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Drug Specificity 3/1/2011 12:07:00 AM
y Specificity of Drug Actiono No drugs is entirely specific in the sense that it acts exclusively
only on one type of cell or tissue, having just the desired effect and
no other
o Drugs vary in their specificities and the usefulness of a drugclinically is often directly related to its specificity
o Poison: A compound which has deleterious effects on cell functionwithout having any therapeutic effects
Example: cyanide combines strongly with Fe3+ found inmany proteins interfering in their functioning
o Some drugs have absolutely no toxicity at concentrations usedclinically.
Example: penicillin inhibits a bacterial enzyme involved in theformation of bacterial cell walls.
Humans lacking cell walls are unaffected by theseconcentrations of penicillin
In between these two extremes (cyanide and penicillin) aremany dugs used clinically
y Methotrexateo Methotrexate is a drug used in cancer chemotherapy and to treat
severe cases of psoriasis (using doses of 2.5-5 mg/kg)
o It cants by inhibiting the rapid reproduction of epithelial cells inpsoriatic plaques.
o However, at slightly higher doses, methotrexate also inhibitsreproduction of mucosal cells in the intestine, which would lead to
ulceration and diarrhea
y Thus useful drugs actions are instances of selective toxicity, while non-selective toxicity gives rise to poisoning
y Generally, the useful, therapeutic effects of drugs are separable from thetoxic effects based on differences in:
o Their respective mechanisms of actiono Their dose-response relationships if their mechanisms of action are
similar
o The sites at which therapeutic and toxic effects are producedy Attempts to increase the utility of a drugs are based on improved
Pharmacodynamic specificity (if the mechanisms of toxic and therapeutic
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effects differ) or an enhanced pharmacokinetic selectivity (distribution to
the desired target site)
y For specific drug:receptor interactions to occur, the drug molecule musthave several points of attachmentto corresponding points on the receptor
moleculeo The nature of these points of attachment and their relative positions
and distances apart are all critical for the drugs ability to combine
with a receptor and to produce a response
y Molecular features necessary for acetylcholine actiono 1) positively charged No 2) Three Ch3 groups attached to No 3) Ester linkageo 4) Spacing between N and Carbonyl C
y Acetylcholine has actions at muscarinic and nicotinic acetylcholinereceptors, but many other drugs act at one but not the other.
o The acetylcholine molecule changes its shape between cis and transforms
o This happens since it contains only single bonds that do not limitrotation
o This changes the distance between the N atom and the carbonyl C.o For binding to the nicotinic acetylcholine receptor, this distance
should be about 3.5 angstroms, and for the muscarinic receptor, tneeds to be 5-7 angstroms.
o Ligands specific to either the nicotinic or muscarinic subtypes havestructures that limit intramolecular rotation
y Antagonists at muscarinic and nicotinic acetylcholine receptors haveenough of the structural molecular features that all of them bind to their
respective receptors, but not all the features that allow them to exert a
functional effect after binding
o These compounds (atrophine and muscarinic sites and curare atnicotinic sites) have structures that limit intramolecular rotation,
thus preserving their selective effects on these receptors
o Examples of other receptors showing such specificity are alpha andbeta adrenergic receptors, nine types of serotonin receptors, two
major classes ofGABA receptors (A and B) and at least four major
subtypes of opiate receptors
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y Molecular selectivity of drugs binding to specific receptors helps in thedevelopment of new therapeutic agents displaying fewer side effects
o Raclopride is a highly selective antagonist at dopamine D2 and D3(but not D1, D4, or D5) receptors.
o It is a potent antipsychotic agent used in the treatment ofschizophrenia
o Use ofRaclopride leads to fewer of the troublesome side effects(anti-psychotic induced parkinsonism) that are seen when all
dopamine receptor subtypes are blocked.
o The use of specific antagonists also helps in understanding diseasemechanisms.
o That D1 receptor specific antagonists have no utility in thetreatment of schizophrenia tells us that dopamine actions at D1
receptors are not important in schizophrenia
yy Stereospecificity
o Stereospecificity is not an obligatory feature of receptor selectivityfor drugs but may add significantly to it
o Many drugs have optically isomeric forms in which only one isomeris active, or one isomer is considerably more potent that the other.
o This is consistent when at least three points of attachment need toexist between a receptor and its ligand, there exists either a centeror plane of asymmetry in the drug
y Examples of Stereospecificityo D and LHyoscyamine, of which only the L form is active as
muscarinic receptor blocker
o Morphine has D and L forms, of which only the L form has analgesicactivity, although both forms act as antitussives
o Only the L-form of norepinephrine elevates blood pressureo D-amphetamine is much more effective CNS stimulant than L
amphetamine , but they are equipotent in producing hallucinations
y Degrees of Selectivityo An example of a drug with an extremely high degree of selectivity is
tetrodotoxin, which binds only to Na+ channels, blocking action
potential propagation.
o There are also less selective drugs for example R-(CH2)3-N-(CH3)2
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Enables a compound at least to some extent to interactwith receptors for histamine, acetylcholine and possibly
catecholamines
If the R group is large, it can also function as anantihistamine or local anesthetic
o For example chlorpromazine, procaine, and diphenhydramine sharea number of properties: they are all good local anesthetics, H1
receptors antihistamines and myocardial antiarrhythmic
However, unique parts of each of their molecules also givethem pharmacological properties that are not shared with the
other compounds.
y An example of how a singular molecular structure can be modified to yielda number of different drugs that have differing and specific actions
y Pharmacokinetic Selectivityo For those drugs that either do not act selectively on particular
receptors, or act on receptors that are found on many cell types or
tissues
o Selectivity can still be obtained due to: Selective distribution of drug to an intended site Metabolic differences that make one tissue more sensitive to
the effect of the drug than another
y Selectivity related to drug distributiono Topical applications
Injection into abscess or joint cavity, or drops in the eye Selectivity arises from the fact that any drug absorbed
systematically from the site is diluted in a large volume of
circulating blood
Vasoconstrictors may increase usefulnesso Intra-arterial injection
Useful for antitumor agents Dissolving chemotherapeutic in an oily carrier enables oily
droplets to be trapped capillaries of the tumor and facilitates
drug uptake into tumor cells
o Selectivity by ionization
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Propantheline and atropine are both good muscarinic blockersbut the former does not cross the blood brain barrier because
it has a quaternary N, which makes it a permanent cation
o Differential Blood Flow Drugs given I.V. are initially primarily distributed to tissues
with high blood flow (remember VRG?)
Thiopental, because it is highly lipophilic, will rapidly cross theblood-brain barrier as it is brought to the brain
o Distribution by selective carriers: CD20 is a cell surface antigen found on 90% of B-cell
lymphomas but not normally on B-cells
131-I is linked to an antibody to CD20 to radiate B-celllymphomas
o Selective concentration by excretion Many drugs are concentrated in urine because they undergo
glomerular filtration or secretion but are poorly reabsorbed
Thiazides used as diureticsy Selectivity related to tissue differences
o Selective cellular binding Some drugs that are capable of acting on many different
types of cells if present in high enough quantities, show
selectivity at normal dosages when they bind to cellularcomponents in certain cells
Quinine has a high affinity for malarial DNAo Selective uptake by tissues:
Some tissues can concentrate drugs Thyroid concentrates Iodine, so 131-I is concentrated in the
thyroid in treatment of hyperthyroidism
o Selective intracellular activation Some drugs are given as pro-drugs that need to be
bioactivated to function
If the tissue to be targeted has the ability to convert theprecursor to the active form, that increases selectivity
Enteric sulfonamides are bioactivated by gut bacteria to freesulfathiazole which has antibacterial activity locally in the gut
o Selective tissue vulnerability
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A drug may be relatively nonselective in terms of the range oftissues it acts upon, yet may have therapeutic specificity if
the cellular function it affects is more important in one tissue
than in the rest.
