* Specificity of Drug Action

* Specificity of Drug Action
o 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 drug clinically is often directly related to its specificity
o Poison: A compound which has deleterious effects on cell function without having any therapeutic effects
* Example: cyanide combines strongly with Fe3+ found in many proteins interfering in their functioning
o Some drugs have absolutely no toxicity at concentrations used clinically.
* Example: penicillin inhibits a bacterial enzyme involved in the formation of bacterial cell walls.
* Humans lacking cell walls are unaffected by these concentrations of penicillin
* In between these two extremes (cyanide and penicillin) are many dugs used clinically
* Methotrexate
o 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 in psoriatic plaques.
o However, at slightly higher doses, methotrexate also inhibits reproduction of mucosal cells in the intestine, which would lead to ulceration and diarrhea
* Thus useful drugs actions are instances of selective toxicity, while non-selective toxicity gives rise to poisoning
* Generally, the useful, therapeutic effects of drugs are separable from the toxic effects based on differences in:
o Their respective mechanisms of action
o Their dose-response relationships if their mechanisms of action are similar
o The sites at which therapeutic and toxic effects are produced
* Attempts to increase the utility of a drugs are based on improved Pharmacodynamic specificity (if the mechanisms of toxic and therapeutic effects differ) or an enhanced pharmacokinetic selectivity (distribution to the desired target site)
* For specific drug:receptor interactions to occur, the drug molecule must have several points of attachmentto corresponding points on the receptor molecule
o The nature of these points of attachment and their relative positions and distances apart are all critical for the drug’s ability to combine with a receptor and to produce a response
* Molecular features necessary for acetylcholine action
o 1) positively charged N
o 2) Three Ch3 groups attached to N
o 3) Ester linkage
o 4) Spacing between N and Carbonyl C
* Acetylcholine has actions at muscarinic and nicotinic acetylcholine receptors, but many other drugs act at one but not the other.
o The acetylcholine molecule changes its shape between cis and trans forms
o This happens since it contains only single bonds that do not limit rotation
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, t needs to be 5-7 angstroms.
o Ligands specific to either the nicotinic or muscarinic subtypes have structures that limit intramolecular rotation
* Antagonists at muscarinic and nicotinic acetylcholine receptors have enough 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 at nicotinic 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 and beta adrenergic receptors, nine types of serotonin receptors, two major classes of GABA receptors (A and B) and at least four major subtypes of opiate receptors
* Molecular selectivity of drugs binding to specific receptors helps in the development 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 of schizophrenia
o Use of Raclopride 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 disease mechanisms.
o That D1 receptor specific antagonists have no utility in the treatment of schizophrenia tells us that dopamine actions at D1 receptors are not important in schizophrenia
* Stereospecificity
o Stereospecificity is not an obligatory feature of receptor selectivity for drugs but may add significantly to it
o Many drugs have optically isomeric forms in which only one isomer is active, or one isomer is considerably more potent that the other.
o This is consistent when at least three points of attachment need to exist between a receptor and its ligand, there exists either a center or plane of asymmetry in the drug
* Examples of Stereospecificity
o D and L Hyoscyamine, 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 analgesic activity, although both forms act as antitussives
o Only the L-form of norepinephrine elevates blood pressure
o D-amphetamine is much more effective CNS stimulant than L amphetamine , but they are equipotent in producing hallucinations
* Degrees of Selectivity
o 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
* Enables a compound – at least to some extent – to interact with receptors for histamine, acetylcholine and possibly catecholamines
* If the R group is large, it can also function as an antihistamine or local anesthetic
o For example chlorpromazine, procaine, and diphenhydramine share a number of properties: they are all good local anesthetics, H1 receptors antihistamines and myocardial antiarrhythmic
* However, unique parts of each of their molecules also give them pharmacological properties that are not shared with the other compounds.
* An example of how a singular molecular structure can be modified to yield a number of different drugs that have differing and specific actions
* Pharmacokinetic Selectivity
o 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
* Selectivity related to drug distribution
o 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 usefulness
o 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
* Propantheline and atropine are both good muscarinic blockers but 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 the blood-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-cell lymphomas
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 diuretics
* 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 cellular components in certain cells
* Quinine has a high affinity for malarial DNA
o 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 the precursor to the active form, that increases selectivity
* Enteric sulfonamides are bioactivated by gut bacteria to free sulfathiazole which has antibacterial activity locally in the gut
o Selective tissue vulnerability
* A drug may be relatively nonselective in terms of the range of tissues 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.
* Individual and species differences
o Bacteria VS. Host
* Differential sensitivity between bacterial and animal cell forms the basis for antibacterial therapy
* Penicillin acts on bacteria that have cell walls but not on animal cells
* Animal cells take up folic acid but bacteria synthesize it and cannot take it up
* Sulfonamides act as competitive antagonists of PABA, a precursor 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 insects
o Genetic differences within species
* Selective toxicity arising from genetic variations within a species can be harmful, beneficial or both
* A hereditary deficiency of G6P dehydrogenase renders affected individuals sensitive to primaquine-induced hemolytic anemia
* But at the same time also makes them more resistant to the growth of malaria in the liver

