General Pharmacology

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VETERINARY Veterinary pharmacology CLINICAL MEDICINE/ THERAPEUTICS Clinical pharmacology PSYCHOLOGY Psycho pharmacology PHARMACY Pharmaceutical sciences BIOTECHNOLOGY Biopharmaceutics Pharmakocinetics/ Drug Metabolism Biochemical Pharmacology

Molecular Pharmacology Medical pharmacology

Pharmacology
Chemotherapy

PATOLOGY Toxicology

Systems Pharmacology
Neuropharmacology Cardiovascular pharmacology Gastrointestinal pharmacology Immuno pharmacology Respiratory pharmacology

CHEMISTRY Chemistry

Pharmacogenetic GENETICS

Pharmacoeconomics HEALTH ECONOMICS

Pharmacogenomic GENOMIC

Ari Y - STF Bandung'13 Pharmacoepidemiology

CLINICAL EPIDEMOLOGY

Know the disease

Know the patient Know the drug

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Mechanism of Action Dose-response relationship relationship (how to (how adjust to adjust doses) doses) Sources of variability Sources pharmacokinetic of variability pharmacodynamic pharmacokinetic Know the drug pharmacodynamic Expected effects Expected beneficial effects adverse beneficial adverse Drug interaction
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GENERAL PHARMACOLOGY

Pharmacokinetics Pharmacodynamics
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Pharmacology
Pharmacokinetics Pengaruh tubuh thd obat
Drug

Pharmacodynamics Pengaruh obat thd tubuh

Drug

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Pharmacokinetics
Qualitative Absorption Distribution Metabolism Elimination Quantitative Pharmacokinetics parameter (T , Vd, Cl, AUC)

Therapeutic Drug Monitoring

Drug Drug Interactions
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PK PD Model

Pharmacodynamics

Type of Pharmacology effects Receptor Concepts Drug Mechanisms Dose response relationships

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General Pharmacology Pharmacokinetics

Pharmadynamics

The Right drug The Right patient The Right dose

The Right time

The Right Response
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Administered dose

Phases of Drug Activity- Medication errors

- Patient compliance Absorption

Pharmaceutics Phase Disintegration - Dissolution

Pharmacokinetics Phase

Distribution Metabolism

- Sources of

Elimination

individual variation - Drug interactions

Pharmacodynamics Phase Drug Recept. interaction Genetics,

Pharmacotherapy Phase

Pharmacology Effect

Physiology, Pathophysiology

Therapy Effect Side Effect

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Toxic Effect

Steps in appearance of intact drug in circulation

pH = 1 - 3
dissolution disintegration absorption

Pharmacological effect

hepatic metabolism

gastric emptying rate

pH = 5 - 7
intestinal transit rate
dissolution
intestinal metabolism

disintegration

absorption

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faeces

clearance

Basic Process of Pharmacokinetics

Absorption
Distribution Site of Action liver

GIT

Metabolism

blood
Another Route

kidney Excretion
Tissues

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Absorption Process
Biotransport Mechanism pH Partition Theory Route of Administration First Pass Effects (FPE) Bioavaibility Other factors
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Biotransport
External Barrier (Outer systemic) Blood Tissue Barrier (Blood / plasma tissue / organ) - General - Specific : Blood Brain Barrier Blood CFS Barrier Blood Placenta Barrier Blood Ocular Barrier Blood Testis Barrier
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Drug Biotransport
Molecule weight & chirality lipophilicity Ionic status

Vascular System
DRUG

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Schematic diagram of membrane

Lattice of protein
Inner lipoidal matrix

Hydrophilic tail

Hydrophobic head Lattice of protein

Aqueous pores
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Biotransport
passive diffusion
carrier-mediated transport

Active
ATP ADP-Pi

Facilitated

endocytosis

Transporter
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Aqueous channels