Cardiac Glycosides such as digitalis inhibit Na+K+ ATPase,but the heart enzyme is more sensitive than that in skeletal
muscle, liver, kidney, etc.
y Individual and species differenceso Bacteria VS. Host
Differential sensitivity between bacterial and animal cell formsthe basis for antibacterial therapy
Penicillin acts on bacteria that have cell walls but not onanimal cells
Animal cells take up folic acid but bacteria synthesize it andcannot take it up
Sulfonamides act as competitive antagonists ofPABA, aprecursor of folic acid
o Insects VS. Mammals Malathion is an organophosphate cholinesterase inhibitor that
is metabolized quickly in birds and mammals but slowly in
insects
Yielding relatively specific toxicity to insectso Genetic differences within species
Selective toxicity arising from genetic variations within aspecies can be harmful, beneficial or both
A hereditary deficiency ofG6P dehydrogenase rendersaffected individuals sensitive to primaquine-induced hemolytic
anemia
But at the same time also makes them more resistant to thegrowth of malaria in the liver
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Ligand Gated Ion Channels 3/1/2011 12:07:00 AM
The action potential travels down the axon and causes neurotransmitter
release
y This is a chemical neurotransmissionNeurotransmitters are small molecules released by neurons which bind
receptors and elicit functional effectsy Ex) Glutamate, GABA, Dopamine, Serotonin, Acetylcholine
What do neurotransmitters do?
y Excitatory postsynaptic potentials (EPSPs)o Increase the likelihood of action potential generation in the
postsynaptic cells
o Increases membrane potentialy Inhibitory PSPs (IPSPs)
o Decreases the likelihood of action potential generationo Decrease membrane potential
Nature of postsynaptic cells response to neurotransmitter depends on:
y The type of neurotransmitter releasedy The type of receptors on the postsynaptic cellsy The magnitude of the response to neurotransmitter which itself
depends on:
o Quantity of neurotransmitter releasedo Receptor numberso State of the receptors
Two major types of neurotransmitter receptors
y Ionotropico Neurotransmitter binding causes a conformational change in
the receptor which leads to the rapid opening in the receptor,
permitting ions to flow down their electrochemical gradients
y Metabotropico Neurotransmitter binding causes a conformational change in
the receptor which leads to a second messenger cascades (ie
through G-protein activation).
o These responses are of slow onset and long during, comparedto ionotropic receptors
General characteristics of ionotropic receptors
y Multi-subunit protein complexes with membrane spanning domainsy Very fast onset (sub-millisecond time scale)
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y Ion selectivity cation vs. anion selectivityy Most desensitize rapidly after exposure to agonist
Major types of ionotropic receptors (or ligand gated ion) channels
y Glutamate receptorsy Cys-loop ion channels
Three rings of negatively charged amino acids face the pore. These ensure
that only cations can pass through the pore
y Ach receptor channelsAcetylcholine binding to the receptor
y There are two binding sites for acetylcholine in the extracellulardomain of the receptor
y Cooperativity of binding between the two sites is evidentIf you only have a few kinds of transmitters, how do you maintain diversity?
y The subunit compositions of recombinant receptors determine theirpharmacological profiles
y Amino acid sequence homology is greatest within classes ofsubunits compared to between classes
Consequences of agonist binding to a neurotransmitter receptor
yUse of patch clamp technique to measure channel function
y The opening and closing events exhibited by individual ion channelsresult in averaged current seen by electrophysiologists, not by
performing single channel measurements
y total current curve = hyperbolicy Average open time is one the 1ms timescale
GABA(a)R and GlyR are the major inhibitory neurotransmitters in the brain
and spinal cord (conduct Cl- ions)
y Inhibition ofGABA(a) or Gly receptors cause convulsions(pictrotoxin).
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y Enhancement ofGABA(a) or Gly receptor function would beexpected to lead to sedation and anesthesia (think alcohol and
volatile anesthetics)
An example of an allosteric modulator: Benzodiazepines
y Eg) diazepam (valium), flunitrazepam (Rohyphonal),chlordiazepoxide (Librium)
y Clinically useful as sedatives, hypnotics, anxiolytics,anticonvulsants.
y Danger of tolerance and dependencey Agonists at the benzodiazepine receptor site enhance GABA-
mediated currents by left shifting the GABA concentration response
curves (compared to just GABAs concentration response curve)
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GProtein Coupled Receptors 3/1/2011 12:07:00 AM
Referring back to lecture 14, we learned that there were two major classes
of neurotransmitter receptors, ionotropic receptors and
The second major type of neurotransmitter receptor
y Metabotropico Neurotransmitter binding cause a conformational change in
the receptor which leads to G protein binding and to the
production of intracellular metabolites through enzymatic
processes
o These responses are of slow onset and long during, comparedto ionotropic receptors
o These receptors are sometimes referred to as G-proteincoupled receptors (GPCRs)
Some history
y In the 1950s Sutherland and Rall found that stimulation of cardiaccells with epinephrine resulted in increased concentrations of a
water soluble nucleotide called cAMP. They proposed that cAMP
acted as a second messenger
y Neurotransmitters, hormones, and drugs that cannot cross the cellmembrane (first messengers) exert their effects inside cells through
molecules (second messengers such as cyclic nucleotides, ions,
phospholipids) that act intracellulary
Most hormones and many neurotransmitters act by regulating intracellularsecond messengers
y In most cases, there are multiples receptors for singleneurotransmitters that bind to GPCRs. Predicted from classical
binding studies
y For example, there are 5 classes of muscarinic acetylcholinereceptors and 6 classes of adrenergic receptors.
y In many cases, the complex pharmacological responses producedby a single ligand are due to its actions on a number of different
receptors
y The physiological roles of many of the receptors and why thisdiversity exists are poorly understood
Three components required for G-Protein signaling
y Receptor (on cell surface)
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y G-protein (couples to receptor on intracellular side of cellmembrane)
y Effects (usually enzymes)y All three are either imbedded I the cell membrane or tightly
associated with itWhat does a GProtein coupled receptor look like?
y Huge family of related receptors, each a product of a different geney Each contains 7 transmembrane domainsy Neurotransmitter binds to GPCR on extracellular side of membraney G proteins bind to intracellular sections ofGPCRy Neurotransmitters binding likely stabilizes receptor so it can
efficiently bind to G protein trimer
When a GPCR is stimulated by an agonist, the effect is usually of limited
duration.
y There are two major mechanisms of limiting the actions ofneurotransmitter agonist at GPCRs
o Receptor Desensitization Where the extent of interaction between receptor and G
proteins can be decreased.
This is usually accomplished through phosphorylation ofserine and threonine residues on GPCRs, by specific
intracellular enzymes (kinases).o Receptor down regulation
Proloned exposure to agonist leads to the internalizationof receptors from cell membrane, thus decreasing the
numbers ofGPCRs that can interact with G proteins.
