Basic Pharmacology

Eric Hodgson Addington Hospital March 2009

Drug Action Characterization

 Drug: Any chemical substance used for disease: diagnosis treatment prevention contraception  Action  Biochemical = chemical processes and transformations (oral hypoglycaemics)  Physiologic = N ormalisation of deranged body systems (anti-hypertensives)  Organ system = A ltering an organ system (anaesthetics)

Basic Pharmacology

Pharmacology: A science which studies the actions and uses of drugs in the therapy of diseases



Pharmacokinetics



Pharmacodynamics

Pharmacokinetics

What our body does to the drug ?

Pharmacodynamics

What the drug does to our body ?

General principles of drug action

Sites of drug action Local - Dermatological: - Antiseptic: – Lignocaine: - Capsaicin Systemic steroids; antimicrobials alcohol; chlorhexidine; povidone iodine infiltration / transdermal

General principles of drug action

Sites of drug action Systemic a.

b.

c.

Selective vs. General Midazolam (GABA agonist) vs (induction agent) Propofol Central vs. Peripheral Atropine vs. Glycopyrrolate Primary or direct vs. Secondary or indirect Digoxin → Congestive heart failure (CHF) → contractility ↑( direct ), → edema ↓( indirect )

General principles of drug action

Sites of drug action Systemic d.

e.

Immediate action vs. Late or delayed action Halothane → Anaesthesia ( early )

，

→ Hepatotoxicity ( late ) Therapeutic vs. Toxic Morphine → Analgesia Resp Depression Therapeutic index – Difference between Max therapeutic & Min Toxic level

Drugs Can Effect:

    

Synthesis of neurotransmitter

-e.g. B6 Cofactor

Storage of neurotransmitter

-e.g. Cocaine

Release of neurotransmitter

-e.g. Amphetamines

Reaction of Postsynaptic Receptor to neurotransmitter binding

-e.g. Phenylephrine

Reaction of Presynaptic Receptor to neurotransmitter binding

-e.g. Dexmedetomidine  

Metabolism of neurotransmitter

-e.g. Vigabatrin

Reuptake of neurotransmitter

-e.g. TCAs 

Metabolism of neurotransmitter -

Drugs can effect one or more process,

e.g. neostigmine

for one or more neurotransmitter

S

tructure-

A

ctivity

R

elationship



Structure activity relationship (SAR): A change in chemical structure of a drug may



or



: - Pharmacological (therapeutic or toxic) effects. Ether – Halothane – Isoflurane - Sevoflurane Metabolic conversion Cocaine – Lignocaine – Bupivacaine - Ropivacaine Isomerism

Isomers

http://www.frca.co.uk/SectionContents.aspx?sectionid=66  Compounds have similar atomic formulae  Different structural arrangement  Different pharmacological properties  Two broad categories of isomerism:  Structural isomerism 

Tautomerism

e.g. keto  enol forms  Stereoisomerism 

Geometric isomers



Optical isomers:



Chirality (r +/- / s +/-)

Clinical Selectivity :

Beneficial vs. Side effects or Toxic effects of drugs 1. Beneficial and toxic effects mediated by the same receptor-effector mechanism 2. Beneficial and toxic effects mediated by identical receptors but in different tissues or by different effector pathways 3. Beneficial and toxic effects mediated by different types of receptors Think isoproterenol and propranolol

Efficacy

  

Specificity



Binding UNAFFECTED by [drug] Selectivity



Binding DEPENDENT on [drug] Potency



Receptor binding



Agonist / Antagonist / Inverse Agonist



Synaptic effect



Strong vs. Weak



Agent specific

In Vitro Selectivity: COX-2/COX-1 Ratio lumiracoxib etoricoxib rofecoxib valdecoxib > 50-fold COX-2 selective etodolac nimesulide diclofenac celecoxib meloxicam 5- 50-fold COX-2 selective Warner et al. FASEB J. 2004:18:790-804 fenoprofen ibuprofen tolmetin naproxen < 5-fold COX-2 selective aspirin indomethacin ketoprofen ketorolac -3 -2 -1 0 1 2 3 Increasingly COX-2 Selective Increasingly COX-1 Selective Range of COX Selectivity for COX-1 and COX-2 (log 10 IC 50 COX-2/COX-1)