The action potential travels down the axon and causes neurotransmitter release
* This is a chemical neurotransmission
Neurotransmitters are small molecules released by neurons which bind receptors and elicit functional effects
* Ex) Glutamate, GABA, Dopamine, Serotonin, Acetylcholine
What do neurotransmitters do?
* Excitatory postsynaptic potentials (EPSPs)
o Increase the likelihood of action potential generation in the postsynaptic cells
o Increases membrane potential
* Inhibitory PSPs (IPSPs)
o Decreases the likelihood of action potential generation
o Decrease membrane potential
Nature of postsynaptic cell’s response to neurotransmitter depends on:
* The type of neurotransmitter released
* The type of receptors on the postsynaptic cells
* The magnitude of the response to neurotransmitter which itself depends on:
o Quantity of neurotransmitter released
o Receptor numbers
o State of the receptors
Two major types of neurotransmitter receptors
* Ionotropic
o 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
* Metabotropic
o 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, compared to ionotropic receptors
General characteristics of ionotropic receptors
* Multi-subunit protein complexes with membrane spanning domains
* Very fast onset (sub-millisecond time scale)
* Ion selectivity – cation vs. anion selectivity
* Most desensitize rapidly after exposure to agonist
Major types of ionotropic receptors (or ligand gated ion) channels
* Glutamate receptors
* Cys-loop ion channels
Three rings of negatively charged amino acids face the pore. These ensure that only cations can pass through the pore
* Ach receptor channels
Acetylcholine binding to the receptor
* There are two binding sites for acetylcholine in the extracellular domain of the receptor
* Cooperativity of binding between the two sites is evident
If you only have a few kinds of transmitters, how do you maintain diversity?
* The subunit compositions of recombinant receptors determine their pharmacological profiles
* Amino acid sequence homology is greatest within classes of subunits compared to between classes
Consequences of agonist binding to a neurotransmitter receptor
Use of patch clamp technique to measure channel function
* The opening and closing events exhibited by individual ion channels result in averaged current seen by electrophysiologists, not by performing single channel measurements
* total current curve = hyperbolic
* 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)
* Inhibition of GABA(a) or Gly receptors cause convulsions (pictrotoxin).
* Enhancement of GABA(a) or Gly receptor function would be expected to lead to sedation and anesthesia (think alcohol and volatile anesthetics)
An example of an allosteric modulator: Benzodiazepines
* Eg) diazepam (valium), flunitrazepam (Rohyphonal), chlordiazepoxide (Librium)
* Clinically useful as sedatives, hypnotics, anxiolytics, anticonvulsants.
* Danger of tolerance and dependence
* Agonists at the benzodiazepine receptor site enhance GABA-mediated currents by left shifting the GABA concentration response curves (compared to just GABA’s concentration response curve)