G proteins
y The family ofG proteins that transduce signals from membranereceptors to effector enzymes and ion channels are known as
heterotrimeric (3 different subunits) G proteins
y Three subunits are called alpha, beta, and gamma in decreasingsize
y The alpha subunit binds guanine nucleotides and is the majormediator of the G proteins actions on its effector
y The beta and gamma subunits primarily function to support theinteractions of alpha subunit with the plasma membrane and with
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GPCRs, but like the alpha subunit, they may also regulate effectors
directly
The G protein activation/inactivation cycle
y In the resting state, the three G protein subunits are boundtogether with guanosine disphosphate (GDP) attached to the alphasubunit
y This heterotrimer can bind to an inactive GPCR.y When an agonist binds to the GPCR, a conformational change
occurs, leading to the rapid dissociation of the G protein
heterotrimer from the GPCR
y This agonist binding also results in the release ofGDP from thealpha subunit of the G protein heterotrimer
y The empty guanylyl nucleotide binding site on the alpha subunit isthen occupied by guanosine triphosphate (GTP) that is present at
high concentrations in cytoplasm.
y GTP binding causes the alpha subunit to release from GPCR as wellas from the beta-gamma dimer
y The alpha subunit then binds to an effector; within a few seconds,the intrinsic GTPase activity in the alpha subunit hydrolyzes the
bound GTP to GDP, inactivating the alpha subunit
y The GDP-bound alpha subunit dissociates from the effector, re-associates with the betagamma dimer and is ready for anothercycle of activation by GPCRs
y
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Functional diversity of different members of the G protein family arises from
the more than 20 different types of alpha subunits identified thus far
y Some of the most common are Gs, which stimulates adenylylcyclase (leading to production of cAMP)
y Gi, which inhibits adenylyl cyclase.y Gs and Gi can also interact with some ion channelsy Some G proteins are widely expressed in cells while others have a
more limited distribution and more specialized functions.
y For example Gt is found in rods and cones of the retinaSome G proteins are targets of toxins
y The Gs-alpha subunit is modified for the cholera toxin such that itbinds ADP-ribose to the guanyl nucleotide binding site
y This prevents the intrinsic GTPase from acting and results inpersistent activation ofGs-alpha.
y In the intestine this leads to marked elevations in CaMP levels,causing cells to secrete large amounts of water into the gut, leading
to the severe diarrhea that is seen in cholera infections.
y Another bacterial toxin, pertussis acts on Gi-alpha and Go-alphasubunits, preventing their activation by GPCRs.
y With the disruption of the inhibitory actions ofGi on adenylylcyclase, once again cAMP levels rise, leading to characteristic cough
seen in whooping coughEffector enzymes regulated by G proteins
y Adenylyl cyclases and phospholipases C are the most commoneffector enzymes by which G proteins exert their effects
y Adenylyl Cyclases and cAMP as 2nd messengerso Adenylyl cyclases, imbedded in the cell membrane, catalyze
the synthesize of cAMP from ATP
o There are at least nine forms of adenylyl cyclase.All arestimulated by Gs-alpha but differ in their sensitivities to
inhibition by Gi-alpha
o cAMP acts by activating the cAMP-dependent protein kinases(protein kinase A; PKA) which can then phosphorylate other
proteins at specific serine or threonine residues
Phospholipase C and phospholipid 2nd messengers
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y Members of the Gq family and G-proteins transduce signalsbetween GPCRs and enzymes known as phospholipase C.
y These enzymes use phospholipids as substratesy GPCR occupation by ligand activates Gq.y The Gq-alpha subunit binds to the phospholipase on the inner
surface of the cell membrane
y This activated phospholipase then rapidly breaks down themembrane constituent PIP2 to IP3 and DAG.
y IP3 and DAG can both act as 2nd messengersy IP3
o Small water soluble molecule that diffuses through thecytoplasm to bind to specific receptors on the membrane
surrounding the endoplasmic reticulum, resulting in release of
Ca2+ stores
o This in turn initiates a wide variety of calcium mediatedevents in the cell, such as the activation of
calcium/calmodulin dependent protein kinases
y DAGo Remains in cell membrane where in concert with
phosphatidylserine and calcium, it activates protein kinase C
(PKC) another serine/threonine kinase.
o Activation ofPKC involves translocating it to the cellmembrane where it becomes able to phosphorylate a wide
variety of substrate proteins such as receptors, ion channels
and other enzymes
Signal Amplification
y Each GPCR/agonist complex activates several G proteins before theagonist dissociates
y Each G protein, in turn initiates the production of many 2ndmessenger molecules
y Thus the binding of agonist to one GPCR can lead to the activationof many effectors (enzymes)
How do we prove that the action of a neuromodulator is through a GPCR?
y Intracellular GTP is requiredy Non-hydrolyzable GTP analog greatly prolongs action or makes
effect irreversible
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y High affinity GDP beta-s analog cannot be displacedy Block with pertussis toxin inactivates a subset ofG-alpha proteins
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Pharmacogenetics 3/1/2011 12:07:00 AM
Introduction
y Pharmacogenetics is the study of the influence of heredity on theresponse to drugs, or their fates in the body.
y How do pharmacogenetic defects differ from other inborn errors ofmetabolism?
o Pharmacogenetic defects tend to be silent in the absence ofdrug challenge
Why is pharmacogenetics important?
y 1) Increases physician awareness of abnormal drug responsesy 2) Knowledge of frequently occurring genetic defects that alter drug
responses enables drug manufacturers to avoid introduction of
unreliable drugs
y 3) Genetic defects can be useful to scientists to elucidatemechanisms underlying normal drug responses
Pharmacogenetics can be divided in three major ways
y functional subdivisiony pharmacological subdivisiony genetic subdivision
Functional subdivisions
y disorders characterized by increased sensitivity to drugsy therapeutic failures resulting from increased resistance to drugsy disorders exacerbated by enzyme-inducing drugsy Diseases to which chronic drug exposure may contributey Disorders of unknown etiologyy Disorders associated with diet
Pharmacological subdivision
y The pharmacological classification distinguishes between alterationsin a drugs pharmacodynamics and alterations in pharmacokinetics
o Pharmacokinetic: Most affecting drug metabolizing enzymeso Pharmacodynamic: Variation in systems targeted by drugs
Genetic Subdivisions
y The primary genetic subdivision is between monogenic (single genelocus defects) versus multigenic variants.
o Most important differences between people are multigenic.Examples include adult height and predisposition to
alcoholism
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y Monogenic Variantso Monogenic variant in pharmacogenetics could be an absence
of a particular drug metabolizing enzyme, resulting in
improper metabolism of the drug
o This is often due to a mutation in a critical region of a genefor an enzyme
o Assume that there is a gene with a functional allele with afrequency ofp and a nonfunctional allele with a frequency of
q in a population, such that p+q = 1.
o Individuals each get one allele of each gene from each parentso that any person may be pp, pq, qp, or qq at that gene.
Genotype frequencies in a population are determined by the
Hardy-Weinberg Law: p^2 + 2pq + q^2 = 1.
