmacokinetic

“the rate and manner in which drugs are absorbed, distributed,

metabolized and eliminated within and from the body”

“รางกายท าอะไรกบยา”

“What the body does to the drug”

Dosage regimen Effects

PHARMACOKINETICS PHARMACODYNAMICS

PlasmaConcen-tration

Sitesof

action

Pharmacokinetic = A D M E

A

D

M

E

Pharmacokinetic process

–Absorption- For local effect

* Application to skin* Application to mucous membranes

# nose, throat, mouth, eye, genitourinary tract* Oral administration (limited)

# cathartics, antacids or drugs used to treat parasiticor bacterial infections of gastrointestinal tract

* Various techniques for administering local anesthetics or agents useful in pulmonary diseases


–Absorption- For systemic effect

* Sublingual administration* Oral administration* Rectal administration* Inhalation* Subcutaneous administration* Intramuscular administration* Intravenous administration* Intrathecal (injection into spinal subarachnoid space)


–Absorption from GI tract

FIGURE :Drug concentration-time curve following a single oral dose showing the maximum systemic exposure (Cmax) and the time of its occurrence (tmax). The concentration could represent drug in whole blood, plasma, or serum.

Area under the curve (AUC)

Pharmacokinetic process–Distribution

- Occurs when drugs reach the systemic circulation

- 2 phases: initial phase, distribution phase


- Plasma drug concentration depends on

* Dose taken

* Distribution of drug after absorption


- Special barrier to distribution

* Blood-brain barrier ---> permeable only lipid-soluble drugs

or low molecular weight

- Redistribution

* Lipid-soluble drugs redistribute into fat tissues

* Resulting in longer duration than the first dose

* Amiodarone ---> deposit in adipocytes ---> long half-life


- Plasma protein binding

* Competition (drug-drug interaction)

# high plasma protein binding

* Hypoproteinemia (hypoalbuminemia)

# transient increase ratio of free form : bound form drug

# transient increase therapeutic effect & adverse effect

of drugs


- Plasma protein binding

FIGURE 4-19. The percent of drug in plasma unbound varies widely among drugs.

Flurbiprofen

Pharmacokinetic processConditions in which the plasma concentration of the

two major plasma proteins to which drugs bind are altered

Plasma protein Condition Change in concentrationof plasma protein

Albumin Hepatic cirrhosis DecreaseBurn DecreaseNephrotic syndrome DecreaseEnd-stage renal disease DecreasePregnancy Decrease

α1-Acid glycoprotein Myocardial infarction IncreaseSurgery IncreaseCrohn’s disease IncreaseTrauma IncreaseRheumatoid arthritis Increase


- Volume of distribution (Vd)

* Calculate loading dose

# an initial higher dose of a drug that may be given at the

beginning of a course of treatment before dropping

down to a lower maintenance dose

* Needed to rapidly achieve a therapeutic response

* Ex: phenytoin loading dose

Loading dose = Vd

x Cp


- Volume of distribution (Vd)

FIGURE 4-17. The apparent volume into which drugs distribute varies widely.

Pharmacokinetic process–Biotransformation (Metabolism)

- Termination of activities

- Generation of active compounds

- Transform into more water-soluble

- Liver is the major site

- Phase I & Phase II reactions


- Phase I reactions

* Oxidation

* Reduction

* Hydrolysis


- Microsomal enzymes

Cytochrome P450 mixed function oxidase (CYP450)

* Major enzyme systems involved in phase I reactions

* CYP450 superfamily

CYP3A4

CYP2D6

CYP2C9

CYP2C1

9

CYP1A2

CYP3A4Family

SubfamilyGene product


- Enzyme inducers

* Induced enzyme synthesis that use in biotransformation

of substrate drugs (clinically significant effect ~ 2 weeks)

* Decrease therapeutic effects of substrate drugs

* Ex: rifampicin, carbamazepine, phenytoin, phenobarbital,

griseofulvin


- Enzyme inhibitors

* Inhibit enzyme activity that use in biotransformation

of substrate drugs (clinically significant immediate effect)

* Increase therapeutic & adverse effects of substrate drugs

* Ex: cimetidine, erythromycin, azole antifungals, amiodarone,

fibrates, protease inhibitors


- Phase II reactions

* Conjugation with endogenous compounds

# glucuronidation

# acetylation

# sulfation

# methylation


- Factors affecting biotransformation

* Genetics

* Other drugs

* Environmental pollutants

* Disease

* Age

Pharmacokinetic process–Excretion

- Kidney is most important

* Glomerular filtration

* Passive tubular reabsorption

* Active tubular secretionFIGURE 5-13. Schematic representation of the functional unit of the kidney, the nephron. Drug enters the kidney via the renal artery and leaves partly in the exiting renal vein and partly in urine. Urinary excretion (4) is the net effect of glomerular filtration of unbound drug (1) and tubular secretion (2), processes adding drug into the proximal part of the lumen of the tubule, and tubular reabsorption of drug from the lumen and collecting tubule back into the perfusing blood (3).

