M1: Ch4 Drug Metabolism & Excretion Flashcards
Substance absorbed or ingested in food and drink or deliberately as drugs. Inadvertent or accidental exposure. Can provoke biologic responses the depend on conversion of the absorbed substance into an ____________.
Xenobiotics. Active metabolite.
Metabolized by same enzymatic pathways and transport systems that are utilized for dietary constituents.
Xenobiotics
Xenobiotics: many are ________ that, without metabolism, would not be efficiently eliminated and would accumulate in the body which may lead to possible ________.
Lipophilic. Toxicity.
Xenobiotics: most are subjected to metabolic pathways that convert these _________ into more _________ derivatives that are readily eliminated in ______ or _____.
Hydrophobic. Hydrophilic. Urine or Bile.
Metabolism & Excretion collectively named as this.
Biotransformation
Processes responsible for elimination of drug (parent and metabolite) from the body.
Metabolism & Excretion
Frequently but not universally less pharmacologically active.
Metabolite
Changes the chemical structure of a drug to produce a drug metabolite
Drug Metabolism
Lipophilic drug that has no metabolism and excretion is impossible
Metals & Toxins
Drug Disposition: more water soluble = easily ______.
Excretable
Phases of Metabolism
Phase I (Redox) & Phase II (Conjugation)
As you hydrolyze, it becomes more _______ and then ________.
Polar. Soluble.
Convert the parent drug to a more polar metabolite by introducing or unmasking a functional group. Often metabolites is inactive, although in some instances activity is only modified or even enhanced.
Phase I Redox
Act by causing the drug molecule to undergo oxidation or more rarely reduction.
Enzymes
If Phase I metabolites are sufficiently ________, they may be readily excreted.
Polar
Splitting a bond
Hydrolysis
Bonds that are cleaved in Phase I
Ester & Amide bonds
Undergoes Hydrolysis of the ester bond with the help of Acetylcholinesterase
Acetylcholine
Undergoes Hydrolysis of the ester bond with the help of Esterase. It becomes active once metabolize.
Acetylsalicylic acid
Bond used by Angiotensin
Peptide/Amide bond
A peptidase/amidase that causes hydrolysis to Angiotensin
ACE
Angiotensin I is activated to this which is a vasoconstrictor
A2
Enzyme used in converting A1 to A2
Angiotensinase
Has an amide bond and is an Anesthetic agent
Prilocaine
Remove alkyl group then increases polarity
N-Dealkylation
Major Reactions involved in Drug Metabolism
Oxidative & Hydrolysis Reactions
Oxidative Reactions
N-Deakylation, A-Deakylation, N-Oxidation, Aliphatic hydroxylation, S-Oxidation, Aromatic hydroxylation & Deamination “NANA SAD”
Many Phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate is added.
Phase II Conjugation
Endogenous substrates. Combine with the newly incorporated functional group to form a highly polar conjugate.
Glucuronic acid, Acetic acid, Glutathionase, Amino acid & Sulfuric acid “GAGAS”
Hallmark of Phase II Metabolism
Conjugation/Synthetic Reaction
Conjugation Reactions in Phase II
Methylation, Acetylation, Glucuronidation & Sulfation “MAGS”
The most important of Phase II Conjugation reactions. Reaction does not proceed spontaneously. Requires its activated form.
Glucuronidation
Activated form of glucuronic acid
Glucuronic Acid Uridine Diphosphate
Drug that causes Grey baby syndrome
Chloramphenicol
When chloramphenicol is given without regard for infant’s diminished capacities for hepatic detoxification and renal elimination these will occur
Grey discoloration, Cyanosis, Hypothermia, Acidosis & Vomiting “G CHAV”
Immature activity of this enzyme in Grey Baby Syndrome
Glucuronosyl Transferase
Xenobiotic Metabolic Enzyme for Phase I
Oxygenases
Xenobiotic Metabolic Enzyme for Phase II
Transferases
An anticonvulsant used in treatment of epilepsy is virtually insoluble in water
Phenytoin
Phase I: Phenytoin ————> 4-OH-Phenytoin
Cytochrome P450 enzymes
Phase II: 4-OH-Phenytoin ————-> 4-glucoronate
UDP glucuronosyltransferase
Also terminates the biologic activity
Metabolism
May also precede Phase I reactions
Phase II
Site of cellular metabolism
Endoplasmic Reticulum
Endoplasmic Reticulum: Phase I enzymes
FMOs, Ehs & CYPs “FEC”
Endoplasmic Reticulum: Phase II enzymes
Conjugating enzymes, UGTs
Enter the cell and embed in the lipid bilayer, where they encounter the Phase I enzymes.