For example, ifq=0.1 then 81% of the people will have two
p alleles, 18% will have a p and a q (heterozygotes), and
1% of people will have two non-functional q alleles of the
gene
o If the deficiency is functionally evident only in the qqindividuals who are homozygous for the defective allele, the
deficiency is referred to as recessive.
o If heterozygous (pq) also show functional deficiency, thedefect is dominant
o Examples of monogenic variants include: alcoholdehydrogenase; cytochrome P450 CYP2C8 (phenytoin
metabolism); glucose-6-phosphate dehydrogenase (hemolytic
disorders); ryanodine receptors (malignant hyperthermia)
y Multigenic variantso Examples include complex phenotypes such as height, IQ and
increase in heart rate after administration of epinephrine
o Environmental factors often contribute to expression ofmultigenic traits
o Heritability values are usually derived from studies comparingmonozygotic and dizygotic twins.
o These can vary markedly for different effects of differentdrugs: i.e. some drug effect variability have a greater genetic
contribution than others.
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Examples ofGenetic influences on drug biotransformation
y Plasma cholinesterase variantso PC hydrolyzes a number of drugs, including cocaine, but its
greatest clinical significance is that it inactivates the muscle
relaxant succinylcholine that is used as a muscle relaxant inanesthesia
o An atypical cholinesterase is found in 1/2000 Caucasians, andin these people the muscle relaxant effects of succinylcholine
last about an hour instead of a few minutes (these patients
required prolonged ventilation)
o The biochemical cause of the defect is a significantly loweredaffinity of the plasma cholinesterase for succinylcholine
clinical failure of drug elimination
y Acetylation polymorphismo The genetic control of acetylation was first observed for
isoniazid (used in tuberculosis treatment) and is now known
to be important for the elimination of a large number of
compounds
o The capacity for rapid drug acetylation occurs in families witha Mendelian pattern of inheritance.
o There are marked ethnic differences in acetylation; less than50% of Caucasians are rapid acetylators, unlikeapproximately 90% of Asians and North American Indians
o Defective acetylation in slow acetylators is due to a markedreduction in the quantity of functional N-acetyltransferase-2
(NAT2) in liver. This is due to a number of mutations that
can lead to:
Decreased translation ofNAT2 mRNA A decreased stability of the expressed enzymes Changes in the amino acid sequence ofNAT2 that lead
to decrease in rate of substrate metabolism
o Are there any consequences to being a slow or fastacetylators?
Rapid acetylators may metabolize some drugs morequickly than the physician thinks and this may lead to
inadequate dosing
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Defects in metabolism by cytochrome P450
y Example: The metabolism of debrisoquin (an antihypertensive) byCYP2D6 is markedly affected in about 8% of the British population,
such that the doses given to various patients can vary almost 30
fold.y The metabolism of a number of other drugs (including beta-
adrenoceptor blockers, antipsychotics, antidepressants, and
antiarrhythmic) is also affected by the same defect in this enzyme
Effects of genetics on drug responses at their targets
y Many genes can confer increased vulnerability or decreasedresponses of a target tissue by a drug
y Glucose-6-Phosphate dehydrogenase (G6PD) deficiencyo A deficiency in G6PD predisposes patients to hemolytic drug
reactions.
o The exact mechanism remains unknown but appears to belinked to the cells inability to maintain sufficient
concentrations of the reduced form of glutathione
o Drugs that are oxidized from H2O2 in the RBC and thisoxidizes glutathione which in turn may become attached to
hemoglobin
o This leads to the oxidation and denaturing of hemoglobinwhich can damage the erythrocyte membrane and lead tohemolysis
o Approximately 400 million people carry the trait for G6PDdeficiency and about 300 enzymic variants are known
o Two common variants are the A- variant found largely inAfrican Americans and the Mediterranean variant.
o In the A- variant, the enzyme is unstable such that G6PDactivity is normal in young RBCs but decreases as they age
o In the Mediterranean variant there is a low G6PD activity inall RBCs.
o A number of drugs (eg. Quinine, ASA) precipitate hemolyticcrises in subjects with the Mediterranean but not A- variant
o Why havent these mutations been weeded out by Darwinianevolution
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G6PD deficiency increases resistance to Plasmodiumfalciparum malaria; G6PD gene defects thus accumulate
in countries with endemic malaria
o Many different types of drugs can cause hemolysis in G6PDdeficient subjects
Malignant Hyperthermia
y Used to be one of the main causes of death due to anesthesiay Anesthetics trigger a release of calcium from sarcoplasmic reticulum
in susceptible individuals
y Major body temperature increases up to 43 C.y This is accompanied by skeletal muscle rigidity and death by cardiac
failure.
y Most cases due to a mutation in ryanodine (plant alkaloid) receptorwhich is the sarcoplasmic reticulum (SR) calcium release channel
y Treatment with Dantrolene (SR Ca++ channel antagonist)y Diagnostic Test for patient susceptibility to malignant hyperthermia
o Caffeine is much more potent in producing (biopsied) musclecontractions in susceptible individuals
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Variations in Drug Responses 3/1/2011 12:07:00 AM
Dosing amounts and schedules are determined empirically, based onextensive clinical observations
These doses are those that have therapeutic efficacy in most patients onmost occasions, and produce the desired therapeutic effect with an
acceptably low risk of toxicityo If a normal dose of a prescribed, why do some patients show either
too much or too little response?
1) Compliance? Did the patient take the drug? 2) Bioavailability ? IF the drug was take properly, was it
absorbed properly and delivered to the systemic circulation?
3) Pharmacokinetics? Was the drug distributed normally inthe body
4) Pharmacodynamics? Did the target disuse respond todrug in the expected manner?
Complianceo Most patients fully intend to follow their physicians instructions
regarding their prescriptions
o Indeed, 97% of prescriptions are filled within 5 dayso So why is patient compliance and issue?
Compliance with a physicians instructions is variable anddepends on a number of factors
y 1) Duration of treatment: There is lowered compliancefor drugs that must be taken for a long time
y 2) Complexity of the dosing regimen (inconvenience):o Ameliorated somewhat by marketing of
pharmaceutical mixtures
o Eg. Glucocorticoid and Beta-adrenoceptor agonistadministered in one dose for asthma.
o But this results in loss of therapeutic flexibilityy 3) Patients perception of the seriousness of the
disease and of the importance and efficacy of treatment
y 4) Side effects of therapy, if serious, tend to decreasecompliance
y 5) Continuity and ease of contact with physiciano Noncompliance is a serious problem in the treatment of
hypertension
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High blood pressure itself does not cause symptoms in mostpatients
antihypertensive may often make patients feel miserable This decreases drug taking compliance In the case of hypertension, compliance was increased by
allowing a test group of subjects to measure their own BP
readings daily, and this was reinforced with biweekly
physician supervision
o Important measures to assure compliance in long-term therapiesinclude:
Simplified dosing schedules Use of long acting rather than short acting drugs Minimizing side effects Continuous supervision of the patient Patient education
Drug dosing variations affected by bioavailabilityo Factors affecting bioavailability
GI or liver pathologyy E.g.) Diarrhea, biliary obstruction, hypermotility,
rescued GI blood flow
Formulation of the drug preparation, leading to differences inrelease of drug into GI Fluids
o Brand names are often (but not always) better formulated thangeneric drugs, giving more uniform and better bioavailability
Pharmacokinetic variation in drug responseso Many pharmacokinetic reasons for variability to drugs responses
were covered earlier (enzyme induction and pharmacogenetics)
o Other factors that may play a role are: Liver disease may affect metabolism Age
y (e.g. elimination rate of Mecillinam is 4 times slower inelderly)
Smokingo Pharmacokinetic variation is most evident in early infancy and
advanced age, but may also be affected by disease processes at
any age.