Concn

Time (h)

0 1 2 4

C0

C = C0e-kt

Dose t1/2

10

8

6

4

2


- Elimination kinetics

* First-order kinetics

* Zero-order kinetics



* First-order kinetics

# Type of elimination for most drugs

# Rate of elimination is directly proportional to plasma level

# Exponential decay versus time

Time (h)

Plas

ma

conc

entra

tion



* Zero-order kinetics

# Constant rate of elimination

# Independent of plasma concentration

# Saturation kinetics (saturated metabolizing enzymes)

# Narrow therapeutic index ---> high toxicity

# Phenytoin, theophylline, ethanol

Time (h)

Plas

ma

conc

entra

tion


- Biliary excretion

* Enterohepatic circulation

- Other routes: feces, milk, saliva

FIGURE 2-10. Drugs sometimes are excreted from the liver into the bile and stored in the gall bladder. On emptying the gall bladder, particularly when induced by food, drug passes into the lumen of the small intestine, where it may be absorbed into a mesenteric vein draining the small intestine and colon, and conveyed by blood back to the liver via the portal vein. The drug has then completed a cycle, the enterohepatic cycle, as shown in color.

PHARMACODYNAMICS

Definition

study of the biochemical and physiological effects of drugs and their mechanisms of action

– how drugs affect the body

– the interaction of drugs with receptors

– the consequences of this interaction

“ยาท าอะไรกบรางกาย”“What the drug does to the body”

Metabolism & Elimination

Drug concentration in systemic circulation

Dose of drug

administered

Drug concentration at site of action

AbsorptionDistribution

Drug in tissues

Drug metabolized

and excreted

PKs

Pharmacological effect

EfficacyToxicity

Clinical responsePDs

Relationship between Pharmacokinetics and Pharmacodynamics

Targets for drug binding

• Protein structure :-

– receptors (physiological receptor of endogenous ligands :-hormones, growth factors, neurotransmitters and autacoids)

– enzymes (e.g., DHFR* , AChE*)

– ion channels (Na+ K+-ATPase)

– carrier molecules (Na-K-2Cl cotransporter, proton pump)

– secreted glycoproteins

– cytoskeleton (tubulin)

• Non-protein :-

– nucleic acid for chemotherapeutic drug

DHFR* = Dihydrofolate reductase, AChE* =Acetylecholinesterase

Drug-Receptor Interaction

• Drugs that bind to receptors and response like the

regulatory effects of the endogenous signaling

compounds are termed agonists (e.g. acetylcholine,

epinephrine, histamine).

• Drugs that bind to receptors without regulatory effect, but

their binding blocks the binding of the endogenous

agonist and inhibit the action of an agonist are termed

antagonists (e.g. atropine inhibits acetylcholine).

39

Diseases Resulting from Receptor Malfunction

• myasthenia gravis

– antibody to acetylcholine receptor on motor end plate

• diabetes mellitus

– insulin resistance, antibody to insulin receptor

• Familial hypercholesterolemia

– ↓ LDL receptor

Non receptor-mediated drug effect

• antacid

– neutralization of gastric acid

• mesna

– detoxifies & antagonizes free radical, metabolites of chemotherapeutic drugs

• mannitol

– osmotic effect and changing in the distribution of water

• cholestyramine

– binds cholesterol from GI

• antiseptic (alcohol)

Pharmacodynamic Interaction

• Both drugs have reached the target site of

clinical effect before the interaction (synergism or antagonism) occurs.

• Synergism

– summation or addition (1 + 1 = 2)

– synergistic effect (1 + 1 > 2)

– potentiation (0 + 1 > 1)

Pharmacodynamic Interaction

• Antagonism

– functional or physiological antagonism

– chemical antagonism or inactivation

– dispositional antagonism

– antagonism at the receptor (reversibly competitive

antagonism)

Clinical Applications

Applications

• Drug used in pediatric

• Drug used in pregnancy and lactation

• Drug used in geriatric

• Drug used in liver disease

• Drug used in renal disease

• Drug interaction

• Adverse drug reaction

Therapeutic Drug Monitoring (TDM)

“plasma concentration of drug is

measured and the dose adjusted

to achieve a desired therapeutic

drug concentration”

Drug candidates for TDM

• low therapeutic index

• no physiologic or therapeutic endpoints to

guide dosage

• pharmacokinetics vary widely between

individuals

Drugs with narrow therapeutic index

• Antiepileptics: phenytoin, valproate

• Antibiotics: Aminoglycosides (amikacin, vancomycin)

