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312 Cards in this Set

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What is toxicology?
The area pharmacology concerned with the undesirable effects of chemicals and biological systems.
What are drugs?
Substances that act on living systems at the chemical, molecular level
What are drug receptors?
The molecular components of the body with which a drug interacts to bring about its effects.
What is pharmacodynamics?
The actions of a drug on the body, including receptor interactions, dose response phenomenon, and mechanisms of therapeutic and toxic action.
What is pharmacokinetics?
The actions of the body on the drug, including absorption, distribution, metabolism, and elimination.
What are the four forms of permeation?
1. Aqueous diffusion.
2. Lipid diffusion.
3. Transport by special carriers.
4. Endocytosis, pinocytosis
None
What are the five determinants of drug distribution?
1. Size of the organ.
2. Blood flow.
3. Solubility
4. Binding
5. Ion trapping
None
What is first -- pass effect?
When a significant amount of the drug agent is metabolized in the gut wall, portal circulation, and liver before it reaches the systemic circulation
What is first ordered drug elimination?
When the rate of elimination is proportionate to the concentration of the drug. These drugs have a characteristic half-life of elimination, that is constant regardless of the amount of drug in the body.
What is a zero order elimination?
When the rate of elimination of a drug is constant regardless of its concentration.
What is the volume of distribution?
The ratio of the amount of a drug in the body to its concentration in the plasma or blood.
What is Clearance?
the ratio of the rate of elimination of a drug to its concentration in plasma or blood.
What is a half life?
the time it takes for the amount or concentration of a drug to fall to 50% of an earlier measurement. For 1st order drugs it is constant regardless of concentration, but for zero order kinetics it is not.
What is bioavaliablity (F)?
The fraction or percentage of the administered dose of a drug that reaches the systemic circulation.
What is the area under the curve (AUC)?
The graphic area under a plot of a drug concentration in plasma versus time after a single dose of a drug or during a single dosing interval. It is used to calculate the bioavailability of a drug given by any route other than IV.
What are Peak and Trough Concentrations?
The max and min drug concentrations in plasma or blood measured during cycles of repeated dosing.
What is minimum effective concentrations (MEC)?
the plasma concentration below which a patient's response is too small for therapeautic benefit.
What is the first pass effect?
The elimination of drug that occurs after administration but before it reaches the systemic circulation
What is steady state?
The condition in which the average total amount of drug in the body does not change over multiple dosing intervals
What is extraction?
The fraction of a drugn in the plasma that is removed by an organ as it passes thorugh that organ
What is bioequivalence?
The equivalence of blood conc. of two preparations of the same drug measured over time. ie. show comparable bioavailability
What is biodisposition?
The process of drug absorption, distribution, and elimination. Synonym of Pharmacokinetics
What are three important drugs which follow zero-order rather than first-order kinetics?
ethanol, aspirin, phenytoin
What are 4 general mechanism by which drugs effects are produced?
Interaction with receptors, alteration of the activity of enzymes, antimetabolite action, nonspecific chemical or physical interactions
What is volume of distribution (Vd) and how is it calculated?
the hypothetical volume of total body fluid into which a drug appears to distribute.
Vd = amt of drug administered (mg)/initial plasma conc. (mg/L)
None
What is the Henderson-Hasselbalch equation?
pH = pKa + log [unprotonated species]/[protonated species]
Does an acid or a base have a low pKa?
Acid
What physical factors influence drug absorption?
Blood flow to the absorption site; total surface area available for absorption; contact time at the absorptive surface
What is therapeutic equivalence?
Drugs which have comparable efficacy and safety.
What factors affect bioavailablity?
first pass metabolism, solubility of the drug, chemical instability; nature of the drug formulation
What is a class I drug?
A drug given at a dose which is less than the binding capacity to albumin, maintains a high bound-drug fraction.
What is a class II drug?
A drug given at a dose which is higher than the binding capacity of albumin, a large portion of the drug is in the free state.
