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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2. Factors that modify absorption in the GI tract
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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2. Factors that modify absorption in the GI tract
4) Blood flow at the absorption site
- maintain concentration gradient driving force
Blood
Membrane
Absorption of Drugs
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2. Factors that modify absorption in the GI tract
5) Surface area of absorption
small intestine
Absorption of Drugs
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2. Factors that modify absorption in the GI tract
6) Route of administration
GI tract first pass effect
Absorption of Drugs
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2. Factors that modify absorption in the GI tract
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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2. Factors that modify absorption in the GI tract
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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2. Factors that modify absorption in the GI tract
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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Excretion of Drugs filtration
Activesecretion
PassiveReabsorption(unionized, lipid soluble)
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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Excretion of Drugs filtration
Activesecretion
PassiveReabsorption(unionized, lipid soluble)
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.
Excretion of Drugs
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4. Pulmonary excretion
Gasses and volatile liquids
Simple diffusion from the blood into the airway
Excretion of Drugs
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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
Excretion of Drugs
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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
Excretion of Drugs
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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.