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o Penicillin, and other antibiotics, do not normally cross the bloodbrain barrier
o However, inflammatory processes (e.g. meningitis) increaseantibiotic permeability, increasing their effectiveness
o But this may also increase the risk for toxicity (highconcentrations of penicillin can cause seizures)
o In contrast, bacteria in localized abscesses or other walled-offinfections may be resistant to antibiotics because they cant gain
access
Variation in dosages for adults vs. childreno In adults, drug dosing is generally calculated on the basis of body
size and body composition (lean body mass)
o Most differences in drug doses between men and women are due todifferent body composition.
o An obese person will require a smaller dose of a highly water-soluble drug than a lean person of the same weight, and a higher
does of a lipid-soluble drug (fat acts as a drug reservoir)
o However, the required dose is actually more proportional to themetabolic rate, which is in turn closely proportional to body surface
area than body weight
o This discrepancy is not large in adults but is important in babies andsmall children whose surface area to mass ratio is considerablyhigher than adults
1) Calculation of childrens dose by age (Youngs Rule):y Age/(Age+12) = fraction of adult dose
2) Calculation of Childrens dose by body surface area:y (1.5 weight[in Kg]) + 10 = percentage of adult dose to
give child
The body surface area calculation method is superior (#2)especially with young children
Pharmacodynamic variationo Pharmacodynamic variations, leading to altered target tissue
responses to drugs may be due to genetic abnormalities (see
pharmacogenetics) or to disease processes
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o Hyperthyroidism is frequently associated with an increased numberof beta adrenoceptor, resulting in an increased sensitivity to the
cardiovascular effects of norepinephrine
o Sometimes drug interactions will alter Pharmacodynamic sensitivityto one or more of the drugs administered
o For example. Patients with chronic left ventricular failure are oftentreated with a diuretic (to reduce edema) and a cardiac glycoside
(to increase cardiac muscle contractility).
o Increased cardiac output by the cardiac glycoside increases renalblood flow which increases the urinary response to diuretic.
o This may lead to excessive loss of K+ into urine, and the resultinghypokalemia increases myocardial sensitivity to the cardiac
glycoside, increasing the chances for arrhythmia.
Tolerance to one drug can also be expressed as cross tolerance to theeffects of another
o This is most clearly seen in relation to central nervous systemdepressants such as alcohol, benzodiazepines and other sedatives
o Prolonged use of any of these compounds results in an adaptation(tolerance) that occurs to the effects of these drugs
o Not only can this lead to decreased responses to the drug that hasbeen taken chronically but it can also lead to decreased responses
to other drugs that produce similar effectso For example. Alcoholics show significantly decreased responses to
general anesthetics, necessitating the administration of higher
doses
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Drug Interactions 3/1/2011 12:07:00 AM
y Drug Interactionso The simultaneous usage of several therapeutic agents concurrently
is commonplace, with most patients in general hospitals receiving
at least 5 drugs concurrently at some point in their stays.
o The media number of drugs administered to patients duringhospitalization is 10-13, with many receiving more than 20 drugs.
o In addition, many patients also consume analgesics, cold remediesand other drugs that are available without a prescription
o Furthermore, there is a universal exposure to other bioactivechemicals found in food additives, insecticides, cleaning agents and
cosmetics
o A major concern is that the administration of one drug will changethe effect of another by enhancing or diminishing its effects at its
site of action
y Classification of Drug Interactionso Consequence
Beneficial or adverseo Site
External or internalo Mechanism
Pharmacodynamic Pharmacokinetic Physiologic
y Classification of drug interactions based on consequenceo Can have an enhanced or diminished therapeutic efficacyo Can also have an enhanced or diminished toxic effect
y Classification based on site of interactiono External
Physiochemical incompatibilities (e.g. precipitation orinactivation) may prevent drugs from being mixed together in
I.V vials or syringes
o Internal This can refer to either a body site (e.g. GI tract) or the site
of action (e.g. cell membrane, receptor site)
Examples:
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y Some antibiotics (kanamycin, gentamicin) enhance thedepolarizing block produced by succinylcholine at the
neuromuscular junction
y Morphine induced respiratory depression is reversed byopioid antagonist naloxone
y Classification based on mechanismo Physiological
Physiological interactions are those in which the actions ofdrugs are mediated at different sites or organ systems (such
as heart and kidney), but have the net effect of augmenting
or offsetting each other
An excellent example is the cardiac glycoside/diuretic scenarioo Pharmacodynamic interactions
Pharmacodynamic interactionsy Pharmacodynamic interactions are those occur when
the effects of two drugs impinge on a common effector.
The consequences of this are:
o Additiveo Supra-additiveo Infra-additive
y The descriptions additive, supra-additive and infra-additive provide no information regarding themechanism of drug interaction
Example of a pharmacodynamic interaction between alcoholand a barbiturate
y Note concentration for barbiturate in barbiturate andethanol combo for death is much lower than for death
by a barbiturate alone.
Another example of a pharmacodynamic interactiony Complex interactions, involving regulation of
neurotransmitter receptor numbers, can affect drug
responses
y Guanethidine (an antihypertensive) decreases therelease of norepinephrine pre-synaptically; a
consequence of this NE receptor up regulation after
chronic Guanethidine treatment
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y If a patient taking Guanethidine is also administereddesipramine (an antidepressant that blocks NE uptake),
this leads to significant increases in blood pressure
o Pharmacokinetic interactions Absorption, Distribution, Biotransformation, Excretion Gastrointestinal absorption
y Physicochemical interactionso Changes in GI pH produced by one drug (such as
the H2 receptor antagonist cimetidine, or
antacids) can affect the ionization of another drug
o Chelation of Ca2+ or Fe3+ by tetracycline;o Binding of warfarin by cholestyramineo Absorption of drug by activated charcoal in
treatment of poisoning
y Changes in gastrointestinal motilityo Changes in GI motility affect the rate and/or
completeness of drug absorption
y Increased gastric emptying and intestinal motilityo Ex: Metoclopramide increases the rate of gastric
emptying which can result in earlier and higher
peak concentration
o Cathartics increase rate of intestinal motility,which decreases completeness of absorption
y Decreased gastric emptying and intestinal motilityo Opioid analgesics and anticholinergics decrease
the rate of gastric emptying, slowing absorption
and decreasing the peak drug concentration
y Drug-induced changes in mucosal functiono Drugs with GI toxicity (ex. colchicine) may
damage the GI mucosa altering absorption of
other drugs
Drug Distributiony Blood flow
o Organ uptake and clearance of drugs depends onblood flow
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o Some drugs like beta blockers andantiarrhythmics decrease cardiac output and
thus the hepatic clearance of drugs such as
lidocaine which have a high extraction rate in liver
y Serum protein bindingo Many drugs are bound to serum proteins,
especially to albumin
o Such drugs may be displaced by other highlybound drugs administered concurrently
o When a displacing drug is added to therapy, it canin theory lead to the immediate appearance of
toxicity to the first drug
o Even a small amount of displacement of a highlybound drug can cause a large relative increase in
free drug in serum
o Clinically important pharmacokinetic interactionsdue to displacement from plasma proteins will
occur only when:
Administration of the displacing drug isstarted in high doses during chronic
administration of displaced drug
The Vd of the displaced drug is small The response to the displaced drug occurs
faster than redistribution or enhanced
elimination
Biotransformationy Pharmacokinetic interactions between drugs can occur
by drug either inducing or inhibiting an enzyme that
metabolizes another.