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
* Metabotropic
o 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, compared to ionotropic receptors
o These receptors are sometimes referred to as G-protein coupled receptors (GPCRs)
Some history
* In the 1950’s Sutherland and Rall found that stimulation of cardiac cells with epinephrine resulted in increased concentrations of a water soluble nucleotide called cAMP. They proposed that cAMP acted as a second messenger
* Neurotransmitters, hormones, and drugs that cannot cross the cell membrane (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 intracellular second messengers
* In most cases, there are multiples receptors for single neurotransmitters that bind to GPCRs. Predicted from classical binding studies
* For example, there are 5 classes of muscarinic acetylcholine receptors and 6 classes of adrenergic receptors.
* In many cases, the complex pharmacological responses produced by a single ligand are due to its actions on a number of different receptors
* The physiological roles of many of the receptors and why this diversity exists are poorly understood
Three components required for G-Protein signaling
* Receptor (on cell surface)
* G-protein (couples to receptor on intracellular side of cell membrane)
* Effects (usually enzymes)
* All three are either imbedded I the cell membrane or tightly associated with it
What does a G Protein coupled receptor look like?
* Huge family of related receptors, each a product of a different gene
* Each contains 7 transmembrane domains
* Neurotransmitter binds to GPCR on extracellular side of membrane
* G proteins bind to intracellular sections of GPCR
* 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.
* There are two major mechanisms of limiting the actions of neurotransmitter 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 of serine and threonine residues on GPCRs, by specific intracellular enzymes (kinases).
o Receptor down regulation
* Proloned exposure to agonist leads to the internalization of receptors from cell membrane, thus decreasing the numbers of GPCRs that can interact with G proteins.
G proteins
* The family of G proteins that transduce signals from membrane receptors to effector enzymes and ion channels are known as heterotrimeric (3 different subunits) G proteins
* Three subunits are called alpha, beta, and gamma in decreasing size
* The alpha subunit binds guanine nucleotides and is the major mediator of the G protein’s actions on its effector
* The beta and gamma subunits primarily function to support the interactions of alpha subunit with the plasma membrane and with GPCRs, but like the alpha subunit, they may also regulate effectors directly
The G protein activation/inactivation cycle
* In the resting state, the three G protein subunits are bound together with guanosine disphosphate (GDP) attached to the alpha subunit
* This heterotrimer can bind to an inactive GPCR.
* When an agonist binds to the GPCR, a conformational change occurs, leading to the rapid dissociation of the G protein heterotrimer from the GPCR
* This agonist binding also results in the release of GDP from the alpha subunit of the G protein heterotrimer
* The empty guanylyl nucleotide binding site on the alpha subunit is then occupied by guanosine triphosphate (GTP) that is present at high concentrations in cytoplasm.
* GTP binding causes the alpha subunit to release from GPCR as well as from the beta-gamma dimer
* 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
* The GDP-bound alpha subunit dissociates from the effector, re-associates with the beta-gamma dimer and is ready for another cycle of activation by GPCRs
Functional diversity of different members of the G protein family arises from the more than 20 different types of alpha subunits identified thus far
* Some of the most common are Gs, which stimulates adenylyl cyclase (leading to production of cAMP)
* Gi, which inhibits adenylyl cyclase.
* Gs and Gi can also interact with some ion channels
* Some G proteins are widely expressed in cells while others have a more limited distribution and more specialized functions.
* For example Gt is found in rods and cones of the retina
Some G proteins are targets of toxins
* The Gs-alpha subunit is modified for the cholera toxin such that it binds ADP-ribose to the guanyl nucleotide binding site
* This prevents the intrinsic GTPase from acting and results in persistent activation of Gs-alpha.
* 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.
* Another bacterial toxin, pertussis acts on Gi-alpha and Go-alpha subunits, preventing their activation by GPCRs.
* With the disruption of the inhibitory actions of Gi on adenylyl cyclase, once again cAMP levels rise, leading to characteristic cough seen in whooping cough
Effector enzymes regulated by G proteins
* Adenylyl cyclases and phospholipases C are the most common effector enzymes by which G proteins exert their effects
* Adenylyl Cyclases and cAMP as 2nd messengers
o 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 are stimulated 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
* Members of the Gq family and G-proteins transduce signals between GPCRs and enzymes known as phospholipase C.
* These enzymes use phospholipids as substrates
* GPCR occupation by ligand activates Gq.
* The Gq-alpha subunit binds to the phospholipase on the inner surface of the cell membrane
* This activated phospholipase then rapidly breaks down the membrane constituent PIP2 to IP3 and DAG.
* IP3 and DAG can both act as 2nd messengers
* IP3
o Small water soluble molecule that diffuses through the cytoplasm 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 mediated events in the cell, such as the activation of calcium/calmodulin dependent protein kinases
o Remains in cell membrane where in concert with phosphatidylserine and calcium, it activates protein kinase C (PKC) another serine/threonine kinase.
o Activation of PKC involves translocating it to the cell membrane where it becomes able to phosphorylate a wide variety of substrate proteins such as receptors, ion channels and other enzymes
Signal Amplification
* Each GPCR/agonist complex activates several G proteins before the agonist dissociates
* Each G protein, in turn initiates the production of many 2nd messenger molecules
* Thus the binding of agonist to one GPCR can lead to the activation of many effectors (enzymes)
How do we prove that the action of a neuromodulator is through a GPCR?
* Intracellular GTP is required
* Non-hydrolyzable GTP analog greatly prolongs action – or makes effect irreversible
* High affinity GDP -beta-s analog cannot be displaced
* Block with pertussis toxin – inactivates a subset of G-alpha proteins

