1.Principles of Pharmacology-2

8/12/2019 1.Principles of Pharmacology-2

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2. Factors that modify absorption in the GI tract

2) Formulation factors materials added to the drug during processingcan affect the solubilization of the drug.

a. Fillers add bulk to the tablet

b. Disintegrators cause tablet to break down into granules

c. Binders hold tablet together

d. Lubricants prevent tablet from sticking to machinery

Formulation factors - not clinically important if the drug is absorbed effectively and mayhave important influence on drug absorption for these drugs which are not effectivelyabsorbed in the GI tract - influence drugs bioavailability.

Absorption of Drugs


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3) Concentration of drug at the absorption site

Passive diffusion

Driving force the concentration gradient.

The higher the concentration of the drug, the faster the rate of absorption.

Absorption of Drugs


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4) Blood flow at the absorption site

- maintain concentration gradient driving force

Blood

Membrane

Absorption of Drugs


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5) Surface area of absorption

small intestine

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6) Route of administration

GI tract first pass effect

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7) Gastric emptying

small intestine primary site of drug absorption

Anything that delays/accelerates gastric emptying willdecrease/increase drug absorption.

For all drugs - acidic, basic or neutral substances.

Absorption of Drugs


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8) Food

High fat food delay gastric emptying slow absorption

Absorption of Drugs


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2. Factors that modify absorption in the GI tract9) Intestinal motility

depends on whether the drug is completely absorbed undernormal condition.

a. Completely absorbed early upon entry into the small intestine,increasing intestinal motility will not significantly affect absorption.

b. Not completely absorbed before entry into the small intestine,increasing/decreasing intestinal motility will slow down/facilitatedrug absorption.

Absorption of Drugs


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10) Metabolism of drug by GI tract

a. Drug metabolizing enzymes in the GI tract

b. Microbes in the GI tract - metabolize certain drugs

- Drug metabolites are not usually absorbed.

Absorption of Drugs


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3. Bioavailability

Fraction of administrated drug that reaches thesystemic circulation

Absorption of Drugs


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3. Bioavailability

Determination of Bioavailability

Absorption of Drugs


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4. Other sites of drug administration/absorption .

1). Lung gases, liquid droplets or solid particles

Advantages:The drug can have local effects - Epinephrine for asthma.

The drug can have systemic effects - general anesthetics Large surface area, limited thickness of pulmonary membrane and

high blood flow allow for almost instant absorption by diffusionAvoid first pass effect

Disadvantages:Administration is cumbersome - must use specific machines or equipmentPatients must be able to inhale with certain timing and depth in order to

get full effects of drugImpaction may occur, if drug particles size is too large to pass through the

bronchi and reach the alveoli.

Absorption of Drugs


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4. Other sites of drug administration/absorption

2) Skin Most drugs that are incorporated into creams or ointments

are applied to the skin for local effect.

Drug absorption through the skin - Passive diffusion lipid solubility

Absorption of Drugs


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Drug Distribution

Transfer of drug from systemic circulation to tissues

Interstitial fluid

Blood plasma

Intracellular

Capillary endothelium cells


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Drug Distribution

1. Factors that affect drug distribution1) Regional blood flow2) Capillary permeability3) Rate of transfer from interstitial fluid into tissues4) Binding to plasma proteins

2. Barriers to drug distribution

D Di ib i


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Drug Distribution

1. Factors affecting distribution:

1) Regional blood flow unequal distribution of cardiac output

Perfusion rate: blood flow to tissue mass ratio

Higher: heart, kidney, liver, lung and brainModerate: muscle and skinLow: adipose tissue

The perfusion rate affects the rate at which a drug reaches the equilibrium inthe extracellular fluid of a particular tissue.

The greater the blood flow, the more rapid the drug distribution from plasmainto interstitial fluid. Therefore, a drug will appear in the interstitial fluid ofliver, kidney and brain more rapidly than it will in muscle and skin.