y This is particularly true for the cytochrome P450 familyof enzymes, responsible for the metabolism of many
drugs
o Enzyme induction Hundreds of drugs such as analgesics,
anticonvulsants, oral hypoglycemic,
sedatives and tranquilizers stimulate the
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biotransformation of either themselves or
other drugs
Consequences of enzyme induction are:y Increased rate of hepatic
biotransformation of drugy Increased rate of production of
metabolites
y Increased hepatic drug clearancey Decreased serum drug half-lifey Decreased serum total and free drug
concentrations
y Decreased pharmacological effects ifmetabolites are inactive
o Enzyme inhibition Clinically important inhibitors of drug
biotransformation are:
y Acute ethanol exposure which inhibitspropranolol, diazepam and
chlordiazepoxide metabolism
y Cimetidine (decreases gastric acidsecretion) is a potent cytochrome
P450 inhibitor and inhibitsbiotransformation of acetaminophen,
diazepam, digoxin, phenytoin and
warfarin among other drugs
y Disulfuram inhibits aldehydedehydrogenase, causing acetaldehyde
accumulation after alcohol
consumption
y Grapefruit juice contains abioflavonoid that is transformed in the
liver to naringenin. This is a potent
inhibitor of CYP3A4, CYP1A2 and
CYP2A6, and reduces the first-pass
metabolism of a number of drugs
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including calcium channel blockers,
cyclosporine, midazolam and caffeine
In general, inhibition of drugbiotransformation is the clinically most
important mechanism of pharmacokineticinteractions
Excretiony Theoretically, drug interactions could alter rates of
excretion by any route, but the only careful studies of
these phenomena have been performed involving renal
excretion. The following phenomena have been
observed:
o Glomerular filtration of drugs Is increased by displaced from albumin
binding sites
o Tubular reabsorption of drugs Is decreased by diuretics (sometimes),
urine alkylinizers (for weakly acidic drugs
such as ASA and barbiturates) or urine
acidifiers (for weak amines such as
amphetamine or methadone)
o Tubular secretion of drugs Is decreased by competition for active
transport enzyme systems.
Probenicid was used to block Penicillin Gsecretion during WWII
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Adverse Drug Reactions 3/1/2011 12:07:00 AM
y Adverse Drug Reactionso All drugs have the potential to produce deleterious consequenceso Before drugs are approved for use in the general populace, they are
first tested in animals and then in selected populations of patients
to determine their efficacies and pharmacological profiles.o Some adverse effects (the most common ones) are detected in
these pre-market studies
o Many more adverse effects of drugs are detected after the drugcomes to market and is used by large numbers of patients over a
long period of time, especially if the adverse drug effects are rare
o A major impetus into the study of adverse reactions came from thethalidomide disaster of 1961.
y Thalidomideo In 1961, physicians began noticing a sudden outbreak of children
being born with deformities characterized by the upper portion of a
limb being absent or poorly developed Phocomelia
o These birth defects were soon associated with the use of pregnantwomen of a presumably safe new hypnotic called thalidomide
o Use of thalidomide in the first trimester, when forelimb buds weredeveloping caused the deformities
o This disaster led to the re-evaluation of the methodology andregulations applied to the testing of the safety of drugs.
o More stringent legislation was enacted in many countries toimprove the likelihood that serious toxicity would be detected
before drugs come to market
y ADEVS. ADRo Some patients develop unwanted signs or symptoms during drug
therapy (called adverse drug events; ADE)
o But is this due specifically to the drug therapy?o If so, the reaction is called an adverse drug reaction (ADR)o An ADR is any noxious, unintended or undesired effect of a drug
that is observed at doses usually administered therapeutically.
o This does not include cases of drug overdose, drug abuse ortherapeutic errors
y Severity of ADRso Mild
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No antidote, therapy or prolongation of hospital stay isrequired
o Moderate requires a change in drug therapy, although not necessarily
discontinuation of the use of the drug It may prolong hospitalization and require specific treatment
o Severe Potentially life-threatening, requires discontinuation of the
drug and specific treatment of the ADR
o Lethal Directly or indirectly contributes to the death of the patient
y The adequate assessment and classification of ADRs requires a knowledgeof the mechanisms by which they are produced
y ADRs are the result of the interplay between the characteristics of theadministered drug and some inherent or acquired characteristic of the
susceptible patient
y Reaction to a drug are due to one of three possibilities:o Some physicochemical or pharmacokinetic property of the drug; i.e.
its formulation or the dosing regimen
o Some characteristic of the patient; i.e. his genetic makeup orsomething unusual or pathological about his physiology
o A combination of the first two possibilitiesy Some ADRs are dose-related
o E.g. CNS depression by sedative hypnoticso Are by far the most common occurrences of ADRs (95%)o These ADRs, which can be prevented by adjusting the patients
dose, may be due to impairment of drug elimination by renal
disease (for drugs such as digoxin that are predominantly excreted
by the kidney) or due to liver dysfunction (for drugs eliminated
after biotransformation by the liver)
o The ADRmay be either an extension of the usual pharmacologicaleffects of the drug or an unusual toxicity caused by the drug and/or
its metabolites
y Other ADRs are not dose relatedo These are less common and are due to an increased susceptibility
of the patient
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o The ADR usually manifests as a qualitative change in the patientsresponse to the drug and may be caused by a pharmacogenetic
variant or an acquired drug allergy
o Most ADRs resulting from a pharmacogenetic basis are detectedonly after the patient is exposed to the drug
o E.g. slow acetylators of isoniazid are more prone to a geneticallydetermined polyneuropathy
y Major Features of ADRs
yy Allergic or hypersensitivity immunological reactions
o 1) anaphylactico 2) Cytotoxico 3) Immune-complex-mediatedo 4) Cell-mediated
y Anaphylactico Immediate hypersensitivity reactions involving interaction of
allergen (drug) and IgE antibody on the surface of basophils and
mast cells.
o This causes the release histamine, kinins, and prostaglandins thatlead to capillary dilation, contraction of smooth muscle and edema
o This reaction may be limited to a weal, but can also result in life-threatening anaphylaxis (shock and bronchoconstriction) or asthma
o Anaphylactic reactions may occur after injection of penicillin orother antimicrobials.
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o Up to a quarter of asthmatic patients are intolerant of ASA, whichmay cause severe bronchospasms, by a mechanism unrelated to
IgE
y Cytotoxico These are complement fixing reactions between antigen and
antibody on the cell surfaces ofRBCs, WBCs and platelets, leading
to cell lysis
o Drugs usually act as haptens, binding to a receptor on the cellsurface to make up a complete antigen, against which an antibody
reacts.
o Ag/Ab reactions with complement fixation may lead to a number ofclinical outcomes including hemolytic anemia, agranulocytosis, or
thrombocytopenic purpura
y Immune-complex mediatedo These reactions occur when Ag/Ab complexes deposit on target
cells.
o Complement is then activated, causing tissue destruction by releaseof lysosomal enzymes.
o This can cause glomerulonephritis and collagen diseasey Cell mediated
o These allergic arises from a direct interaction between an allergenand sensitized lymphocytes, leading to the release of cytokines.
o Most cases of eczematous and contact dermatitis are cell-mediatedallergic reactions.
o Common causes are topical antihistamines and PABAy Frequencies of ADRs
o Most studies show that ADRs in hospitalized patients (excludingmild cases) is between 10% and 20%
o Between 0.2% and 21% (median = 5%) of all patients are admittedto a hospital because of an ADR, and 10-20% of those are severe.
o ADR lethality occurs in 0.5-0.9% of those hospitalized for ADRs.o Most ADRs are caused by cardiac glycosides, diuretics,
antimicrobials, anticoagulants and NSAIDs
y Risk Factors associated with ADRso Age
Older subjects (>60) are more susceptible to ADRs.