* Pharmacogenetics – is the study of the influence of heredity on the response to drugs, or their fates in the body.
* How do pharmacogenetic defects differ from other inborn errors of metabolism?
o Pharmacogenetic defects tend to be “silent” in the absence of drug challenge
Why is pharmacogenetics important?
* 1) Increases physician awareness of abnormal drug responses
* 2) Knowledge of frequently occurring genetic defects that alter drug responses enables drug manufacturers to avoid introduction of unreliable drugs
* 3) Genetic defects can be useful to scientists to elucidate mechanisms underlying normal drug responses
Pharmacogenetics can be divided in three major ways
* functional subdivision
* pharmacological subdivision
* genetic subdivision
Functional subdivisions
* disorders characterized by increased sensitivity to drugs
* therapeutic failures resulting from increased resistance to drugs
* disorders exacerbated by enzyme-inducing drugs
* Diseases to which chronic drug exposure may contribute
* Disorders of unknown etiology
* Disorders associated with diet
Pharmacological subdivision
* The pharmacological classification distinguishes between alterations in a drug’s pharmacodynamics and alterations in pharmacokinetics
o Pharmacokinetic: Most affecting drug metabolizing enzymes
o Pharmacodynamic: Variation in systems targeted by drugs
Genetic Subdivisions
* The primary genetic subdivision is between monogenic (single gene locus defects) versus multigenic variants.
o Most important differences between people are multigenic. Examples include adult height and predisposition to alcoholism
* Monogenic Variants
o 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 gene for an enzyme
o Assume that there is a gene with a functional allele with a frequency of p 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 parent so 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, if q=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 qq individuals who are homozygous for the defective allele, the deficiency is referred to as recessive.
o If heterozygous (pq) also show functional deficiency, the defect is dominant
o Examples of monogenic variants include: alcohol dehydrogenase; cytochrome P450 CYP2C8 (phenytoin metabolism); glucose-6-phosphate dehydrogenase (hemolytic disorders); ryanodine receptors (malignant hyperthermia)
* Multigenic variants
o Examples include complex phenotypes such as height, IQ and increase in heart rate after administration of epinephrine
o Environmental factors often contribute to expression of multigenic traits
o Heritability values are usually derived from studies comparing monozygotic and dizygotic twins.
o These can vary markedly for different effects of different drugs: i.e. some drug effect variability have a greater genetic contribution than others.
Examples of Genetic influences on drug biotransformation
* Plasma cholinesterase variants
o 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 in anesthesia
o An atypical cholinesterase is found in 1/2000 Caucasians, and in 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 lowered affinity of the plasma cholinesterase for succinylcholine – clinical failure of drug elimination
* Acetylation polymorphism
o 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 with a Mendelian pattern of inheritance.
o There are marked ethnic differences in acetylation; less than 50% of Caucasians are rapid acetylators, unlike approximately 90% of Asians and North American Indians
o Defective acetylation in slow acetylators is due to a marked reduction 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 of NAT2 mRNA
* A decreased stability of the expressed enzymes
* Changes in the amino acid sequence of NAT2 that lead to decrease in rate of substrate metabolism
o Are there any consequences to being a slow or fast acetylators?
* Rapid acetylators may metabolize some drugs more quickly than the physician thinks and this may lead to inadequate dosing
Defects in metabolism by cytochrome P450
* Example: The metabolism of debrisoquin (an antihypertensive) by CYP2D6 is markedly affected in about 8% of the British population, such that the doses given to various patients can vary almost 30 fold.
* 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
* Many genes can confer increased vulnerability or decreased responses of a target tissue by a drug
* Glucose-6-Phosphate dehydrogenase (G6PD) deficiency
o A deficiency in G6PD predisposes patients to hemolytic drug reactions.
o The exact mechanism remains unknown but appears to be linked to the cell’s inability to maintain sufficient concentrations of the reduced form of glutathione
o Drugs that are oxidized from H2O2 in the RBC and this oxidizes glutathione which in turn may become attached to hemoglobin
o This leads to the oxidation and denaturing of hemoglobin which can damage the erythrocyte membrane and lead to hemolysis
o Approximately 400 million people carry the trait for G6PD deficiency and about 300 enzymic variants are known
o Two common variants are the A- variant found largely in African Americans and the Mediterranean variant.
o In the A- variant, the enzyme is unstable such that G6PD activity is normal in young RBCs but decreases as they age
o In the Mediterranean variant there is a low G6PD activity in all RBCs.
o A number of drugs (eg. Quinine, ASA) precipitate hemolytic crises in subjects with the Mediterranean but not A- variant
o Why haven’t these mutations been weeded out by Darwinian evolution
* G6PD deficiency increases resistance to Plasmodium falciparum malaria; G6PD gene defects thus accumulate in countries with endemic malaria
o Many different types of drugs can cause hemolysis in G6PD deficient subjects
Malignant Hyperthermia
* Used to be one of the main causes of death due to anesthesia
* Anesthetics trigger a release of calcium from sarcoplasmic reticulum in susceptible individuals
* Major body temperature increases up to 43 C.
* This is accompanied by skeletal muscle rigidity and death by cardiac failure.
* Most cases due to a mutation in ryanodine (plant alkaloid) receptor which is the sarcoplasmic reticulum (SR) calcium release channel
* Treatment with Dantrolene (SR Ca++ channel antagonist)
* Diagnostic Test for patient susceptibility to malignant hyperthermia
o Caffeine is much more potent in producing (biopsied) muscle contractions in susceptible individuals

