(341334)

1
. .

(pharmacology) pharmakon logia

(molecular mechanisms)
2 (pharmacokinetics)
(pharmacodymanics) 1

(absorption)
(distribution) (metabolism) (excretion)

(onset) (duration of action)

1

(Toxicology)

 (Pharmacotherapeutic) clinical pharmacology

(Drugs, Medication)

.. 2510

(1)
(2)

(3)

(4)

(1) (2) (4)

()
()

()

(Pharmacopoeia)
(medical substances) (quality specifications)
(descriptions) (method of testing) (legal
standards ofpurity) (quality and strength)
/

1. (Thai Pharmacopoeia: TP)

2. (International Pharmacopoeia: IP)
3. (The United StatesPharmacopoeia: USP)
4. (Bitrish Pharmacopoeia: BP)
5. (European Pharmacopoeia: PhEur)
6. (The Pharmacopoeia of Japan)

 4
4
1. Chemical name

N-acetyl-p-aminophenol
2. Generic name
INN
(International nonproprietary name) paracetamol
3. Trade name, Brand name, Registered name

Tylenol, Paracet, Paracap

4. Official name
Acetaminophen USP
Acetaminophen BP

(Dosage Form of Pharmaceutical preparations)

(Pharmaceutical preparations, Pharmaceutical products)
(dosage form)
2 (active ingredients)
(adjuncts)

1.
2.
3.
4.


4 (liquid
dosage forms) (semi-solid dosage forms) (solid dosage forms) (miscellaneous)

1. (Syrups)
sorbitol


2. (Elixirs)
3 5% 21 23%

3. (Suspensions)

colloid
(gels)

4. (Emulsions)
(emulsifying agents)
oil in water O/W emulsion
water in oil, W/O emulsion -

1. (Tablets)



7



(sugar coated tablets)

(film coated tablets)
(enteric

coated tablets)

(Sublingual tablets)

(Chewable tablets)
(Effervescent
tablets)
(sodium bicarbonate)

(citric acid) (tartaric acid)

(Subtended released tablets)

3
Immediate release
(disintegrating tablets)
(chewable tablets) (effervescent tablets) (sublingual tablets)
(buccal tablets)
Extended release
(zero order release)
Delayed release

immediate release enteric coated tablets
2. (Capsules) (solid dosage forms)
(gelatin)
2
(Hard gelatin capsules) 2

(powders) (antibiotics) amoxicillin
(Soft gelatin capsules)
(hermatic sealed)
(fish liver oil)


1. Ointments Pastes (base)

pastes
2. Creams


3. Gels polymer

4. Suppositories
2

1. (Skin patches)
(rate
controlling membrane)

2. Aerosols


(nasal spray)
butorphanol

(Drug Administration)

1. Enteral administration
Oral route
mucous membrane




Sublingual route Buccal route

6



nitroglycerin

Suppository route

50%
rectal mucosa

2. Parenteral administration

(Intravenous route)




(Intramuscular route)



2 10
(Subcutaneous or hypodermic route)
0.5 2


adrenaline
3. Transdermal administration

(systemic effects) nitroglycerin

4. Inhalation administration

5. Topical administration
(mucosal surface)
(local effects)

steroids

(Pharmacokinetics)

(absorption) (site of administration)
(distribution) (metabolism
biotransformation) (excretion) 2


1. (drug absorption)


(unionized form)
(pKa)

2. (Distribution of drug)
intracellular fluid interstitial fluid
(well perfused organs)

(free drug)
free drug

free drug


(half-life)

3. (biotransformation metabolism)


free
drug (tubular reabsorption)

3.1

1. (active form) (inactive form)

lorazepam lorazepam glucuronide
2.
3. metabolite diazepam
oxazepam
4.

3.2 2 (Phase)
Phase I (parent drug) metabolites
phase I oxidation, hydrolysis, epoxidation, aliphatic
(aromatic) hydroxylations, dealkylation, deamination
Phase II (conjugation reaction)
functional group glucuronic acid, glutathione, sulfate, amino acid acetate functional group
phase II metabolites

2 2
phase I phase II phase II phase I
3.3
enzyme

3.4 Cytochrome P450 monooxygenase enzyme

oxidation phase I

CYP 450 (gene) 12
CYP3, CYP2 CYP1 subtype CYP3A4
3.5 (enzyme induction and inhibition)
CPY 450 (enzyme
induction) subtype
subtype metabolite
(active form) rifampicin
CYP 3A4 phenytoin
phenytoin