What are first order kinetics?
When the rate of drug metabolism is directly proportional to the concentration of free drug such that a constant fraction of drug is metabolized per unit time. The drug concentration is much less than the Michaelis constant Km.
What are zero-order kinetics?
When the rate of drug metabolism remains constant over time and the catalyzing enzyme becomes saturated due to the drug concentration being much greater than Km. This results in a constant amount of drug being metabolized per unit time.
What is Phase I metabolism?
The conversion of lipophilic molecules to more polar molecules by introducing or unmasking polar functional groups often by using the P450 system. This may/may not change the drug's activity.
What is the generalized oxidation equation of Phase I conversion catalyzed by P450?
Drug + O2 + NADPH + H --> changed drug + water + NADP+
What is cytochrome P450 (CYP)?
Many families of heme-containing isozymes which reside in the SER of cells and catalyze the Phase I oxidative metabolism of drugs. Specific isozymes are responsible for the metabolism of specific drugs.
What are inducers of P450?
Certain drugs which are capable of increasing the synthesis of one or more CYP isozymes and thus increasing the metabolism of themselves or other drugs (ie. phenobarbital, rifampin, carbamazepine)
What are inhibitors of P450?
Drugs which either compete for the same isozyme as another drug or inhibiting other CYPs thus leading to reduced metabolism of other drugs.
What are Phase I reactions which do not involve P450?
amine oxidation, alcohol dehydrogenation, and hydrolysis
What is Phase II metabolism?
Conjugation reactions with endogenous substrates to make metabolites from Phase I even more water soluble and able to be excreted by the kidneys
What is ion trapping?
The manipulation of the pH of the urine to increase the ionized form of an undesirable drug and thus minimize its back-diffusion in the kidneys and increase its clearance.
What is the equation for a drug's half life?
t1/2 = (0.693 Vd)/ CL
What is the equation for a drug's renal clearance?
CL = RPF x extraction ratio
What is total body clearance?
The sum of the clearances from the various drug metabolizing and eliminating organs.
What abnormalities in patients will prolong a drug's half-life?
diminished renal plasma flow or hepatic blood flow; decreased extraction ratio; decreased metabolism
What is the equation for total body clearance?
CLtotal = (k) Vd
What is the equation for the steady state concentration?
Css = rate of infusion/ CL
Does doubling the infusion rate of a drug change the time needed to reach steady state?
No, it only doubles the achieved steady state concentration
How much of the steady state concentration is achieved in the time of one half-life for the drug?
50% of the steady state concentration
How many half-lives does it take for a drug to reach steady state?
4 half-lives
How long does it take for a drug to wash out of the system after reaching steady state?
The same amount of time to reach steady state.
What is a loading dose and how is it calculated?
A single dose to achieve the desired plasma level rapidly, followed by an infusion to maintain the steady state (maintenance dose)
loading dose = (Vd)(desired steady state plasma conc.)
None
How do you change the drug dosing to reduce the amplitude of swings in drug concentration?
use smaller doses at shorter intervals
How much time does it take to reach 90% of the steady state on IV administration?
3.3 x half-life
What is Fick's Law of Diffusion?
Rate of diffusion = (C1-C2) x (Permability coefficient/thickness) x area
What are the three types of drug receptors?
Type I: plasma membrane
Type II: cytoplasm
Type III: nucleus
None
What is One-Compartment distribution?
When a rapid equilibrium is achieved between plasma and tissue distribution following drug administration. Plasma concentration time profile declines mono-exponentially.
What is Two-Compartment distribution?
Rapid distribution of a drug to a central compartment followed by slow distribution to tissues/binding sites. This results in a bi-exponential plasma concentration time profile.
What are characteristics of an active parent drug?
very lipid soluble, less polar, less ionized, weak electrolyte, more able to penetrate cell membrane
What are the characteristics of an inactive drug or drug metabolite?
less lipid soluble, more polar, more ionized, strong electrolyte, less able to penetrate cell membranes
What are the five important interactions with drugs that affect drug metabolism?