* Dosing amounts and schedules are determined empirically, based on extensive clinical observations
* These doses are those that have therapeutic efficacy in most patients on most occasions, and produce the desired therapeutic effect with an acceptably low risk of toxicity
o 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 in the body
* 4) Pharmacodynamics? Did the target disuse respond to drug in the expected manner?
* Compliance
o Most patients fully intend to follow their physician’s instructions regarding their prescriptions
o Indeed, 97% of prescriptions are filled within 5 days
o So why is patient compliance and issue?
* Compliance with a physician’s instructions is variable and depends on a number of factors
* 1) Duration of treatment: There is lowered compliance for drugs that must be taken for a long time
* 2) Complexity of the dosing regimen (inconvenience):
o Ameliorated somewhat by marketing of pharmaceutical mixtures
o Eg. Glucocorticoid and Beta-adrenoceptor agonist administered in one dose for asthma.
o But this results in loss of therapeutic flexibility
* 3) Patient’s perception of the seriousness of the disease and of the importance and efficacy of treatment
* 4) Side effects of therapy, if serious, tend to decrease compliance
* 5) Continuity and ease of contact with physician
o Noncompliance is a serious problem in the treatment of hypertension
* High blood pressure itself does not cause symptoms in most patients
* 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 therapies include:
* 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 bioavailability
o Factors affecting bioavailability
* GI or liver pathology
* E.g.) Diarrhea, biliary obstruction, hypermotility, rescued GI blood flow
* Formulation of the drug preparation, leading to differences in release of drug into GI Fluids
o Brand names are often (but not always) better formulated than generic drugs, giving more uniform and better bioavailability
* Pharmacokinetic variation in drug responses
o 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
* (e.g. elimination rate of Mecillinam is 4 times slower in elderly)
* Smoking
o Pharmacokinetic variation is most evident in early infancy and advanced age, but may also be affected by disease processes at any age.
o Penicillin, and other antibiotics, do not normally cross the blood brain barrier
o However, inflammatory processes (e.g. meningitis) increase antibiotic permeability, increasing their effectiveness
o But… this may also increase the risk for toxicity (high concentrations of penicillin can cause seizures)
o In contrast, bacteria in localized abscesses or other walled-off infections may be resistant to antibiotics because they can’t gain access
* Variation in dosages for adults vs. children
o 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 to different 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 the metabolic 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 and small children whose surface area to mass ratio is considerably higher than adults
* 1) Calculation of children’s dose by age (Young’s Rule):
* Age/(Age+12) = fraction of adult dose
* 2) Calculation of Children’s dose by body surface area:
* (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 variation
o Pharmacodynamic variations, leading to altered target tissue responses to drugs may be due to genetic abnormalities (see pharmacogenetics) or to disease processes
o Hyperthyroidism is frequently associated with an increased number of beta adrenoceptor, resulting in an increased sensitivity to the cardiovascular effects of norepinephrine
o Sometimes drug interactions will alter Pharmacodynamic sensitivity to one or more of the drugs administered
o For example. Patients with chronic left ventricular failure are often treated with a diuretic (to reduce edema) and a cardiac glycoside (to increase cardiac muscle contractility).
o Increased cardiac output by the cardiac glycoside increases renal blood flow which increases the urinary response to diuretic.
o This may lead to excessive loss of K+ into urine, and the resulting hypokalemia increases myocardial sensitivity to the cardiac glycoside, increasing the chances for arrhythmia.
* Tolerance to one drug can also be expressed as cross tolerance to the effects of another
o This is most clearly seen in relation to central nervous system depressants 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 has been taken chronically but it can also lead to decreased responses to other drugs that produce similar effects
o For example. Alcoholics show significantly decreased responses to general anesthetics, necessitating the administration of higher doses