Biotransport Mechanisms
Passive diffusion (Most common of drugs) Concentration gradient Only for unionized form (lipid soluble) Didnt need energy Facilitated transport (e.g. Vit. B12, Cephalosporins)
- Blood brain barrier, renal tubule Active transport (e.g., 5-fluorouracil) - Neuron,choroid plexus, renal tubule, hepatocytes Pinocytosis (up take thyroglobuline oleh thyroid follicular cell) Aqueous channels (ion- ion)
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Properties of facilitated diffusion & active transport Membutuhkan carrier Transport menjadi jenuh (saturated) pada konsentrasi tinggi Proses selektif Dua obat yang ditranspor oleh mekanisme yg sama akan menghambat satu sama lain Melawan concentration gradient ( active transport) Tdk melawan cocentration gradient ( facilitated transport) Memerlukan energy Mekanisme transport dapat dihambat oleh obat obat yang mempengaruhi cellular Ari Y - STF Bandung'13 metabolism

Anti Transporters

P-Glycoprotein (Pgp)

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ATP-dependent drug efflux pump Broad substrate specificity for drugs: Digoxin, quinadine, and others Coded by MDR-1 gene: Induced by rifampin Inhibited by verapamil, quinidine, macrolides, antifungals, etc Expressed on some cells like CYP3A: Intestine: influence of absorption Liver: biotransformation Kidney: drug excretion Brain: distribution

pH Partition Theory
Weak Acid : HA H+ + AHenderson-Hasselbach Equation : pH = pK + Log10[A-]/[HA]
Weak Base :BH+ B + H+ Henderson-Hasselbach Equation : pH = pK + Log10[B]/[BH+]
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 Obat obat merupakan asam lemah atau basa lemah aspirin, barbiturates (acid) : propranolol, opioids (base)

Ion Trapping /Ph-Partition - Theory

Asam lemah : HA==H+ + APersamaan Henderson-Hasselbach : pH = pK + Log10[A-]/[HA] Basa lemah :BH+ ==B + H+ Persamaan Henderson-Hasselbach : pH = pK + Log10[B]/[BH+] pKa dari suatu obat : pH obat dlm bentuk 50% ionised dan 50% unionised aspirin (pKa=3.5 ):pada pH =3.5 50% U/I propranolol (pKa= 9.4) : pada pH = 9.4 50% U/I Makin asam pH makin banyak obat asam dlm bentuk unionized, dsb untuk obat basa Unionized fraction : lipid soluble dan mudah menembus cell membranes. Ionized fraction : lipid insoluble dan sulit menembus membran
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Weak Acid
H+

Weak Base
H+ B BH+

HA

A-

AHA B BH+ H+

H+

ionized = polar = water soluble Ari Y - STF= Bandung'13 non-ionized = nonpolar more lipid-soluble

Route of Administration

ENTERAL
Oral

PARENTERAL
Intravenous (IV) Intra-arterial (IA) Subcutaneous (SC) Intradermal (ID) Intramuscular (IM) Intraperitoneal (IP) Lungs (Inhalation) Skin (Topical)
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Sublingual
Rectal

Nose (Intranasal) Eye (Opthalmic) Ear (Otic) Vagina Urethra Urinary Bladder Intrathecal Epidural Directly Into Target Tissue

Route of Administration (general)

Parenteral (IV)
Inhaled Oral

Transdermal
Parenteral (SC, IM) Rectal

Topical

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First-Pass Effect (FPE)

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First-pass Effect
Pada beberapa obat menyebabkan tidak efektif bila digunakan peroral Dosis obat p.o lebih besar dari dosis i.v Bila obat dimetabolisme menjadi bentuk aktif,menyebabkan kumulatif dari metabolit
Dipilihkan rute pemberian lainnya (misalnya, IV atau intramuscular injection) Diberikan dosis oral permulaan yang tinggi ( loading) dengan tujuan menjenuhkan liver enzymes
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Bioavailability
AUC: Area Under Curve
Bioavailability = (AUC oral/AUC iv) x 100 IV Dose

Drug Concent. On plasma (mcg/ml)

Oral Dose

Dose

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Time (hours)

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Plasma Level vs Time Plots

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Other Factors
Kecepatan pelepasan obat dari sediaan Ukuran dan bentuk molekul (BM dan chirality) Permeabilitas membran dari obat Kelarutan dlm lipid lipophilicity/hydrophobicity) Koefisien partisi Keadaan ionisasi Luas permukaan absorpsi Aliran darah menuju tempat pengabsorpsian Kerusakan obat pada/dekat tempat pengabsorpsian Ikatan obat dengan protein
Ari Y - STF Bandung'13