Drug-Age interaction; Drug-Drug interaction; Drug-Endogenous substance interaction; Drug-Disease interaction; Drug-Genetic interaction
How do liver and cardiac disease affect drug metabolism?
Both slow metabolism by limiting the livers functionality and blood flow to the liver respectively.
What are the chemical forces involved in drug binding?
electrostatic forces; hydrogen bonding; van der waals forces; hydrophobic bonds
Note: most drug binding interactions are NOT covalent
None
What is a drug receptor?
any component tat is receptive to interacting with drugs or endogenous substances and is capable of initiating a subsequent response
What are drug binding sites?
receptive components that can interact with or bind to substances but are not capable of initiating any subsequent response (eg. Albumin)
What is the equation to calculate loading dose?
LD = Css x Vd (L/kg) x Wt
What kind of drugs bind to albumin?
acidic drugs
What kind of drugs bind to alpha1 glycoprotein in the serum?
basic drugs
Which drugs display two compartment pharmacokinetics?
digoxin, lidocaine, and phenytoin
How do you calculate Vd?
dose/initial blood concentration
What are some drugs which undergo only renal clearance?
gentamicin, tobramycin, vancomycin
What are some drugs which undergo only hepatic clearance?
theophylline, warfarin, phenytoin, lidocaine
What are some drugs which undergo both renal and hepatic clearance?
digoxin, procinamide, penicillin G
What are some drugs which follow zero order or dose dependent kinetics?
at high doses: phenytoin, aspirin, and ethyl alcohol
What is the use of digoxin?
atrial fibrillation, atrial flutter, and CHF
What are some of the pharmaocokinetic characteristics of digoxin?
narrow therapeutic index, large Vd, high F, two compartment distribution profile
What are some of the pharmaocokinetic characteristics of gentamycin/tobramycin?
cleared exclusively by the kidney, tobramycin doesn't pass the GI tract so can only be given IV or IM
What are some of the pharmaocokinetic characteristics of lidocaine?
low F, eliminated primarily by the liver, two-compartment model of distribution
What are some of the pharmaocokinetic characteristics of penicillin G?
elimination is dependent on renal function,
What are some of the pharmaocokinetic characteristics of phenytoin?
approximates zero order kinetics of elimination, high F, eliminated primarily by the liver, two compartment model of distribution
What are some of the pharmaocokinetic characteristics of propanolol?
low F (extensive 1st pass metabolism), lipid soluble, large Vd
What are some of the pharmaocokinetic characteristics of theophylline?
narrow therapeutic index, approaches zero-order kinetics, high F, eliminated primarily by the liver
What are some of the pharmaocokinetic characteristics of vancomycin?
not absorbed orally, must be given IV, eliminated by the kidney
What are some of the pharmaocokinetic characteristics of warfarin?
long half life, highly protein bound so takes a while to reach therapeutic effect, high F, eliminated primarily by liver
What is the use of gentamycin/tobramycin?
aminogycoside antibiotic, treat bacterial infections esp. gram negative
What is the use of lidocaine?
local anesthetic and antiarrhythmic
What is the use of penicillin G?
antibiotic used as prophylaxis and treatment of gram positive bacteria
What is the use of phenytoin?
antiepileptic, stabilizes the inactive state of voltage gated sodium channels
What is the use of propranolol?
beta-blocker, used in treatment of hypertension
What is the use of theophylline?
methylxanthine drug used to treat respiratory dz such as COPD and asthma
What is the use of vancomycin?
glycopeptide antibiotic to treat gram positive bacteria
What is the use of warfarin?
anticoagulant
What is the drug interaction concern with using procaine (novacaine) or procaine amide (pronetyl) in patients that are using sulfa drugs?
the phase I metabolism of the procaine family drugs produces PABA which is a structural analog to sulfonamide and would competitively inhibit the antibacterial effect
What is a wide therapeutic index?
a drug with concentration ranges in which the probability of efficacy is high and toxicity is low
What are some drugs with a wide therapeutic index?