Selectivity vs. Potency

90 80 70 60 50 40 30 20 10 0 Ketorolac Diclofenac Meloxicam Celecoxib COX 1 COX 2

Ex vivo COX-1 and COX-2 Inhibition Etoricoxib vs. Plasma Concentration 100 80 PGE 2 TXB 2 60 40 Maximum celecoxib plasma concentration 20 COX-2 COX-1 0 –20 0.01

0.1

1 10 100 Plasma concentration of celecoxib (µM)

Drug actions and doses

1. Action vs. Effect / Response 2. Pharmacological effects & doses lethal toxic Therapeutic or medical dose [ max. effective min. effective Antibiotics & chemotherapeutic agents - Dangerous if subtherapeutic subtherapeutic

Dose-response relationship

a. Graded response b. All-or-none or quantal response Response= receptor activation L + R → LR Kd = [R][L] ──── [LR]



Efficacy



binding

  

affinity



effect efficacy, signal transduction



intrinsic acitivity maximal effect



Potency



ED 50



Potency



Efficacy

GABA

A

Receptor Interactions (2)

Benke, Dietmar. Molecular Pharmacology Notes. Signal Transduction Group, Dept. of Applied Biosciences University of Zurich. See www.unizh.ch/phar/ molneuro/benson/

GABA

A

Receptor Interactions (1)

Three drugs types that affect GABA receptor

Dr Peter Dodd, University of Queensland, © Trends Neurosci, see http://www.pr.mq.edu.au/macnews/sept01/apaf.htm

.



Efficacy : A=C=D>B



Potency : A>C>D>B

Definitions



ED 50 : median effective dose



TD 50 : median toxic dose (response = toxic)



LD 50 : median lethal dose (response = lethal)



Therapeutic index: TI = LD50 ─── or ED50 TD50 ─── ED50

Agonists and Antagonists



Agonists Full agonist Partial agonist - intrinsic activity =

１ －

intrinsic activity <

１

; > 0



Antagonists Antagonist



Inverse Agonists - intrinsic activity = 0 - intrinsic activity < 0; > -1

Agonists and Antagonists



Antagonists intrinsic activity =

０ 

Competitive antagonist



Agonist activity ~ [Agonist] vs. [Antagonist] Antagonist



agonist



ED 50

， 

E max

， 

Non-competitive antagonist Irreversible receptor inactivation Prior antagonist: Concurrent admin: No site for agonist to bind



Antagonist effect E.G. Aspirin vs. NSAIDs

Aspirin & Ibuprofen

Spare receptors

irreversible antagonist non-competitive antagonist agonist



ED50

， 

Emax Spare receptors: Max effect before full occupancy

Factors affect drug actions A. Potentiation Addition or summation Co-administration NO effect on activity e.g. Propofol + Thiopentone Synergism Co-administration



activity of each e.g. Fentanyl + Midazolam

Effect of Drug Combinations

 Pharmaceutical – Precipitation  Pharmacological - Absorption / Distribution - Receptor interaction - Excretion

Effect of Drug Combinations

Factors affect drug actions B. Antagonism:

  

Chemical e.g. tetracycline + cations, heparin+ protamine Physiological (Functional

）

e.g. caffeine + phenobarbital Pharmacological e.g. propranolol + epinephrine

2. Species and race Pharmacogenetics e.g. Morphine e.g. Codeine - cat (excitation) - dog (depression) – metaboliser status 3. Presence of diseases e.g. aspirin, diuretics

4. Sensitization Idiosyncrasy Hypersensitivity generic factor - NO Prior exposure Ag-Ab reaction (penicillin) - Prior exposure required 5. Desensitization, Tolerance

Desensitization, Tolerance Tachyphylaxis Phenylephrine Congenital G enetic Acquired Morphine, EtOH Cross tolerance – Habituation – EtOH vs. Propofol Caffeine / Cocaine Addiction EtOH – Opioids Cocaine / Amphetamine Physical and/or psychological dependence Withdrawal Pseudo-addiction

Basic Pharmacology Pharmacokinetics

 P harmaco k inetics (PK, ADME):

What the body does to drugs ?