(metabolites)
10

3.6

propanolol

4. (excretion of drug)
(metabolize)

() ()
4.1 (Renal excretion)

1. (glomerular filtration) arterial bowmans capsule

5,000 glomerular
free drug
2. (active tubular secretion) metabolites 80
efferent arterioles peritubular capillaries proximal
convoluted tubule metabolites proximal convoluted tubule
3. (passive tubular reabsorption) proximal distal
tubule
(excretion)
aspirin pKa 3.4 pH 6.4
1,000:1 pH 8.4 100,000:1
aspirin
4.2 (bile and feces excretion)
phase II
(duration)

A 10 mg/L 2 5 mg/L A 2 2
A 50
4.3
(glomerular filtration rate: GFR)
creatinine clearance

11

 (pharmacodynamics)
(pharmacodynamics)

1. (Mechanism of drug action)

(receptor) receptor
2

1.1 non receptor-mediated action
receptor

surface active agent
mineral oil activated carbon
toxin
-

(inactivation) (alteration of pH)

(alteration of body fluid chemistry) chelation
1.2 receptor-mediated action
Receptor endogenous substances hormones,
growth factors, (neurotransmitters), autacoids cytokines receptor
(recognize)

receptor receptor
receptor receptor
receptor

12

 3 receptors ligands
receptor receptor (effecter
protein) (intermediated) second messenger second
messenger receptor effecter system signal transduction pathway
1 receptor
Receptor
Cholinergic receptor
Muscarinic receptor
(subtypes M1, M2, M3, M4, M5)
Nicotinic receptor (subtypes Nn)
Nicotinic receptor (subtypes Nm)
Adrenergic
1
2
1
2
3
Histamine
H1
H2

, ,

Lypolysis

HCl parietal gland

2. receptor
Receptor 4
2.1 Protein synthesis regulating receptor
Receptor receptor (cytosol) (nucleus)
(regulate gene transcription) receptor

13

 receptor (steroid) (thyroid hormone) receptor

4

4 steroids receptor
2.2 G protein coupled receptor
receptor guanine nucleotide binding protein (G protein) G protein
transducer effecter proteins adenylatecyclase, phospholipase C plasma
membrane ion channel selective to Ca2+ K+, receptor
helix 7 receptor 2
N-terminal cell membrane C-terminal
G protein 3 units , subunit
receptor G protein
receptor receptor effecter
5

5 G protein coupled receptor

14

2.3 Ligand gate ion channel

Receptor ion channel (ion)
receptor nicotinic acetylcholine receptor motor end plate, GABAA receptor gammaaminobutyric receptors glutamate, aspartate glycine
nicotinic acetylcholine receptor 5 subunits (2 subunits, , subunits)
6 nicotinic receptor ion channel Na+
K+ membrane depolarization action potential

6 nicotinic receptor
2.4 Ligand regulated enzyme
receptor receptor receptor
insulin ( 7) insulin receptor receptor conformation
tyrosine kinase enzyme phosphate tyrosine residue
protein

7 insulin receptor

15

3. Regulation of receptors
receptor 3
1. Agonist receptor receptor

2. Partial agonist receptor receptor

partial agonist agonist
3. Antagonist receptor receptor
agonist
agonist
neurotransmitters hormone
antagonist
receptor

4.
tolerance

drug resistance (antimicrobial drugs)
(antitumor drugs)

1. change in receptors receptor
neuromuscular junction receptor agonist receptor
ion channel phosphate
receptor agonist
2. loss of receptors agonist
receptor agonist
neurotransmitter hormone receptor
receptor receptor
3. exhaustion of mediator mediators
amphetamine noradrenerline amine
amphetamine

4. increased metabolic degradation

barbiturates

5. physiological adaptation
thiazide

16

 rennin angiotensin

6. active extrusion of drug from cells
tetracyclines

5.
Onset of action
onset onset

Duration of action duration
duration
Onset of action, peak effect duration of action
diazepam 3
3 pharmacodynamics of diazepam (for sedation)
route
onset of action
peak effect
Oral
30-60 minutes
1-2 hours
Intramuscular
Within 20 minutes
30-90 minutes
Intravenous
1-5 minutes
15-30 minutes

duration of action
Up to 24 hours
Unknown
15-60 minutes

6. Therapeutic index
Therapeutic index (TI)
therapeutic index
therapeutic index

Therapeutic index = LD50 / EC50

(drug interactions)
(drug interactions)

object drug precipitant drug
(pharmacokinetic interactions)
(pharmacodynamic interactions)