* Drug Interactions
o 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 during hospitalization is 10-13, with many receiving more than 20 drugs.
o In addition, many patients also consume analgesics, cold remedies and other drugs that are available without a prescription
o Furthermore, there is a universal exposure to other bioactive chemicals found in food additives, insecticides, cleaning agents and cosmetics
o A major concern is that the administration of one drug will change the effect of another by enhancing or diminishing its effects at its site of action
* Classification of Drug Interactions
o Consequence
* Beneficial or adverse
o Site
* External or internal
o Mechanism
* Pharmacodynamic
* Pharmacokinetic
* Physiologic
* Classification of drug interactions based on consequence
o Can have an enhanced or diminished therapeutic efficacy
o Can also have an enhanced or diminished toxic effect
* Classification based on site of interaction
o External
* Physiochemical incompatibilities (e.g. precipitation or inactivation) 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:
* Some antibiotics (kanamycin, gentamicin) enhance the depolarizing block produced by succinylcholine at the neuromuscular junction
* Morphine induced respiratory depression is reversed by opioid antagonist naloxone
* Classification based on mechanism
o Physiological
* Physiological interactions are those in which the actions of drugs 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 scenario
o Pharmacodynamic interactions
* Pharmacodynamic interactions
* Pharmacodynamic interactions are those occur when the effects of two drugs impinge on a common effector. The consequences of this are:
o Additive
o Supra-additive
o Infra-additive
* The descriptions “additive, supra-additive and infra-additive” provide no information regarding the mechanism of drug interaction
* Example of a pharmacodynamic interaction between alcohol and a barbiturate
* Note concentration for barbiturate in barbiturate and ethanol combo for death is much lower than for death by a barbiturate alone.
* Another example of a pharmacodynamic interaction
* Complex interactions, involving regulation of neurotransmitter receptor numbers, can affect drug responses
* Guanethidine (an antihypertensive) decreases the release of norepinephrine pre-synaptically; a consequence of this NE receptor up regulation after chronic Guanethidine treatment
* If a patient taking Guanethidine is also administered desipramine (an antidepressant that blocks NE uptake), this leads to significant increases in blood pressure
o Pharmacokinetic interactions
* Absorption, Distribution, Biotransformation, Excretion
* Gastrointestinal absorption
* Physicochemical interactions
o 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 cholestyramine
o Absorption of drug by activated charcoal in treatment of poisoning
* Changes in gastrointestinal motility
o Changes in GI motility affect the rate and/or completeness of drug absorption
* Increased gastric emptying and intestinal motility
o 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
* Decreased gastric emptying and intestinal motility
o Opioid analgesics and anticholinergics decrease the rate of gastric emptying, slowing absorption and decreasing the peak drug concentration
* Drug-induced changes in mucosal function
o Drugs with GI toxicity (ex. colchicine) may damage the GI mucosa altering absorption of other drugs
* Drug Distribution
* Blood flow
o Organ uptake and clearance of drugs depends on blood flow
o Some drugs – like beta blockers and antiarrhythmics – decrease cardiac output and thus the hepatic clearance of drugs such as lidocaine which have a high extraction rate in liver
* Serum protein binding
o Many drugs are bound to serum proteins, especially to albumin
o Such drugs may be displaced by other highly bound drugs administered concurrently
o When a displacing drug is added to therapy, it can in theory lead to the immediate appearance of toxicity to the first drug
o Even a small amount of displacement of a highly bound drug can cause a large relative increase in free drug in serum
o Clinically important pharmacokinetic interactions due to displacement from plasma proteins will occur only when:
* Administration of the displacing drug is started 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
* Biotransformation
* Pharmacokinetic interactions between drugs can occur by drug either inducing or inhibiting an enzyme that metabolizes another.
* This is particularly true for the cytochrome P450 family of 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 biotransformation of either themselves or other drugs
* Consequences of enzyme induction are:
* Increased rate of hepatic biotransformation of drug
* Increased rate of production of metabolites
* Increased hepatic drug clearance
* Decreased serum drug half-life
* Decreased serum total and free drug concentrations
* Decreased pharmacological effects if metabolites are inactive
o Enzyme inhibition
* Clinically important inhibitors of drug biotransformation are:
* Acute ethanol exposure which inhibits propranolol, diazepam and chlordiazepoxide metabolism
* Cimetidine (decreases gastric acid secretion) is a potent cytochrome P450 inhibitor and inhibits biotransformation of acetaminophen, diazepam, digoxin, phenytoin and warfarin among other drugs
* Disulfuram inhibits aldehyde dehydrogenase, causing acetaldehyde accumulation after alcohol consumption
* Grapefruit juice contains a bioflavonoid 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 including calcium channel blockers, cyclosporine, midazolam and caffeine
* In general, inhibition of drug biotransformation is the clinically most important mechanism of pharmacokinetic interactions
* Excretion
* 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 G secretion during WWII