B-lactam antibiotics, H-2 antagonists
What are some drugs with a narrow therapeutic index?
digoxin, aminoglycosides
When are dose adjustments best made and why?
at steady state; minimizes potential for over/underdosing, assumes max and stable distribution
Why are loading doses used?
used with meds with long half lives which will take a long time to reach a therapeutic effect (steady state will still take ~4 half-lives), in patients with critical dz states which need the effect of the drug immediately
What kind of drugs are given by continous infusion?
drus which are not safe to give a bolus or loading dose, those drugs which require a maintenance of concentration, often meds with a short half-life
What kind of medication interactions affect absorption?
chelation, changes in stomach pH
What kind of medication interactions affect distribution?
competition for binding sites, changes in protein binding in disease states
What kind of medication interactions affect metabolism?
inducers/inhibitors of CyP450, and other metabolic pathways
What kind of medication interactions affect elimination?
competition for elimination pathways esp in kidney
What are three types of medication interactions?
drug-drug; drug-disease state; drug-nutrient
What is the drug interaction between sucralfate and digoxin?
sucralfate coats the stomach and decreases digoxin absorption
What is the drug interaction between ciprofloxacin and aluminum hydroxide?
chelation leading to decreased absorption of cipro
What is the drug interaction between itraconazole and raniditine?
raniditine decreases stomach pH and decreases absorption of itrazonazole
What is the drug interaction between aspirin and warfarin?
aspirin competes for protein binding sites of warfarin leading to increased free warfarin concentration and increased active drug and increased efficacy of warfarin
What is the drug interaction between carbamazepime and oral contraceptives (OCP)?
carbamazepime is a CyP450 inducer which leads to increased OCP metabolism and failure
What is the drug interaction between saint john's wort and warfarin?
st. Johns wort is a CyP450 inducer and leads to increased metabolism of warfarin
What is the drug interaction between voriconazole and tacrolimus?
voriconazole is a CyP450 inhibitor and leads to increased tacrolimus conc. And supratherapeutic effects
What is the drug interaction between disulfiram and whiskey?
disulfiram inhibits alcohol dehydrogenase and leads to increased alcohol concentrations and sickness
What is the drug interaction between probenecid and ampicillin?
probenecid blocks tubular secretion of ampicillin and leads to increased ampicillin concentrations
What is the drug interaction between gentamicin and cyclosporine?
both renally eliminated and nephrotoxic
What is the drug interaction between ciprofloxacin and ensure nutrient supplements?
divalent and trivalent cations of ensure bind to the cipro and result in chelation and decreased cipro absorption
What is the drug interaction between phenytoin in a burn patient?
decreased albumin, decreased bound phenytoin, increased free phenytoin and possible overdose
What is the drug interaction between tobramycin in an ascitic patient?
increased extracellular fluid, increased tobramycin Vd, possible supratherapeutic levels
What is drug affinity?
the propensity of a drug to bind to a receptor, typically expressed by its Kd value (k2/k1) or (rate to for DR complex/rate to break DR complex)
What is the relationship btw Kd and affinity?
inverse relationship since Kd is the conc of a drug that will occupy 50% of receptor population
What does the fraction of receptors occupied by a drug depend upon?
affinity and concentration of drug
What does the total number of receptors occupied by a drug depend upon?
fraction of the receptor population occupied and the number of receptors in the given tissue
What is drug selectivity?
a drug's ability to interact with one type of receptor versus other receptors; for any drug selectivity will decrease as dose is increased
What is the drug-dose relationship?
the correspondence btw the amt of drug and the magnitude of the response produced
What is the simple occupancy theory of drug-dose response?
the linear relationship btw the number of receptors occupied by a drug and the magnitude of response, only when all receptors are occupied is the max response achieved
What is the modifiec occupancy theory of drug-dose response?
