Dwi Indria Anggraini1; Rovina Ruslami2

Definitions

Pharmacology • Pharmacokinetic

• Pharmacodynamic

Pharmacy

Pharmacognosy

Clinical Pharmacolog

y

PharmacogeneticPharmacotherapeuti

cPharmacoeconomic

In order to work adequate conc. in target tissues.Two important process:

A. translocation of drug moleculesAbsorption and distribution of drugs

B. chemical transformation Metabolism and excretion

Pharmacokinetics• The study of absorption, distributions, biotransformation and

excretion of drugs• What the body do to the drugs• Involved in how the concentration of drug in the body varies

with time

A. Translocation of drug molecules How the drugs cell membranes? 1. Diffuse directly

through the lipid (passive diffusion)

2. Carrier-mediated3. Diffuse through

aqueous channel (aquaporins)

4. Pynocytosis

1. Passive diffusion through the lipid Along a gradient concentration main factor influenced: lipid solubility

• Weak acid drugs (aspirin) needs alkaline pH to ionized absorbed• Weak base drugs (pethidine) need acid pH to ionized absorbed

2. Carrier-mediated• In renal tubule, BBB, PBB, GIT epithellium

• ! For drugs that chemically related to the endogenous substance (exp: amino acid, sugar, metal ions, neurotransmitter)a. Facilitated diffusion

does not need energyb. Active transport

against e-chemical gradient

* P-glycoprotein

4. Pynocytosis• Membrane permeation

• ! For drugs with large molecules

Then…Translocation to the blood transport of drugs in the bloodIssues:

1. Binding to plasma protein2. Partition into body fat and other tissues

> lipid:water partition

exp: morphine (l:w p 0.4) but thiopental (l:w p 1)> accumulation of drugs in fat (chronic use of BZD)

Binding of drugs to plasma protein

only free drugs is pharmacologically active (it can be only 1%)

albumin is the most important; there’s also -globulin• acidic and hydrophobic drugs to albumin• basic drugs to -globulin and 1-acid glycoprotein• neutral and hydrophyllic drugs not to albumin

the binding is reversible non selective competition drug interaction

of drugs that’s bound to protein depend on:• conc. of free drug• affinity to the binding sites• conc. of protein

Binding of drugs to plasma protein

Drug disposition4 stages:1.Absorption from site of administration2.Distribution within the body3.Metabolism4.excretion

Route of drug administration

Drug absorption Transport of the drug from site of administration to the plasma/circulation

• is depend on route of administration• iv : 100% absorption (others: < 100% absorption)

• most of drugs are taken per orally absorption is mainly in the small intestine

Route of administration• enteral (GIT)

• oral, sublingual, per rectal (suppositoria)• parenteral

• iv, im, sc, • when?

• need immediate effect• unconsciousness• can’t be given enterally

• others• inhalation, transdermal, topical

1. Oral administration1. Oral administration• Drug absorption from intestine

• Mechanism = as mentioned previously• Acids will be better absorbed in alkaline pH• Base will be better absorbed in acid pH

• Factors affecting GI absorption• Surface area (more in intestine)• GI motility – some drugs affect this also!• Food intake can alter absorption (delayed to intestine)• Blood flow• Particle size and formulation (exp: capsule, tablet, enteric

coated, slow-release)• Physicochemical factors

• Bioavailability – affected by first-pass metabolism

2. Sublingual administration2. Sublingual administration• To prevent first-pass metabolism

• Higher Bioavailability• Higher efficacy• Exp: ISDN

3. Rectal administration3. Rectal administration• Aim:

• Local effect• Systemic effect but

• Unable to swallow the drug (vomit, post operative)

• Difficult for iv (diazepam supp in children)• Avoid GI irritating

• 50% of drugs will by pass the liver(<< FPM)

Per oral • Most common, cheapest, safest• Absorption varies - factors in stomach and intestine (surface for absorption in duodenum)

Sub lingual

• Underneath the tongue• Directly to systemic circulation (no first past metabolism)

Per rectal • 50% of drugs by pass the liver (<< metabolized)• << degradation due to gastric pH, gastric enzymes• BUT absorption is irregular, not complete• Sometimes irritating

IV • most common parenteral• fastest OOA (100% Bioavailability)• BUT with AEs

IM • as a depo slow release to systemic circ.• OOA is faster than per oral• larger volume

SC • just like IM, but with smaller volume• OOA is faster than per oral

Administration by injectionAdministration by injection

Inhalation • aerosol, directly goes to alveoli• OOA is same like IV

Topical • local effect to the skin, eye, nose, ear and vagina

Transdermal

• topical on the skin that has a systemic effect (slow release)