17

 27.9

1. (Pharmacokinetic interactions)
(absorption
interaction) (distribution interaction) (metabolism interaction)
(elimination interaction)
(absorption interaction)
(therapeutic level)

cholinergic atropine opiates morphine, codeine


1)
(insoluble complexes) Ca2+, Fe2+ divalentcation
tetracycline 2) pH ketoconazole pH
antacid
(distribution interaction)
(protein binding/ displacement interaction)
(cellular displacement interaction)
(free drug)


2
warfarin NSAIDs (anticoagulation) warfarin
4
quinidine, verapamil amiodarone digoxin digoxin
guanethidine tricyclic antidepressants
(metabolism interactions)
metabolism mixed-function oxidase system cytochrome P450 system (CYP P450) hepatic metabolism enzyme inducers
CYP450 isoenzyme
hepatic metabolism
enzyme inhibitors
enzyme
inducers enzyme inhibitors isoenzyme ( 5)

18

 4 (plasma protein
binding displacement)

warfarin
phenylbutazone

clofibrate

chloral hydrate

sulphamethoxazole

sulphinpyrazone

Chlorpopamide
Sulphaphenazole

Dicoumarol

Methotrexate
Salicylate

Phenytoin
Valproate

(elimination interactions)
glomerular filtration rate (GFR), tubular secretion
penicillin, zidovudir probenecid pH
pH
(tubular reabsorption) thiazide lithium lithium lithium
2. (Pharmacodynamic interactions)

2

Antagonistic effects -adrenergic

receptor antagonist theophylline
naloxone opiate analgesics
Additive effects
(additive side effects)
diazepam chloral hydrate
3. (Pharmaceutical interactions)
2 (incompatibility)
epinephrine, erythromycin glucoceptate
cephalothin sodium phenytoin pH

19

 5 CYP450

Isozyme
Substrate
Inhibitors
Inducers
CYP1A2
acetaminophen,
cimetidine,
barbiturates,
caffeine,clozapine,
ciprofloxacin,
cigarettes,
amitriptyline,
diltiazem, enoxacin,
rifampin
tacrine,theophylline
fluvoxamine,tacrine
CYP2C9
fluvastatin, ibuprofen,
amiodarone,
barbiturates,
glipzide, losartan,
cimetidine,
phenytoin,
phenytoin, rosiglitazone,
fluconazole, isoniazid, rifampin
tolbutamine
metronidazole,
sulfamethoxazole
CYP2C19
diazepam, citalopram,
esomeprazole,
barbiturates,
esomeprazole,
fluconazole,
phenytoin,
lansoprazole,
fluoxetine,
rifampin
sertraline
fluvoxamine,
omeprazole
CYP2D6
amitriptyline,
amiodarone,
rifampin
codeine,desipramine,
fluoxetine,
dextromethorphan,
haloperidol,
flecainide,haloperidol,
paroxetine,
imipramine,metoprolol,
propoxyphene,
nortriptyline,paroxetine,
quinidine,
propranolol,thioridazine,
terbinafine,
timolol
thioridazine
CYP3A4
Amiodarone, alprazolam, Clarithromycin,
Barbiturates,
buspirone, cisapride,
troleandomycin,
carbamazepine,
cyclosporin, diltiazem,
cyclosporin,
griseofulvin,
erythromycin, felodipine,
erythromycin,
phenytoin,
indinavir, lovastatin,
grapefruit juice
rifampin, St Johns
midazolam, nifedipine,
wort
pioglitazone, quinidine,
ritonavir, sertraline,
sildenafil,simvastatin,
warfarin, tacrolimus,
triazolam, verapamil,
zolpidem

20

4. (combined toxicity)
2

1.
apothecaries
avoirdupois (household measure) (metric system)
6
6

Exact equivalent

1
5 mL
1
15 mL
1 fliudounce
29.6 mL
1 gallon
3,785 mL

1 grain (gr)
64.8 mg (65 mg)
1 ounce (oz)
28.35 g
1 pound (Ib)
avoirdupois
454 g
apothecaries
373.2 g
2.2 pounds (Ibs)
1 kg

Approximate equivalent

30 mL

60 mg
30 g

2.
1. (body surface area, BSA)

= x

21


(m2) = (kg)0.425x (cm) 0.725 x 0.007184

(m2) =

(kg) x (cm)
3,600

2.

= (kg) x

3.


