Absorption Of Drugs

Pharmacokinetics Definition -Pharmacokinetics (in Greek: 〝 pharmacon 〞 meaning drug and 〝 kinetikos 〞 meaning putting in motion , the study of time dependency) is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. -Pharmacokinetics is the study and characterization of the time course of drug absorption, distribution, metabolism and excretion. This sometimes is referred to as the ADME scheme. - Pharmacokinetics also concerns the relationship of the processes to the intensity and time course of therapeutic and toxicologic effects of drugs.

Pharmacokinetics (ADME)

Measurement of drug concentration 1.Sampling of biological speciments --Invasive methods: Blood, spinal fluid, tissue biopsy. --Non-invasive methods: Urine, salive, feces, expired air ★Measurement of drug concentration in the blood, serum or plasma is the most direct approach to assess the pharmacokinetics of drug in body.

2.Significance of measuring plasma drug concentration ★The intensity of the pharmacologic or toxic effect of a drug is often related to the concentration of the drug at the receptor sites. ★Monitoring the concentration of drugs in the blood or plasma ascertains that the calculated dose actually delivers the plasma level required for therapeutic effect.

Plasma level-time curve ★The plasma level-time curve is generated by measuring the drug concentration in plasma samples taken at various time intervals after a drug product is administered.

MTC Therapeutic range

Intensity MEC

Duration Onset time MEC=Minimum Effective Concentration MTC=Maximum Toxic Concentration

concentration

Time to Peak Concentration 100 90 80 70 60 50 40 30 20 10 0

IV Oral Rectal

0

5

10

20

30

minutes

60

120

180

Pharmacokinetic models ★Drugs are in a dynamic state with the body. ★Various mathematical models can be devised to stimulate the rate processes of drug absorption, distribution and elimination. These mathematical models make possible the development of equations to describe drug concentrations in the body as a function of time. ★Pharmacokinetic models are useful to: 1.predict plasma, tissue and urine drug levels with dosage regimen. 2.calculate the optimum dosage regimen for each patient individually. 3.estimate the possible accumulation of drug and/or metabolites. 4.correlate drug concentration with pharmacologic or toxiciologic activity. 5.evaluate differences in the rate or extent of availability between formulations. 6.describe how changes in physiology or disease affect the absorption.

Absorption (of drugs) ★Definition -The process of uptake of the compound from the site of administration into the systemic circulation. -The rate of absorption will determine how soon the effects of the drug will begin. -The extent of absorption will determine how intense the effects will be.

★At the site of absorption, the systemic absorption of a drug is dependent upon: 1.the anatomy and physiological functions 2.the physicochemical properties of the drugs 3.the nature of the drug product.

Factors in drug absorption ★Physiological considerations 1.movement of drug across the membrane 2.blood flow: a potential rate limiting step 3.gastric emptying 4.pH of GI tract

★Physicochemical considerations 1.pKa and degree of ionization 2.lipid solubility 3.dissolution of rate

Physiological considerations on drug absorption 〝 Cell membrance 〞 ★Passive diffusion : ﹝ 高﹞ →﹝低﹞ , most drugs --The movement of drug from a region of high to one low concentration and no work required.

★Active diffusion : ﹝ 低﹞ →﹝高﹞ , 如： Vitamin C --Carrier

--Specificity

--Saturation of transport

--Competitive inhibition

--against concentration gradient

--ATP needed

★Facilitated diffusion : ﹝ 高﹞ →﹝低﹞ , 如： Vitamin B12 --Carrier

--Specificity

--Saturation of transport

--Competitive inhibition

--With concentration gradient

--Not ATP needed

Physiological considerations on drug absorption 〝 Cell membrance 〞 ★Ion-paired transport : --Highly ionized compounds: quaternary ammonium compound, sulfonic acid.

★Pinocytosis : --The absorption of small fat, oil droplets, solid particle, starch, vitamin A, D, E, K.

★Pore transport : --Very small molecules (urea, water, sugar) are able to rapidly cross cell membranes as the membrane contained pores.

Physiological considerations on drug absorption 〝 Gastric emptying 〞 ■The

transit of drug through stomach

■The

rate of gastric emptying is a controlling step in the speed of drug absorption.

★Retard gastric emptying: --Fatty acid in diet, high concentration of electrolyte or hydrogen ion, high viscosity or bulk mental depression, lying on the left side, gastroenteritis, gastriculcer, hypothyroidism --Drug: desipramine, chlorpromazine (Morefine®), Al(OH)3

★Retard gastric emptying: --Fasting, hunger, alkali buffer solution, anxiety, lying on the right side, hyperthyroidism --Drug: metoclopramide (Primperan®)

Physicochemical considerations on drug absorption 〝 Dissolution rate 〞 Tablet, Capsule

dissolution

disintegration Granules, Aggregates

Drug in solution dissolution

absorption

Factors affecting the dissolution rate ★The effective surface area of the drug: --Particle size: the smaller the drug particles, the greater of surface area for a given amount of drug, especially for a hydrophobic drug. (ex: aspirin, digoxin, phenobarbital) -- Manufacturing process: such as lubricant, disintegrating agent and compression force.

★The saturation solubility of the drug: --Salt form : the dissolution rate of a salt form of a drug should be great than the rate of the non-ionized form of the drug . -- pH effect: as pH increased, the dissolution rate of W.A. is increased; as pH increased, the dissolution rate of W.B. is increased. -- Solvate form: drug can associate with solvent to produce crystalline form called solvate. (ex: caffeine, theophylline, ampicillin)

Factors affecting the dissolution rate ★The influence of food: --GI tract content↑: gastric emptying↓, dissolution rate↓ --High protein content: secretion of bile salt and blood flow ↑ , dissolution rate↑

★The effect of food: --Fatty food: delay stomach emptying time beyond 2 hrs. --Fluid: distend stomach and speed up stomach emptying. --Full glass of water: sufficient water is necessary for dissolution of the drug.

