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PHARMACOKINETICS
Pharmacokinetics is the quantitative study of drug movement in, through and out of the body.
It includes absorption, distribution, binding/localization/storage, biotransformation and excretion of drug.
All pharmacokinetic processes involve transport of the drug across biological membranes..
▪ Drugs are transported across the membrane by :
1) Passive diffusion and filtration
2) Specialized transport
Passive diffusion :
Diffusion of drug across the membrane in the direction of its concentration gradient,
You know what here membrane is not playing any role in this process.
Drugs are foreign substance and specialized mechanism are developed by body for normal metabolites only.
A more lipid soluble drug attains higher concentration in the membrane and diffuses quickly.
Filtration :
Lipid insoluble drug cross biological membranes by filtration if their molecular size is smaller than the diameter of the pores.
Filtration is the passage of drugs through aqueous pores in the membrane or through paracellular spaces.
Specialized transport :
This can be carrier transport or pinocytosis :
Carrier transport : the drug combines with a carrier present in the membrane and the complex then translocates from one face of membrane to the other.
Pinocytosis : it is the process of transport across the cell in particulate form by formation of vesicles.
ABSORPTION
Absorption is the movement of drug from its site of administration into the circulation.
Factors affecting absorption are :
Aqueous solubility :
Drugs given in solid form must dissolve in aqueous biophase before they absorb.
As we know the drug given in watery solution absorb faster than same given in solid form or oily solution.
Concentration :
Drug given as concentrated solution is absorbed faster than from dilute solution.
Area of absorbing surface :
Larger surface area, faster absorption.
Vascularity of absorbing surface :
Increased blood flow hastens drug absorption just as wind hastens drying of clothes.
Route of administration :
This affects absorption of drug because each route has its own peculiarities.
▪ If you are taking drug orally the presence of food dilutes the drug and retards absorption.
▪ Absorption from s.c. site is slower than that from i.m. site, but both are generally faster and more consistent/ predictable than oral absorption.
☆ Do you know ?
Application of heat and muscular exercise accelerate drug absorption by increasing blood flow.
▪ Systemic absorption after topical application depends primarily on lipid solubility of drugs.
▪ Absorption can be enhanced by rubbing.
DISTRIBUTION
Once a drug has gained access to the blood stream, it gets distributed to other tissues that initially had no drug, concentration gradient being in the direction of plasma to tissues.
The extent of distribution of a drug depends on its lipid solubility, ionization at physiological pH, extent of plasma binding and tissue protiens.
Redistribution :
• Highly lipid soluble drugs given i.v. or by inhalation initially get distributed to organs with high blood flow, e.g. brain , heart, kidneys, etc.
• Later, less vascular but more bulky tissues (muscle, fat) take up the drug-plasma concentration falls and the drug is withdrawn from these sites.
• If the site of action of the drug was in one of the highly perfused organ, redistribution results.
• Greater lipid solubility of drug, faster is its redistribution.
Penetration into brain and CSF :
Blood brain barrier and blood CSF barrier are lipoidal and limit the entry of non lipid soluble drugs, e.g. streptomycin, neostigmine.
Passage across placenta :
Placental membrane also are lipoidal and allow free passage of lipophilic drugs.
But it is incomplete barrier, because non- lipid soluble drug in higher concentration can access to the foetus.
Plasma protein binding :
Most drugs possess physicochemical affinity for plasma protiens.
Acidic drugs generally bind to plasma albumin.
Basic drug to alpha 1 acid glycoprotein.
Extent of binding depends on the individual compounds.
☆ Drugs bound to plasma protiens :
To albumin : Barbiturates, Benzodiazepines, NSAIDs, Penicillin, Sulfonamides, Tetracyclines.
To alpha 1 acid glycoprotein : Prazosine, Quinidine, Lignocaine, Bupivacaine.
Tissue storage :
Drugs may also accumulate in specific organs or get bound to specific tussue constituents, e.g. --
Skeletal muscle, heart : digoxin.
Liver : chloroquine, Tetracycline.
Kidneys : digixin.
Brain : acetazolamide.
Retina : chloroquine.
Iris : ephedrine. Atropine.
Bone and teeth : tetracycline.
Adipose tissue : thiopentone, ether, phenoxybenzamine.
BIOTRANSFORMATION (METABOLISM)
Biotransformation means chemical alteration of drug in the body. It is needed to render nonpolar (lipid soluble) polar (lipid insoluble) compound so that they are not reabsorbed in the renal tubules and are excreted.
The primary site for drug metabolism is liver, others are : kidneys, intestine, lungs and plasma.
Biotransformation may lead to the following:
i) Inactivation : most drugs and their active metabolites are rendered inactive or less active, e.g. morphine, propranolol, chloramphenicol.
ii) Active metabolite from an active drug : many drugs have been found to be partially converted to one or more active metabolite; the effects observed are the sumtotal of that due to the parent drug and its active metabolites.
iii) Activation of inactive drug : few drugs are inactive as such and need conversion in the body to one or more active metabolites. Such a drug is called a prodrug.
e.g. Levodopa is prodrug converted to Dopamine in active form.
Biotransformation reaction can be classified into :
A) Non synthetic reaction : metabolite may be active or inactive.
i) Oxidation
ii) Reduction
iii) Hydrolysis
iv) Cyclization
v) Decyclization
B) Synthetic reaction : metabolite mostly inactive.
i) Glucuronide conjugation
ii) Acetylation
iii) Methylation
iv) Sulfate conjugation
v) Glycine conjugation
vi) Glutathione conjugation
vii) Ribonucleoside synthesis
EXCRETION
Excretion is the passage out of systemically absorbed drug. Drugs and their metabolites are excreted in :
1. URINE : Through the kidneys. It is the most important channel of excretion for most drugs.
RENAL EXCRETION
The kidney is responsible for excreting all water soluble substances. The amount of drug or its metabolites ultimately present in urine is the sumtotal of glomerular filtration, tubular reabsorption and tubular secretion.
Glomerular filtration : Glomerular capillaries have pores larger than usual; all nonprotein bound drug presented to the glomerulus is filtered.
Glomerular filtration is depends on its plasma protien binding and renal blood flow.
Tubular absorption : This depends on lipid solubility and ionization of the drug at existing urinary pH.
Lipid soluble drugs filtered at the glomerular back diffuse in the tubules because 99% of glomerular filtrate is reabsorbed.
Tubular secretion : Tubular secretion occurs simultaneously during tubular reabsorption of filtrate.
This is the active transfer of organic acids and bases by seperate non specific mechanisms whuch operates in the proximal tubules.
2. FAECES : Apart from the unabsorbed fraction, most of the drugs present in faeces is derived from bile.
3.EXHALED AIR : Gases and volatile liquids are eliminated by lungs, irrespective of their lipid solubility.
e.g. general anesthetics, alcohol.
4.SALIVA AND SWEAT : These are of minor importance for drug excretion.
Lithium, pot.iodide, rifampin, and heavy metals are present in these secretions.
5.MILK : The excretion of drug in milk is not important for mother, but the suckling infant inadvertently receives the drug.
Most drugs enters breast milk by passive diffusion.
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😊 I hope you've got help, if you have any suggestion or any question regarding this article "Pharmacokinetics,, please comment i will be very happy.
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😊 I hope you've got help, if you have any suggestion or any question regarding this article "Pharmacokinetics,, please comment i will be very happy.
Thanks
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