• Immunosupressive drugs: cyclosporin

• Antiarrythmic drugs: digoxin

Indications for measuring blood levels

• to evaluate suspected toxicity

• to evaluate lack of therapeutic efficacy

• to monitor prophylactic therapy

• to guide dose adjustment

Antibiotics

Acetaminophen Intoxication

Pk Pd

Drug Interactions

• Pharmacokinetic Interaction

Absorption Interaction

Distribution Interaction

Metabolism Interaction

Excretion Interaction

• Pharmacodynamic Interaction: predictable, mechanism of drug

Drug-Drug Interactions

• Narrow therapeutic index: digoxin,theophylline

• High plasma protein binding: warfarin, NSAIDs

• Enzyme inducer or inhibitor

• Saturation kinetics: phenytoin, theophylline

• Long term used and accurate blood level: oral contraceptive drug, antiarrythmic drugs,antiepileptic drugs

Case Example

• ผ ปวยชายอาย 30 ป admit เพราะถกไฟไหมตามตวหลายต าแหนง

• ผ ปวยมโรคเดมเปนโรคลมชก รบประทานยา phenytoin เพอควบคมการชกอย 300 mg/day สามารถควบคมการชกไดด แพทยจงใหยานตอในขณะทอยในโรงพยาบาล

• ระหวางทอยในโรงพยาบาลผ ปวยมอาการเกรง กระตกทงตว เปนอย 2-3 นาท แลวหายไป

• แพทยสงวดระดบยา phenytoin ไดเทากบ 20 mg/L

Choice

a) เพมขนาดยาเพราะยงคมชกไมได

b) ให loading dose เพอคมอาการชกกอน แลวใหกนยาขนาดเดม

c) เปลยนยากนชกเปนชนดอน

d) ผดทกขอ

e) ไมร ถามคนอนดกวา

Dilantin level 20 mg/L

albumin = 4 mg/L

Dilantin level 20 mg/L

albumin = 2 mg/L

Albumin

Albumin

Case example

• ผ ปวยถกไฟไหม มระดบ albumin ในเลอดต า ผ ปวยรายนมระดบ albumin ต ากวาปกตไปประมาณครงหนง

• Phenytoin เปนยาทจบกบ albumin ไดด หาก albumin ต า จะท าใหม free form (active form) มากขน

• การวดระดบยาในเลอดเปน total concentration

(free form+bound form)

• ควรลดขนาดยา phenytoin ในผ ปวยรายน

Case 2• ผ ปวยชายอาย 65 ป

• อาการส าคญ คลนไสอาเจยนมาก เกรงกระตกทงตว ซมลง มา 1 ชวโมงกอนมาโรงพยาบาล

• ประวตปจจบน Underlying disease เปน COPD

• ยาทใชประจ า

o Berodual (fenoterol+ipratropium)2 puff prn for dyspnea

o Seretide(salmeterol+fluticasone) 2 puff bid

o Nuelin SR (theophylline) 1 tab bid

o NAC long 1 tab OD

Case 2

• ประวตปจจบน (ตอ)

• 5 วนกอน มไข เจบคอ ไอมเสมหะสเขยว ภรรยาไปซอยาจากรานขายยามาใหรบประทาน บอกวาเปนยาฆาเชอ กบยาแกไอ น ายามาใหดพบวาเปน Ciprofloxacin 5oo mg bid pc และ Bromhexine 1 tab tid pc

• ไมเคยมประวตชก เกรงกระตก หรอโรคทางสมองมากอน

Physical Examination and Labs

• ขณะแพทยก าลงตรวจรางกายม Generalized Tonic Clonic Seizure อก 1 ครง

• Pulse 130/min irregular, BP 110/75 mmHg

• EKG: Atrial fibrillation with rapid ventricular response rate 120-140 /min

• K+ 3.2 mmol/l

Theophylline level 24 mg/l (10-20)

Theophylline Toxicity

• Seizures

• Tachyarrhythmias

• Metabolic abnormalities: hypokalemia, hypomagnesemia, hypophosphatemia, hypercalcemia, hyperglycemia, and respiratory alkalosis

Theophylline and Ciprofloxacin

• Ciprofloxacin: inhibit both CYP1A2 and CYP3A4

• Decrease clearance of theophylline (30%)

• Increase plasma theophylline concentration (25%)

“Theophylline Toxicity”

Management

• Avoided in the elderly

• Avoided in acutely ill patients

• Monitored dosage and plasma level of theophylline closely

Documents

Pharmacokinetic, Pharmacodynamic and Clinical · PDF fileภาควิชาเภสัชวิทยา ... Pharmacokinetic process Conditions in which the plasma concentration