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They are more likely to bleed during heparin treatment, andare more sensitive to analgesics and more likely to develop
digitalis toxicity
Impaired drug elimination and increased receptor drugsensitivity are proposed mechanisms.
However, older patients also tend to have more diseases andto receive more drugs than younger patients.
Newborns are also more sensitive to some ADRs (e.g.chloramphenicol)
o Gender Women are more likely than men to develop ADRs, especially
drug-induced GI symptoms and problems with digoxin toxicity
o Other factors Patients on multi-drug therapy, patients with histories of
allergic disorders, previous presentation with an ADR, disease
state (especially liver and renal)
y Sample Size required for detecting ADRso Clinical trials are usually short term studies conducted on a few
hundred patients before the drug is marketed.
o Therefore, only the most common ADRs would be detectedo This approach obviously has it limitations. Ex. Clozapine
(antipsychotic) was introduced in Finland in 1975. Within 6months, 17 cases of serious hematological reaction had occurred,
from approximately 3200 users (prevalence of 0.6-0.7%).
Clozapine was withdrawn from the market
o Temafloxacin (antibiotic) was withdrawn from the market after only15 weeks because of ADRs.
o These examples illustrate the importance of postmarkingmonitoring of new drugs.
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Toxicology I 3/1/2011 12:07:00 AM
y Toxicologyy Toxicology is the study of the adverse effects of chemical agents on
biological systems
y A number of classifications can be used to subdivide the generalfield of toxicology
y Toxic agents themselves may be classified according too 1) The potential for a compound to produce toxicityo 2) The source of the toxin (e.g. snake or spider venom or poison
ivy)
o 3) Chemistry of toxinso 4) mechanism of action
y The concentration response curves for the effective, toxic, and lethaldoses of a drug are independent of one another. There are three
assumptions:
o 1) observed response actually due to compound administeredo 2) degree of response related to magnitude of doseo 3) response is quantifiable
y Threshold Doseo The lowest does that evokes a given responseo For example, different doses of ASA produce GI bleeding, tinnitus,
and generalized acidosis
o Some toxicities develop rapidly and reversibly (e.g. inebriation dueto methanol) while others develop more slowly and may be
irreversible (e.g. Methanol producing retinal nerve toxicity, leading
to blindness)
y LD50o The does required to kill 50% of exposed tests animalso Depends on species, strain, sex, age and route of drug
administration
o E.g. Dioxin LD50(s) vary 1000 fold between guinea pig and hamstero Some chemical may produce minimal acute toxicity but can have
long lasting effects (e.g. carcinogens and teratogens)
o Remember that LD50 is used in conjunction with ED50 to determinethe therapeutic index (T.I.)
y Mechanisms ofToxicityo Receptor mediated toxicities
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Reversible binding of parent molecule and/or stableintermediate to a receptor sites
o Reactive intermediate toxicities Bioactivation of a relatively nontoxic chemical to a highly toxic
intermediate that binds to or oxidizes cellular macromoleculessuch as DNA, protein, or lipid
y If given a sufficiently high concentration, most drugs can initiatereversible toxicities, primarily of the sort that stem from the predictable
exaggeration of the pharmacological effect for which the drug is being
employed
o Ex) Severe hypotension arising from a overdose of anantihypertensive
y Alternatively, most carcinogens, teratogens, and chemicals producingneurodegenerative disorders, tissue necrosis or immune system mediated
hypersensitivity reactions are thought to act after the Bioactivation of a
parent drug to a reactive intermediate. The target tissue is determined
by the site of Bioactivation
o Ex) liver and kidney for acetaminophen and lung for paraquaty How can drug toxicity be modified?
o 1) Decrease in function of pathways of drug elimination (primarilyliver and kidney), resulting in excessive accumulation.
Ex) aminoglycoside antibiotics are primarily excretedunchanged by kidney
o 2) Enhanced pathways of Bioactivation to toxic reactiveintermediates
o 3) Reduced detoxifying or cytoprotective pathways for removingreactive intermediates
o 4) Decreased number of binding sites on plasma binding proteins Ex) the anticoagulant warfarin is 90% bound to albumin
o 5) Reduced pathways for repair of cellular macromoleculesdamaged by reactive intermediates
y What factors are important for drug toxicity?o Age
Toxicity of compounds may vary with subject age because ofage dependent differences in relative organ size, maturity of
enzyme systems and toxin distribution.
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y Ex) Malathion toxicity depends inversely on hepaticcyto. P450 activity
Young children are less susceptible to toxicity produced byacetaminophen, digoxin, and theothylline, but are more
sensitive to toxicity produced by antihistamines, lead andsalicylates than are adults.
The very young and elderly tend to have reduced renalfunction which makes them more susceptible to compounds
that are excreted by kidneys
o Route or site of drug administration
IV is gold standardo Duration or frequency of exposure
A) Acute exposure (less than 24 hrs) either single,continuous or repeated dosing
B) Sub-acute exposure (< 1 month) C) Sub-chronic exposure (1-3 months) D) Chronic exposure (> 3 months) Different exposures to the same compound can lead to
different toxicities.
y E.g. acute exposure to benzene leads to CNSdepression, while chronic exposure is associated withhematological malignancy
o Nutrition Presence of food in stomach can decrease the absorption of
some drugs (beta blockers and diazepam) but increase the of
others (penicillin and isoniazid)
Malnutrition reduces absorption of the antibiotics tetracyclinand rifampin
Liver metabolism of drugs is also affected by nutrition stateo Genetic variability
A common cause of predisposition to toxicity is a geneticdifference in one or more critical pathways involved in the
actions of the drugs
y In the case of receptor mediated toxicities, low orabsent levels of critical enzymes such as the
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cytochrome P450 and N-acetyltransferase, result in
drug accumulation and lead to toxic levels
y In the case of toxicities produced by reactiveintermediates, a predisposition to toxicity may arise
from genetically high activity and/or inducibility ofbioactivating enzymes (e.g. P450) or decreased level of
enzymes that metabolize intermediates
o Ex) phenytoin metabolism by epoxide hydrolase,if impaired can lead to liver necrosis
o Ex) deficiency in enzyme that produces GSH leadsto increased levels of highly reactive free radical
intermediates
o Disease Coexisting disease often alter susceptibility to the toxic effect
of dugs, as well as compounds encountered in the
environment
The effects of some of these diseases (e.g. hepatic and renaldiseases) are easily predicted
However, the effects of other diseases (e.g. cardiovascular)may be less easy to predict
y Ex lidocaine metabolism occurs primarily in the liver,and decreased cardiac output would affect its hepaticclearance.
Disease which effect the numbers of plasma binding proteinswill affect toxicities of highly protein bound drugs.
