Download 2-Renal tubular excretion

Pharmacokinetic
Dr. Hayder B Sahib
• Ш-Metabolism:•
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Is a general term for chemical transformation that occur
within the body and its process change drugs in 2 major
ways:a-Reducing lipid solubility.
Making drug molecule more water soluble to be
eliminated in urine.
b-Altering biological activity by
1-Conversion of active to inactive drug: this applies to
most drug.
2-Conversion of active to another active drug: (effect of
prolonging drug action) e.g. amitriptyline to nortriptyline
and codeine to morphine.
3-Conversion of inactive to active drug i.e. prodrug e.g
levodopa to dopamine and terfenadine to fexofenadine.
• *The metabolic processes:• Liver is the most important metabolizing organ , although kidney, gut
mucosa, lung and skin also contributes. Metabolic processes include 2
phases:
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-Phase 1:
- Metabolism brings about a change in the drug molecule by oxidation,
reduction or hydrolysis. The new metabolite may retain biological activity
but have different pharmacokinetic properties e.g. a shorter half life..
- Oxidation is the most important single group of reaction in particular
mixed function (microsomal) oxidases. The most important enzyme is
cytochrome P450
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- Cytochrome P450 enzymes are grouped into families denoted by the
letters CYP fallowed by numerals.
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-6 isoenzymes are the most important for the majority of cytochrome
P450 catalyzed reactions : CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP2E1
and CYP1A2.
• -CYP3A4 is the most important and it is responsible for
about 60% of drugs oxidation reaction in human.
• -*Examples of phase 1 reactions:• -Oxidation P450 dependent(hydroxylation)-phenytoin,
amphetamine
• -Oxidation P450 dependent(deamination)-diazepam
• -Reduction- chloromphenicol, naloxone
• -Hydrolyses(esters)-aspirin
• -Hydrolyses(amides)-lidocaine
• Phase 2:• -A synthetic reaction that involve addition(conjugation)
of subgroups to –OH, -NH2, and –SH functions on drug
molecules.
• -The subgroups that added include glucuronate,
acetate, glutathione, glycine, sulfate, and methyl
groups.
• -Most of these groups are relatively polar and make
the product less lipid soluble.
• *Examples of phase 2 reactions:
• -Glucuronation: digoxin , morphine
• -Acetylation: dapsone, isoniazid
• -Glutathione conjugation: ethacrynic acid.
• -Sulfation: methyldopa.
• -Methylation: histamine.
Co administration of certain agents may alter the metabolism of
many drugs. Mechanisms include the fallowing:-
• 1-Enzyme induction:
• -Induction usually from increase synthesis of cytochrome
P450-dependent drug-oxidizing enzymes in the liver.
• - The most common strong inducers of drug metabolism
are carbamazepin, phenobarbital, phenytoin, and rifampin.
• *Clinical significance of enzyme induction:•
1-Drug interaction may result e.g. failure of oral
contraceptive
• 2-Disease may result e.g. antiepilepsy drugs increase the
breakdown of vitamin D which cause vitamin D deficiency
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• 3-Tolerance to drug therapy may result e.g.
tolerance to antiepileptic drugs.
• 4-Variability in response to drugs increased e.g.
failure to achieve the expected response to
warfarin in heavy smokers.
• 5-Drug toxicity may be more likely. e.g
hepatotoxicity due to paracetamol in patient
taking rifampicin(enzyme inducer)
• 2-Enzyme inhibition:
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-The most important drug inhibitors clinically are
amiodarone, cimetidine, furanocoumarins
present in grapefruit juice, ketoconazole, and
ritonavir.
• -Inhibition is more selective than enzyme
induction.
• -Also important drug interaction may occur due
to enzyme inhibition.
• 3-Inhibitors of intestinal P-glycoprotein:
• -P-glycoprotein (P-gp) is an important modulator of intestinal
drug transport (expel drugs from intestinal mucosa into the
lumen).
• -Inhibition of (P-gp) (similar to enzyme inhibition) will lead to
increase bioavailability of certain drugs.
• -P-gp inhibitors include verapamil, grapefruit .
• -Important drugs that are usually expelled by P-gp include
digoxin, cyclosporine, and saquinavir.
• IV-Elimination:
• Drugs are eliminated from the body after being partly or
wholly converted to water-soluble metabolites, or, in some
cases without being metabolized .
• *Renal elimination:
• 1-Glomerular filtration:
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Substances of mol. wt. less than 10000(which
include almost all drugs) pass easily through the pores
of glomerular membrane.
• 2-Renal tubular excretion:
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- Cells of proximal renal tubule actively transfer
strongly
charged molecules from the
plasma to tubular fluid.
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-There are 2 such systems
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One for acids e.g. penicillin, probenecid, frusemide
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And one for bases e.g. amiloride, amphetamine
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• 3-Renal tubular reabsorption:
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-Since the tubular epithelium has the properties of
a lipid membrane, the extent to which the drug
diffuse back into blood will depend on its lipid
solubility .
-If the fluid become more alkaline, an acidic drug
ionized, become less lipid-soluble and its
reabsorption diminishes, but basic drug become
unionized (more lipid-soluble) and its
reabsorption increases.
• -Manipulation of urine pH is e.g. by given sod.
Bicarbonate to alkalinize the urine is useful in
aspirin overdose
• *Fecal elimination:
• -Less important rout of elimination than renal elimination.
• - Proportion of orally administered drug may be eliminated
through this route.
• -Locally administered drug e.g. neomycin and back diffusion from
blood into gut lumen also eliminated through this route.
• -The effectiveness of activated charcoal by mouth for drug over
dose depend partly on its absorption of such diffused drug ,
which then eliminated in the faeces.
• *Pulmonary elimination.
• -The lungs are the main route of elimination of volatile
anaesthetics.
• -A part from above, they play a unimportant role in drug
elimination.
• *Prolongation of drug action:
• 1-Delay absorption:
• a-Oral administration e.g. sustained release
preparation.
• b-Parenteral administration
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-Aqueous suspension e.g. procaine penicillin,
benzathin pen.
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-Implants or pellets e.g. progestin implants
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-S.C injection of drug along with
vasoconstrictor e.g. adrenaline with local
anaesthetic.
• 2-Delay metabolism:
• E.g co administration of carbidopa with
levodopa(carbidopa inhibit peripheral
decarboxylation of levodopa)
• 3- Plasma protein binding e.g. long acting
sulphonamide.
• 4-Delay excretion e.g.probencid compete with
penicillin and ampicillin at tubular secretion.
• 5-Modification of molecular structure of drug
e.g. benzodiazepines.