Intra techal

• for drugs that can’t pass BBB• give into subarachnoid space

Other administrationOther administration

Bioavailability Bioequivalence

Th/-equivalence1.Bioavailability (BA)

• % of the administrated drugs reaches systemic circulation (in a chemically unchanged form)

• Absolute BA = AUC oral/AUC iv

2.Bioequivalence (BE)• 2 related drugs with comparable BA (under same conditions)

• BIE : 2 related drugs with incomparable BA

3.Th/-equivalence (TE)• 2 similar drugs with comparable efficacy and safety

Drug distribution

Drugs leave the circulation and enter the interstitium (ECF/interstitial fluid) & / cells of tissue.

It is depend on:• blood flow (fast and slow)• permeability

• capillary structure (barrier)• drug structure (lipo/hydro-phylic)

• binding drugs to protein• brain, liver, kidney receive most of the drugs

…Until conc. in tissues is in equilibrium with that in the blood

Body fluid compartment

Drug molecules (bound & free drugs) exist in each compartment BUT ONLY free drugs can move between the compartments

Relative size of VD (BW = 70 kg)

42 L

65% (28 L)

35% (14 L)

10% (4 L)

25% (10 L)

The equilibrium depends on:1.Permeability across tissue barriers2.Binding within compartment3.pH partition4.Lipid : water partition

Volume of distribution

volume of plasma that would contain the total body

content of the drug at the equal conc. to that in plasma.

Implication of Vd:• >> in the plasma.• & hydrophillic >> to ECF (through endothelial slit junctions)

• & hydrophobic >> to ECF(through cell membranes)

• pts with edema Vd (heart, renal, liver failure)• drugs stored in fat Vd (thiopental)

IntroductionDrug elimination:

Irreversible loss of drug from the body- metabolism (involve enzymic conversion)- excretion (unchanged/metabolites)

Main routes:• Kidneys• Hepatobiliary system• Lungs (anesthetic drugs)

Small amounts: saliva, sweat, milk (! Effect to the baby)

Drug Metabolism (= biotransformation)

• lipophilic drug can’t be excreted by kidney they has to be

transformed into more polar OR conjugated drugs• phase I• phase II

• phase I : lipophilic mol more polar (catabolic reaction)• oxidation/reduction/hydrolysis• pharmacologic activity: / / / become toxic / carcinogenic• involving P-450 system (superfamily enzymes)• some drugs inhibits or induce P-450 system !!!

Drug Metabolism (= biotransformation)

• phase II : lipophilic mol conjugated hydrophilic (anabolic)

• conjugation; glucoronidation

• pharmacologic activity: inactive

• involving glucoronic acid, etc

• so…polar or conjugated drugs hydrophylic can pass

the kidney

Factors influence drug metabolism

1. Liver disease2. Genetic abnormality3. Age (pediatric, geriatric patients)4. Gender5. Drug interaction6. Environment

Drug Excretion (= elimination) …via kidney

• Three renal processes involved:• glomerular filtration (GF) 20% are filtered• active tubular secretion • passive diffusion

• Keys:• most drugs, unless highly protein bound, cross GF freely• weak acid/base drugs are actively secreted into renal tubules rapidly excreted• lipid-soluble drugs are passively reabsorbed not efficiently excreted in the urine• acid drugs are excreted better in alkaline urine and

Renal clearance Volume of plasma containing the drug that is removed by kidney in unit time (= xx ml/min)

It is decreased in:• elderly• acute illness• renal impairment

Implication: increased toxicity; lowering the dose

Biliary excretion (& Entero-hepatic circulation)

Drugs is excreted in: Unchanged/ active-metabolites/ inactive

formsHydrophilic conjugated drug (glucoronides) bile intestine hydrolised (active drug once more; reabsorbed (20%): enterohepatic circulation) kidney

So…..

Relationship between time course of drug conc. attained in different regions of body during and after dosing is called by…PHARMACOKINETICS (PK)

Pharmacokinetics• The study of absorption, distributions, biotransformation and

excretion of drugs• What the body do to the drugs• Involved in how the concentration of drug in the body varies

with time

…….Clinical Pharmacokinetics

Time

[drug] Cmax peak effect

AUC

tmax

Th/ window

MEC for desired response

MEC for unwanted response

DOA

OOA

Single compartment model

• T ½ : time needed to lessen the drug conc. becomes 50%

Plasma conc.

Drug excreted

Effect of repeated dose

• there will be a steady-state conc. • it takes about 3-5 x T ½

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