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Tissue Perfusion rate(ml/min/100g tissue)

Lung 400Kidney 350Muscle 5

Skin 5Adipose tissue 3

Blood perfusion rates in adult humans

Drug Distribution


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1. Factors affecting distribution

2) Capillary permeability Drug transfer through capillary filtration

a. Capillary structure: Capillary size

Liver: greater filtration potentialBrain: lower capillary permeability

Liver slit junctionBrain tight junction - blood-brain barrier

Drug Distribution


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D Di t ib ti


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3) Rate of transfer from interstitial fluid into tissues

Passive diffusion, active transport and endocytosis.

Passive diffusion - the most common and quickest means

Drug Distribution

Interstitial fluid

Blood plasma


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4) Binding to plasma proteins - reversible

Drug Distribution

Interstitial fluid

Capillary endothelium cells

Blood

Cells and tissues

A + P = AP


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4) Binding to plasma proteins

f. Types of plasma proteins:

AlbuminLipoproteinsalpha1-acid glycoprotein

Drug Distribution


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More plasma proteins

Less free drug available


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Drug Distribution

2. Barriers to drug distribution:

2) Placental transfer

Placenta - Not a barrier most drugs May have profound affects on fetal development.

3) Blood testicular barrierRegulates the passage of steriodsPrevents chemotherapeutic agents from reaching the testis


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Excretion of Drugs

Drugs are removed from the body or drugs are transferredfrom the internal to the external environment


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Excretion of Drugs1. Sites for drug excretion:

1) Kidney - Urine 2) Liver Bile3) Skin4) Lung5) Milk6) Semen7) Saliva

E ti f D g

Glomerular


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Excretion of Drugs filtration

Activesecretion

PassiveReabsorption(unionized, lipid soluble)

2. Renal excretion

1) Glomerular filtration

Drugs from glomerulus into the renal tubules Pressure blood flow - 20% of blood volume

is filtered at the glomerulus Lipid soluble drugs also by passive

diffusio n

E cretion of Dr gs

Glomerular


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Activesecretion


2. Renal excretion

1) Glomerular filtration

2) Active secretion

Active transport systems:Organic acids/AnionsOrganic bases/Cations

Relatively non-specificAnion/acid system penicillins, phenobarbital, uric

acid, et al.Cation/base system morphine,

catecholamines, histamine, et al. In some cases can remove protein-bound drugsfrom the blood

Excretion of Drugs

Glomerular


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Activesecretion


2. Renal excretion

1) Glomerular filtration2) Active secretion

3) Passive reabsorption

Formation of concentration gradient

of drug in tubular filtrate Transfer of unionized, lipid soluble

drugs back to the blood by passdiffusion passive reabsorption

Excretion of ionized, lipid-insolubledrugs

More ionization more secretion pH of urine = 4.5 8

Excretion of Drugs


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3. Secretion from the liver:

Liver - Metabolizing enzymes Drugs are filtered from liver capillaries into interstitial fluid liver has larger fenestrae

which will allow the filtration of most drugs Drugs in interstitial fluid are transported into hepatocytes by

a. Passive diffusionb. Carrier-mediated transport

Drugs are actively transported from the hepatocytes into the bile capillaries by 4 activetransport systemsa. Acidsb. Basesc. Neutral compoundsd. Bile acids

Lipid insoluble or ionized drugs excretion Enterohepatic cycling: Liver Bile intestine

a. Lipid soluble reabsorption from intestine to bile transport back to the liverb. Prolong drug actionc. Conserve endogenous substances VD3, B12, folic acid, estrogens.

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4. Pulmonary excretion

Gasses and volatile liquids

Simple diffusion from the blood into the airway

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5. Sweat and saliva

Drugs or drug metabolites

Passive diffusion

Drug taste after i.v. administration

Side reaction of the skinExamples(saliva):Phenytoin , Clonidine, Diazepam etc.(Sweat ): Rifampicin

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6. Milk

Passive diffusion

Milk pH 6.5 ion trapping of weak bases

Plasma protein binding decreases drug concentration in milk

Not very important for mother, but may be important for infant

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Some drugs are excreted via the semen. Examples :

FENESTERIDE (hair fall treatment),Ghloroquine (antimalarial) ,Sulfasalazine(sulphonamides) , verapamil(Calciumchannel blocker) ,propranolol , nicotineetc.

Documents

1.Principles of Pharmacology-2