Drugs whose absorption is reduced, delayed, increased, or not affected by the presence of food. Reduced

Delayed

Increased

Not affected

Amoxicillin

Acetaminophen

Hydralazine

Chlorpropamide

Ampicillin

Cefaclor

Hydrochlorothiazide

Glibenclamide

Aspirin

Cephalexin

Metoprolol

Glipizide

Isoniazid

Digoxin

Oxazepam

Metronidazole

Levodopa

Potassium ion

Phenytoin

Prednisone

Furosemide

Sulfadiazine

Propoxyphene

Penicillin G

Sulfadimethoxine

Propranolol

Tetracycline

Sulfanilamide

Theophylline

Rifampin

Sulfasymazine

Doxycycline

Sulfisoxazole

Distribution (of drugs) ★Definition -Distribution refers to the reversible transfer of drug from one location to another within the body.

Factors influence the distribution of drugs 1.Blood circulation and vascular permeability: to achive site of action 2.Plasma protein binding: bound drug do not cross membranes 3.Lipophilicity of drug: lipophilic drugs accumulate in adipose tissue 4.Volume of distribution: a hypothetical volume of body that would be required to dissolve the total amount of drug at the same concentration as that found in the blood.

Blood circulation and vascular permeability Tissue

Blood flow (L/min)

Blood Rapid perfused Brain Liver Kidney Heart Less rapid perfused Muscle Skin Poorly perfused Fat Skeleton

Tissue mass (% of B.W.)

5.4

8.0

0.75 1.55 1.2 0.25

2.0 3.5 0.5 0.5

0.8 0.4

48.0 6.5

0.25 0.2

14.0 17.0

Plasma protein binding Plasma protein

Albumin α-acid glycoprotein Lipoprotein

normal range of concentration (g/L)

35-50 0.4-1.0 variable

drug bound

acidic drug basic drug variable

Factors influence the plasma protein concentration 1. Protein synthesis: liver disease 2. Protein catabolism: trauma, surgery 3. Distribution of albumin between intra- and extravascular space: (ex: burn: extravascular space) 4. Excessive elimination of plasma protein, particularly albumin: (ex: renal disease)

Consequences of drug protein binding 1. Insoluble drugs and endogenous chemicals are carried in the blood in the bound form. (ex: lipophilic steroid, vitamin) 2. Can increase the absorption rate of drug, especially ionized drug remained in GI tract. 3. Lead to an even distribution throughout the body tissue. 4. Serve a storage function 5. Only the unbound drug is available for biotransformation or excretion and a high degree of binding can result in delayed elimination. 6. Change in the binding of highly bound drugs can result in significant change in clinical response or cause a toxic response.

Metabolism (of drugs) Definition -Biotransformation means chemical alteration of the drug in the body. -The majority of metabolism leads to conversion of relatively lipidsoluble drugs into relatively water-soluble forms which are easily excreted in the kidney. -Most hydrophilic drugs e.g. neostigmine, decamethonium are not biotranformed. -Liver is the primary route of drug metabolism.

Biotransformation of drug may Inactivation of drug Active metabolite from an active drug Activation of inactive drugs

Phase I Reaction/Nonsynthetic reaction Oxidative reaction: Barbiturates, Phenothiazine Redcutive reaction: Halothane, Chloral hydrates Hydrolytic reaction: Oxytocin, Pethidne Cyclization: Proguanil Decyclization: Phenytoin

Phase II/synthetic reaction • • • • • • •

Glucuronide conjugation: Oral contraceptive Acetylation: Sulphonamides Methylation: Adrenaline Sulphate conjugation: adrenal and sex steriods Glycine conjugation: Salicylates Glutathione conjugation: paracetamol Ribonucleoside/nucleotide synthesis: alcohol

Other • Microsomal  These are located in the smooth endoplasmic reticulum, primarily in the liver • Nonmicrosomal  These are present in the cytoplasm and mitochondria of hepatic cell.

Drug changes to active metabolite Imipramine (Tofranil®)

Despramine

Propranolol ( Inderal®)

4-hydroxypropranolol

Lidocaine (Xylocainel®)

monoethylglycinexylidide

Drug changes to hazardous metabolite Acetaminophen (Scanol®) Isoniazid (INH®)

N-acetyl-p-benzoquinoneimine

acetylhydrazine

hepatitis

Drug changes to active drug Enalapril (Sintec® , Enalatec® )

Enalaprilat

hepatitis

Drug Excretion -most drugs are excreted in urine either as unchanged or drug metabolites

Renal Function 1. Glomerular filtration 2. Active tubular secretion 3. Passive tubular reabsorption 4. Excretion

Excreted drug = (Filtered+ secreted) - reabsobed

Glomerular Filtration- 1st step in renal drug excretion Drug enters renal tubule as a dissolved solute Drug filtration rate= Free drug Plasma conc. X Glomerular filtration rate (GFR)

Active Tubular Secretion -some drugs especially weak acids and bases undergo active tubular secretion by transport systems located in the proximal tubular cells

Not affected by plasma protein binding as free drug is transported bound drug dissociates to replace free drug that has been transported.

Passive Reabsorption -most substances are reabsorbed across renal tubular cells if unionized and lipid soluble Other routes of excretion: Biliary excretion- drugs with mwts >300 excreted in to bile Enterohepatic cycling-