GI diseases will affect the toxicities of drugs that aremetabolized extensively in intestinal walls during absorption
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Toxicology II 3/1/2011 12:07:00 AM
y Toxicology IIo Predictive toxicology
Assesses risks associated with a situation in which the toxicagent, the subject and exposure conditions are defined
o LOEL Lowest observed effect level
o NOEL No observed effect level
o Increasing technological sophistication means that we can nowdetect measurable amounts of metals, toxin and pesticide that were
undetectable just a few years ago
o We can also detect with greater sensitivity the effects thatcompounds have (in 1971 the acceptable blood level for lead in
children was 40 micrograms/deciliter; in 1993 it was 10
micrograms/deciliter)
y Poisoningso Poisonings are a common occurrence (> 2 million cases/year) with
about a quarter treated at some sort of health care facility with a
fatality rate of 0.07%
o Common poisons Cleaning substances 10.3% Analgesics 9.6% Cosmetics 8.2% Cough and cold remedies 6% Leaves/plant material 5.4% Bites and venoms 4.1%
y Drug categories most responsible for fatalities are (in order)o 1) analgesicso 2) antidepressantso 3) stimulants (including illegal drugs)o 4) hypnotic sedativeso 5) antipsychoticso 6) cardiovascular drugso 7) alcohols
y Break down of poisonings by age:
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o 56% of cases involved children under the age of6, 6% involvedkids aged 6-12 and 48% involved adults
y Poisono Any substance which by its chemical action may cause damage to
structure or disturbance of functiony Antidote
o A remedy for counteracting the effects of a poison.o This may occur by preventing, minimizing or reversing the effects of
the poison
y Principles of poisoning treatmentso 1) minimize systemic absorption of toxino 2) antagonize effects of toxin that has already been absorbedo 3) encourage metabolic processes that reduce toxicity, while
inhibiting processes that might increase toxicity
o 4) Enhance rate of elimination of toxin from bodyo 5) provide good clinical care during the recovery phase
y Modification of absorption and distribution of poisonso A) Poisons taken orally
Most toxins are absorbed orally (about three-quarters).These should be either expelled or prevented from being
absorbed
y 1) emesiso induced vomiting is used to remove toxins from
the stomach
o Ipecac mixture of plant alkaloids is most oftenused; it triggers emesis in 5-20 minutes by acting
at the chemoreceptor trigger zone and by local GI
irritation
o Use ofIpecac is contraindicated by coma orconvulsions, ingestions of a substance that may
rapidly produce coma or convulsions, or ingestion
of a caustic or corrosive substance.
o Passage of toxin through pylorus (or systemicabsorption) decreases the efficacy of emetic so
ipecac isnt given more than half an hour after
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ingestion of a liquid poison, or one hour after
ingestion of a solid poison
y 2) Gastric lavage stomach pumpingo This is often less effective than emesis induced by
ipecac in removing solid material from thestomach
o Lavage may be appropriate when emesis iscontraindicated (ex. Coma and convulsion), but
extreme care must be taken to prevent tracheal
aspiration of fluids
y 3) Activated Charcoalo This is an inert, odorless, tasteless, non-
absorbable, fine black powder that has a high
absorptive capacity
o It will bind most toxins in the lumen of the GI.Tract and thus reduce poison absorption
o It is administered in water (25 g/100 ml water)and taken orally or by nasogastric tube.
o A 10:1 ratio of activated charcoal to toxin shouldbe used.
o The ability of activated charcoal to preventabsorption depends on the poison and the timesince ingestion.
y 4) Local antidoteso These are compounds that change the ionic form
or alter the solubility of the poison, thus reducing
its absorption and consequently also its toxicity.
Ex) calcium (milk) is used to counterfluoride poisoning
Strong acids or bases should never be usedto neutralize ingested strong bases or acids,
respectively (its a highly exothermic
reaction!)
o Pulmonary Route Remove patient from site of exposure to toxic gases
o Dermal Route
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Some toxins are readily absorbed through the skin. Minimizing absorption involves washing skin and removal of
contaminated clothing
Abrasion of skin may help absorption and so should beavoided
o Parenteral Route Application of constricting bands proximal to site of injection,
as well as restriction of movement of afflicted limb, will slow
distribution. This is often applied in the treatment of
snakebite.
y Techniques for altering distribution of toxinso This distribution of some drugs is partially dependent on pH.o The acidemia (acidification of blood) accompanying salicylate
poisoning aids in the transfer of salicylate across membranes (such
as the blood brain barrier).
o Normalizing blood pH to 7.4 reduces the amount of non-ionizedsalicylate, decreasing distribution into the CNS.
o In the case of morphine, if the non-ionized form leaves blood andenters the stomach it becomes ionized and has difficulty re-entering
the bloodstream.
o Repeated dosing with active charcoal can thus still be used intreating morphine overdose even if it is originally administeredparenterally
y Antidotal Therapyo 1) Competitive antagonism
Ex) Naloxone (Narcan) is a competitive antagonist at opioidreceptors, reversibly competing with agonist for binding sites
on the mu and kappa opioid receptors.
Ex) Flumazenil is a competitive antagonist of benzodiazepinereceptor agonist and is used in the treatment of
benzodiazepine overdose
o 2) Noncompetitive antagonism Ex) Atropine is used to treat carbamate or organophosphate
insecticide poisoning. These insecticides inhibit
acetylcholinesterase activity, raising Ach levels. The effects
of this excess Ach are antagonized by atropine
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o 3) Chemical neutralization Ex) Cyanide combines strongly with the ferric form of iron
(Fe3+) in proteins such as cytochrome oxidase (important in
oxidative metabolism).
Treatment consists of giving patient sodium nitrate whichreacts with Fe2+ in hemoglobin, to produce the Fe3+ form
that reacts with cyanide bound to cytochrome oxidase. The
patient is then given sodium thiosulfate which neutralizes the
hemoglobin-bound cyanide to the nontoxic sodium
thiocyanate.
o 4) Metabolic inhibition ex) a metabolite of methanol (formic acid) is toxic to the
retinal nerve. Treatment consists of giving the patient
ethanol which competes with methanol for metabolism by
alcohol dehydrogenase, decreasing the rate of formic acid
production
o 5) Chelation This type of therapy is used to treat metal poisoning Chelating agents bind tightly to metals Examples include dimercaprol (arsenic poisoning), EDTA (lead
poisoning) and deferoxamine (iron poisoning).
o 6) Antigen-Antibody Serum globulins with specific activity against a specific
substance (e.g. the active ingredients in snake or spider
venom) are used as antitoxins.
There are also antitoxins to treat C. Botulinum poisoning anddigoxin overdose
y Excretiono Attempts to increase excretion of a toxin will only work if the
compound is largely excreted unchanged in the urine and if it can
be ionized. Not many toxins meet this criterion
o Enhanced renal secretion is accomplished by the systemicadministration of drugs that change the pH of urine (sodium
bicarbonate to alkalinize, ammonium chloride to acidify). This
changes the ionization of basic or acidic toxin, limiting their
reabsorption from urine back into blood.
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y Dialysiso For dialysis of a poison to be successful, the toxin must pass freely
through the dialyzing membrane and equilibrate quickly between
dialysis fluid and blood.
o If a toxin produces quick and irreversible damage, dialysis is not auseful option
o Decreased renal or hepatic clearance are indicators of the need fordialysis.
o Toxins that respond well to treatment by hemodialysis are ASA,methanol, and ethylene glycol
o