A : absortption D : distribution M : metabolism E : excretion

pH of Selective Body Fluids

Effects of pH and pKa on the ionization and distribution of drug

因此，酸性物質在胃部易吸收，而鹼性物質在腸道較易吸收

II. Absorption, Distribution and Elimination

1. Absorption    Bioavailability Bioequivalency Dissolution rate

II. Absorption, Distribution and Elimination

1. Absorption   Routes of administration Enteral:Sublingual, Oral, Rectal Parenteral IV, IM, Subcutaneous, Inhalational, Epidural, Intrathecal Transnasal, Transdermal First-pass effect： hepatic metabolism pre-systemic elimination

2. Distribution  Lipid solubility：  Redistribution 

Blood flow

： 

Protein binding

：

acidic drug + albumin basic drug + α1 acid glycoprotein



Barriers

：

BBB Placenta

Compartments and volumes of body fluid: 

Major compartments:

Plasma 3 L Extracellular 14 L Total body water 45 L  Volume of distribution (Vd, 分佈體積) Vd = T / C T : amount of drug in the body C: concentration of drug in blood

e.g.: Warfarin 5 – 10 L Chloroquine and quinacrine 15,000 – 40,000 L

Basic Drug Metabolism

A. Liver clearance: metabolism

 Hepatic blood flow: 90 L/h (70Kg) 

First pass-effect:

Extraction ratio (E) = C in

–

C out / C in

B. Systemic clearance:

1.

2.

3.

4.

Renal Lung Breast milk Sweat, saliva, tears

Renal clearance

   Glomerular filtration : ml/kg min / 125 ml/min filtererd Tubular secretion : active transport;  bound and free drug Tubular reabsorption : passive diffusion GFR= 2 Molecules <15

Å

mainly Clr：clearance (volume of plasma cleared of drug per unit time; ml/min in unit) Rate of drug removal by the kidney (mg/min) Clr = ─────────────────── [drug] in the renal artery (mg/ml) Urine pH : can be adjusted by NaHCO 3 , or NH 4 Cl

1. Modes of drug metabolism in liver

Phase 1 : oxidation, reduction,

hydrolysis→ increased polarity, easy excretion in the urine



Aspirin (acetylsalicylate) → salicylic acid

Phase 2 : conjugation

→ usually increases water solubility after conjugation with glucuronic acid, sulfate, glutathione; but decreases water solubility after acetylation

1. Modes of drug metabolism in liver



Drug-metabolizing enzymes: Lipophilic membranes of the endoplasmic reticulum of liver and other tissues

。 

Microsomes: Above lamellar membranes are isolated by homogenation and fractionation of the cells, and the re-form into vesicles which contain rough and smooth surface endoplasmic reticulum

。 

Liver microsomal enzymes

Active metabolites and Prodrugs  Prodrug Gabapentin vs. Pregabalin  Toxic metabolites Paracetamol, Isoniazid

● ● Genetic polymorphisms of drug metabolism

3. Drug interaction

 Induction of metabolic enzymes： barbiturate, smoke ethanol,  Inhibition of metabolic enzymes：cimetidine, erythromycin, ketoconazole Clopidogrel Latest: PPIs and

4. Tissue other than liver

Reduction sulindac (prodrug) sulindac sulfide Oxidation (kidney) sulindac sulfide -- active COX inhibitor (for rheumatoid disease)

Factors modifying drug action Pharmacokinetics 7. Rate of excretion   Initial dose Maintenance dose digoxin antibiotics 8. PK effects in drug interaction a.

b.

c.

Plasma binding Liver microsomal enzyme induction or inhibition Drug absorption or excretion e.g.