Hydrophobic molecules
Once oxidized, drugs are conjugated in the membrane by the
UGTs or by cytosolic transferases
Carry out most drug Metabolism, produce conjugate substrates, transported through bile canalicular membrane then gut elimination.
Hepatocytes
Enzyme Superfamily is the primary Phase I enzyme system involved in the oxidative metabolism of xenobiotics. Also are responsible for all or part of the metabolism and synthesis of a number of endogenous compounds such as steroid hormones and prostaglandin.
CYP450
CYPs are most abundant in the
Liver
Is the most abundantly expressed. Metabolism of 50% of clinically used drugs.
CYP3A4
Rarely involved in metabolism of therapeutic drugs. Catalyze the metabolic activation of many protoxins and procarcinogens.
CYP1A, CYP1B, CYP2A, CYP2B & CYP2E
CYP3A5 whose AA sequence is similar to that of CYP3A4 appears to possess roughly the same substrate specificity characteristics as (not present in all individuals)
CYP3A
Hence, patients expressing both CYP3A4 and CYP3A5 have the potential to exhibit ___________ of CYP2A substrates as compared to individuals expressing only the CYP3A4 isoform.
Increased Metabolism
Expressed only in the fetus and rapidly disappears following birth. Replaced by CYP3A4 and CYP3A5.
CYP3A7
Second most common CYP isoform involved in human drug metabolism; most known for its propensity to exhibit genetic polymorphisms.
CYP2D6
Metabolized several clinically important drugs with narrow therapeutic indices.
CYP2C9
An antiepileptic agent
Phenytoin
An anticoagulant
Warfarin
Induce enzyme = _______ drug effect. Inhibit enzyme = ________ drug effect.
Decrease. Increase.
General metabolizer
CYP3A4
Study of the genetic basis for variation in drug response
Pharmacogenetics
Employs tools for surveying the entire genome to assess multigenic determinants of drug response
Pharmacogenomics
An individual’s response to a given drug depends on a complex interplay among many environmental and genetic factors
Environmental & Genetic factors
A variation in the DNA sequence that is present at an allele frequency of 1% or greater in a population
Polymorphism
Two major types of sequence variations
Single Nucleotide Polymorphism(SNPs) & Insertions/Deletions(Indels)
In Asian, Isoniazid is considered as an _________ which may cause _________.
Rapid Acetylator. Hepatotoxicity.
In American, Isoniazid is considered as an _________ which may cause ___________.
Fast Acetylator. Peripheral neuropathy.
An anti-arrhythmic drug. Slow acetylators are much more likely to develop SLE like syndrome that has been described as a characteristic and therapy-limiting event associated with this drug. The culprit is polymorphism in __________.
Procainamide. N-acetyltransferase.
Are more likely to have complete ulcer healing after therapy with ________(a proton pump inhibitor that reduces gastric acid) than are extensive metabolizers. A positive benefit. 2-3% caucasians & 20-30% asians.
CYP2C19 Polymorphism. Omeprazole.
Drugs are transferred from the internal to the external environment. Thru what?
Excretion. Biliary system, Lungs, Intestines & Kidneys “BLIK”
Is the primary organ of removal of drugs, especially for those that are water soluble and not volatile.
Kidney
Three principal processes that determine the Urinary excretion of a drug
Glomerular filtration, Tubular secretion & Tubular reabsorption (passive-back diffusion) “GTT”
Excretion of a weak acid may be accelerated by ______ the urine with _______.
Alkalinizing. Bicarbonate.
Excretion of a weak base may be accelerated by ________ the urine with _________.
Acidifying. Ammonium chloride.
The rate of urinary drug excretion will depend on its degree of binding protein
Vd
The amount of drug that finally appears in the urine will represent a balance of _______, _______ & _______ drug.
Filtered. Reabsorbed. Secreted.
Passage of xenobiotics from the blood into the liver normally is not restricted because the endothelium of the hepatic blood sinusoid behaves as a porous membrane. Hence, drugs with molecular weights ___________ those of most protein molecules readily reach the hepatic extracellular fluid from the plasma.
Biliary excretion. Lower than.
The physiochemical properties of most drugs are sufficiently favorable for ___________ that the compound will reenter the blood that perfuses the intestine and again to be carried to the liver.
Passive Intestinal Absorption
Gases and other volatile substances that enter the body primarily through the respiratory tract can be expected to be excreted by this route. All volatile materials.
Pulmonary excretion
Lipid insoluble compounds such as urea and glycerol
Sweat & Saliva
More acidic than plasma, basic compounds like alkaloids may be somewhat more concentrated.
Human milk
Examples of Alkaloids
Morphine & Codeine
pH level of Milk
6.5
Other factors of Human milk
Plasma binding, Lipid solubility & Molecular weight “PLM”
Main organ for Drug Metabolism
Liver
Main organ for Drug Excretion
Kidney