(adult dose)

4
3.1. Frieds rule 2
=

() x
150

3.2 Youngs rule 2 12

() x
[ () + 12]

3.3 Clarks rule (lb)

22

()x
150

3.4 Square meter surface area method

(nomogram) 8
=

() x
()

1.73
=

() x
1.73

(intravenous infusion)
100

1. Isotonic solution (osmotic pressure)

0.9% (normal saline 0.9%, NSS) 5% (5% dextrose in water, D5W)
lactated ringers solutions
2. Hypotonic solution
0.45%
3. Hypertonic solution dextrose 5%
in NSS, dextrose 10% in NSS dextrose 5% in 1/2 strength saline

23

 8 Nomogram nomogram
(BSA)

3
2 500 1000 ( 9)

24


1
1 10, 15 20 ( 10)

Bag spike
Drip chamber
Needle end
Injection port

Roller clamp

10

/ =

( ) x 1
()

1000 8 1
10

(/) =
1,000 x 10 /
480
=
20 /

25

 D5W 1,000 10
15 1

15 /1
D5W 1 ml
=
15 drops
D5W 1,000 ml
=
(15 drops x 1,000 ml) / 1 ml
=
15,000 drops
10
600
600 D5W 15,000 drops
1 D5W
=
(15,000 drops x 1 min) / 600 min
=
25 drops/min

(Microdrops)

/ / /
1 60 1 / 1 /
dopamine (2:1000) i.v. 30 microdrops/min 65
dopamine //

dopamine 2:1000 dopamine 1000 dopamine 2

30 microdrops/min= 30 microdrops/hr
dopamine (2:1000) i.v. 30 microdrops/min dopamine = 2 x30 .
1000
= 60 /
= 1000 /
65 dopamine 15.4 //

(References)
1. , , .
1. : ; 2544. . 69-90.
2. . . : , .
1. : ; 2546. . 1-24.
3. . Overlapping paradigms between drug interaction and adverse drug
reactions. : , , , ,
, , , . Review and update on drug interactions.
: ; 2553. 1-7.
26

4. . III : . :
. . . :
; 2552. 647-56.
5. . Cytochrome P450.: , , ,
, , , , . Review and
update on drug interactions. : ; 2553.
6. Katzung BG, Masters SB, Trevor AJ, editors. Basic and clinical pharmacology. 11th ed. Boston:
McGraw-Hill; 2009.
7. Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G. Rang and Dales pharmacology. 7th ed.
Edinburge: Eleservier, 2007.
8. Brunton LL and Parker K, editors. Goodman and Gilmans manual of pharmacology and
therapeytics; New York: McGrawHill. 2008.
9. Claton BD, Stook YN, and Harroun RD. Basic pharmacology for nurse. Missouri: Mosby Elsevier.
2007.
10. Brenner GM, Stevens CW. Pharmacology. 3rd ed. Philadelphia: Saunders, 2009.
11. Lullmann H, Mohr K, Hein L, and Bieger D. Color atlas of pharmacology. New York: Thieme. 2005.
12. Dal MM, Haylett DG. Pharmacology condense. Scotland: Churchill Livingstone. 2005.
13. Hansten PD, Horn JR. Drug interactions analysis and management. Missouri: Wolters Kluwer
Health; 2007.
14. Mandell GL, Dolin R, Bennetts JE. Principle and practice of infectious disease. 7th ed.
Philadelphia: Churchill Livingstone Elsevier:2010.
15. Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM. Pharmacotherapy: a pathological
approach. 8th ed. New York: McGraw Hill: 2011.
16. Finkel R, Clark MA, Cubeddu LX. Pharmacology.4th ed. Place unknown: Lippincott Williams &
Wilkins: 2009.
17. Janchawee B, Wongpoowarak W, Owatranporn T, Chogsuvivatwong V. Pharmacoepidemo-logic
study of potential drug interactions in outpatients of a university hospital in Thailand. J Clin
Pharm Ther. 2005;30:13-20.
18. Neto PRO, Nobili A, Marusic S, Pilger D, Guidoni CM, Baldoni AO, et al. Prevalence and predictors
of potential drug-drug interactions in the elderly: a cross-sectional study in the Brazilian primary
public health system. J Pharm Pharmaceut Sci. 2012;15(2):344 54.
19. Rolan PE. Plasma protein binding displacement interactions-why are they still regarded as
clinically important?. Br J Clin Pharmac. 1994;37:125-8.
20. Byrne BE. Drug interactions: a review and update. Endodontic Topics. 2003;4: 921.

27