* Adverse Drug Reactions
o All drugs have the potential to produce deleterious consequences
o 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 drug comes 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 the thalidomide disaster of 1961.
* Thalidomide
o 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 pregnant women of a presumably safe new hypnotic called thalidomide
o Use of thalidomide in the first trimester, when forelimb buds were developing caused the deformities
o This disaster led to the re-evaluation of the methodology and regulations applied to the testing of the safety of drugs.
o More stringent legislation was enacted in many countries to improve the likelihood that serious toxicity would be detected before drugs come to market
o 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 or therapeutic errors
* Severity of ADRs
o Mild
* No antidote, therapy or prolongation of hospital stay is required
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
* The adequate assessment and classification of ADRs requires a knowledge of the mechanisms by which they are produced
* ADRs are the result of the interplay between the characteristics of the administered drug and some inherent or acquired characteristic of the susceptible patient
* 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 or something unusual or pathological about his physiology
o A combination of the first two possibilities
* Some ADRs are dose-related
o E.g. CNS depression by sedative hypnotics
o Are by far the most common occurrences of ADRs (95%)
o These ADRs, which can be prevented by adjusting the patient’s 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 ADR may be either an extension of the usual pharmacological effects of the drug or an unusual toxicity caused by the drug and/or its metabolites
* Other ADRs are not dose related
o These are less common and are due to an increased susceptibility of the patient
o The ADR usually manifests as a qualitative change in the patient’s response 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 detected only after the patient is exposed to the drug
o E.g. slow acetylators of isoniazid are more prone to a genetically determined polyneuropathy
* Major Features of ADRs
* Allergic or hypersensitivity immunological reactions
o 1) anaphylactic
o 2) Cytotoxic
o 3) Immune-complex-mediated
o 4) Cell-mediated
* Anaphylactic
o 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 that lead 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 or other antimicrobials.
o Up to a quarter of asthmatic patients are intolerant of ASA, which may cause severe bronchospasms, by a mechanism unrelated to IgE
* Cytotoxic
o These are complement fixing reactions between antigen and antibody on the cell surfaces of RBCs, WBCs and platelets, leading to cell lysis
o Drugs usually act as haptens, binding to a receptor on the cell surface to make up a complete antigen, against which an antibody reacts.
o Ag/Ab reactions with complement fixation may lead to a number of clinical outcomes including hemolytic anemia, agranulocytosis, or thrombocytopenic purpura
* Immune-complex mediated
o These reactions occur when Ag/Ab complexes deposit on target cells.
o Complement is then activated, causing tissue destruction by release of lysosomal enzymes.
o This can cause glomerulonephritis and collagen disease
* Cell mediated
o These allergic arises from a direct interaction between an allergen and sensitized lymphocytes, leading to the release of cytokines.
o Most cases of eczematous and contact dermatitis are cell-mediated allergic reactions.
o Common causes are topical antihistamines and PABA
* Frequencies of ADRs
o Most studies show that ADRs in hospitalized patients (excluding mild cases) is between 10% and 20%
o Between 0.2% and 21% (median = 5%) of all patients are admitted to 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
* Risk Factors associated with ADRs
o Age
* Older subjects (>60) are more susceptible to ADRs.
* They are more likely to bleed during heparin treatment, and are more sensitive to analgesics and more likely to develop digitalis toxicity
* Impaired drug elimination and increased receptor drug sensitivity are proposed mechanisms.
* However, older patients also tend to have more diseases and to 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)
* Sample Size required for detecting ADRs
o 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 detected
o This approach obviously has it limitations. Ex. Clozapine (antipsychotic) was introduced in Finland in 1975. Within 6 months, 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 only 15 weeks because of ADRs.
o These examples illustrate the importance of postmarking monitoring of new drugs.

* Toxicology
* Toxicology is the study of the adverse effects of chemical agents on biological systems
* A number of classifications can be used to subdivide the general field of toxicology
* Toxic agents themselves may be classified according to
o 1) The potential for a compound to produce toxicity
o 2) The source of the toxin (e.g. snake or spider venom or poison ivy)
o 3) Chemistry of toxins
o 4) mechanism of action
* The concentration response curves for the effective, toxic, and lethal doses of a drug are independent of one another. There are three assumptions:
o 1) observed response actually due to compound administered
o 2) degree of response related to magnitude of dose
o 3) response is quantifiable
* Threshold Dose
o The lowest does that evokes a given response
o For example, different doses of ASA produce GI bleeding, tinnitus, and generalized acidosis
o Some toxicities develop rapidly and reversibly (e.g. inebriation due to methanol) while others develop more slowly and may be irreversible (e.g. Methanol producing retinal nerve toxicity, leading to blindness)
* LD50
o The does required to kill 50% of exposed tests animals
o Depends on species, strain, sex, age and route of drug administration
o E.g. Dioxin LD50(s) vary 1000 fold between guinea pig and hamster
o 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 determine the therapeutic index (T.I.)
* Mechanisms of Toxicity
o Receptor mediated toxicities
* Reversible binding of parent molecule and/or stable intermediate 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 macromolecules such as DNA, protein, or lipid
* If given a sufficiently high concentration, most drugs can initiate reversible 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 an antihypertensive
* Alternatively, most carcinogens, teratogens, and chemicals producing neurodegenerative 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 paraquat
* How can drug toxicity be modified?
o 1) Decrease in function of pathways of drug elimination (primarily liver and kidney), resulting in excessive accumulation.
* Ex) aminoglycoside antibiotics are primarily excreted unchanged by kidney
o 2) Enhanced pathways of Bioactivation to toxic reactive intermediates
o 3) Reduced detoxifying or cytoprotective pathways for removing reactive 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 macromolecules damaged by reactive intermediates
* What factors are important for drug toxicity?
o Age
* Toxicity of compounds may vary with subject age because of age dependent differences in relative organ size, maturity of enzyme systems and toxin distribution.
* Ex) Malathion toxicity depends inversely on hepatic cyto. P450 activity
* Young children are less susceptible to toxicity produced by acetaminophen, digoxin, and theothylline, but are more sensitive to toxicity produced by antihistamines, lead and salicylates than are adults.
* The very young and elderly tend to have reduced renal function which makes them more susceptible to compounds that are excreted by kidneys
o Route or site of drug administration
* IV is gold standard
o 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.
* E.g. acute exposure to benzene leads to CNS depression, while chronic exposure is associated with hematological 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 tetracyclin and rifampin
* Liver metabolism of drugs is also affected by nutrition state
o Genetic variability
* A common cause of predisposition to toxicity is a genetic difference in one or more critical pathways involved in the actions of the drugs
* In the case of receptor mediated toxicities, low or absent levels of critical enzymes such as the cytochrome P450 and N-acetyltransferase, result in drug accumulation and lead to toxic levels
* In the case of toxicities produced by reactive intermediates, a predisposition to toxicity may arise from genetically high activity and/or inducibility of bioactivating 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 leads to 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 renal diseases) are easily predicted
* However, the effects of other diseases (e.g. cardiovascular) may be less easy to predict
* Ex lidocaine metabolism occurs primarily in the liver, and decreased cardiac output would affect its hepatic clearance.
* Disease which effect the numbers of plasma binding proteins will affect toxicities of highly protein bound drugs.
* GI diseases will affect the toxicities of drugs that are metabolized extensively in intestinal walls during absorption

* Toxicology II
o Predictive toxicology
* Assesses risks associated with a situation in which the toxic agent, the subject and exposure conditions are defined
* Lowest observed effect level
* No observed effect level
o Increasing technological sophistication means that we can now detect 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 that compounds have (in 1971 the acceptable blood level for lead in children was 40 micrograms/deciliter; in 1993 it was 10 micrograms/deciliter)
* Poisonings
o 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%
* Drug categories most responsible for fatalities are (in order)
o 1) analgesics
o 2) antidepressants
o 3) stimulants (including illegal drugs)
o 4) hypnotic sedatives
o 5) antipsychotics
o 6) cardiovascular drugs
o 7) alcohols
* Break down of poisonings by age:
o 56% of cases involved children under the age of 6, 6% involved kids aged 6-12 and 48% involved adults
* Poison
o Any substance which by its chemical action may cause damage to structure or disturbance of function
* 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
* Principles of poisoning treatments
o 1) minimize systemic absorption of toxin
o 2) antagonize effects of toxin that has already been absorbed
o 3) encourage metabolic processes that reduce toxicity, while inhibiting processes that might increase toxicity
o 4) Enhance rate of elimination of toxin from body
o 5) provide good clinical care during the recovery phase
* Modification of absorption and distribution of poisons
o A) Poisons taken orally
* Most toxins are absorbed orally (about three-quarters). These should be either expelled or prevented from being absorbed
* 1) emesis
o induced vomiting is used to remove toxins from the stomach
o Ipecac – mixture of plant alkaloids – is most often used; it triggers emesis in 5-20 minutes by acting at the chemoreceptor trigger zone and by local GI irritation
o Use of Ipecac is contraindicated by coma or convulsions, 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 systemic absorption) decreases the efficacy of emetic so ipecac isn’t given more than half an hour after ingestion of a liquid poison, or one hour after ingestion of a solid poison
* 2) Gastric lavage – stomach pumping
o This is often less effective than emesis induced by ipecac in removing solid material from the stomach
o Lavage may be appropriate when emesis is contraindicated (ex. Coma and convulsion), but extreme care must be taken to prevent tracheal aspiration of fluids
* 3) Activated Charcoal
o 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 should be used.
o The ability of activated charcoal to prevent absorption depends on the poison and the time since ingestion.
* 4) Local antidotes
o 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 counter fluoride poisoning
* Strong acids or bases should never be used to neutralize ingested strong bases or acids, respectively (it’s a highly exothermic reaction!)
o Pulmonary Route
* Remove patient from site of exposure to toxic gases
o Dermal Route
* 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 be avoided
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.
* Techniques for altering distribution of toxins
o 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-ionized salicylate, decreasing distribution into the CNS.
o In the case of morphine, if the non-ionized form leaves blood and enters the stomach it becomes ionized and has difficulty re-entering the bloodstream.
o Repeated dosing with active charcoal can thus still be used in treating morphine overdose even if it is originally administered parenterally
* Antidotal Therapy
o 1) Competitive antagonism
* Ex) Naloxone (Narcan) is a competitive antagonist at opioid receptors, reversibly competing with agonist for binding sites on the mu and kappa opioid receptors.
* Ex) Flumazenil is a competitive antagonist of benzodiazepine receptor 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
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 which reacts 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 and digoxin overdose
* Excretion
o 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 systemic administration 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.
* Dialysis
o 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 a useful option
o Decreased renal or hepatic clearance are indicators of the need for dialysis.
o Toxins that respond well to treatment by hemodialysis are ASA, methanol, and ethylene glycol
Drug Specificity 2/28/11 11:07 PM

Ligand Gated Ion Channels 2/28/11 11:07 PM

G Protein Coupled Receptors 2/28/11 11:07 PM

Pharmacogenetics 2/28/11 11:07 PM

Variations in Drug Responses 2/28/11 11:07 PM

Drug Interactions 2/28/11 11:07 PM

Adverse Drug Reactions 2/28/11 11:07 PM

Toxicology I 2/28/11 11:07 PM

Toxicology II 2/28/11 11:07 PM