the positive, though non-linear relationship btw the number of receptors bound by drug and the response created, the max response can be achieved without all receptors bound and different drugs have varying capacities to elicit a response
What is drug efficacy?
the intrinsic activity of a drug and it is the plateau or max response of a drug's dose response curve, a drug with greater efficacy is able to achieve a greater therapeutic benefit than a less efficacous drug
What is drug potency?
a measure of the amount of drug necessary to produce an effect of a given magnitude, measured by the conc of drug producing 50% of its max response (ED50); depends on a drugs affinity fo the receptor (Kd) and efficiency the drug-receptor complex is coupled to a response
What are spare receptors?
receptors that do not have to bind drug in order for the max effect to be produced, ie, Kd greater than EC50
What are the effects of competitive antagonism?
a change in ED50 results because more of the agonist is required to achieve 50% of the response, but the max response or efficacy of the agonist is not affected because large doses of the drug can overcome the effects of the competitive antagonist
What are the effects of non-competitive antagonism?
a decrease in the maximal response due to the loss of available receptors to interact with the agonist drug, however the remaining receptors would exhibit the same affinity Kd and so the ED50 would not change
What are the effects of partial agonists on full agonists?
since the partial agonists cannot achieve the same max response as the full agonists they can reduce the max response of full agonists when given together
What are three means by which toxic effects can result from drugs?
by the drug's action at the intended receptor but to an excessive degree; the drug's action at identical receptors but in different tissues or affecting different effector pathways; actions mediated by different types of receptors
What is the quantal dose response relationship?
the magnitude of the dose on the proportion of the poulation that responds, are useful in determining doses in which most of the population responds
What is a pharmacologic antagonist?
a drug that binds to its receptor without activating it
What is a competitive antagonist?
a pharmacologic antagonist that can be overcome by increasing the dose of agonist
What is an irreversible antagonist?
a pharmacologic antagonist that cannot be overcome by increasing the dose of agonist
What is a physiological antagonist?
a drug that counters the effects of another by binding to a different receptor and causing opposing effects
What is a chemical antagonist?
a drug that counters the effects of another by binding the drug and preventing its action
What are the characteristics of a intracellular receptor?
bind to lipid soluble compounds (steroids), often alter gene transcription, are slow acting bc of the lag period to synthesize the protein, effects often persist for hours or days bc of the slow turnover of the proteins activated
What are some endogenous substances which utilize tyrosine kinase receptors?
insulin, epidermal growth factor (EDF), platelet derived growth factor (PDGF)
What are some examples of substances which use ligand gated channel receptors to transmit signals?
acetylcholine, GABA, excitatory aas (glutamate, aspartate, glycine)
What is pharmacodynamic tolerance?
desensitization phenomenon where a decreased response to a drug or hormone occurs slowly with time
What is tachyphylaxis?
rapid development of diminished responsiveness after drug administration
What are some mechanisms which down regulate a receptors responsiveness to an agonist?
agonist induced phosphorylation of the activated receptor and binding by beta-arrestin; receptor down regulation; post receptor adaptations
What is homologous desensitization?
when the desensitization of a receptor is restricted to the receptor activated by the agonist
What is heterologous desensitization?
when an agonist activation of one receptor subtype results in a decreased responsiveness to one or more other receptor subtypes; results in a more widespread effect on the system
What is denervation supersensitivity?
a compensatory enhancement of receptor-effector coupling or the number of receptors when there is lower activation such as loss of the agonist or innervation of the receptor
What are the 8 parts of a prescription?
Pt. Name; Date; Superscription (Rx); Inscription (name of drug, strength, drug form); Subscription (instructions for preparing or # units to dispense); Transcription (pt instructions for use); Refill info; Prescriber info/signature
What drugs are classified in schedule I of the Controlled Substances Act?
drugs with high potential for abuse and no accepted medical use in the US (LSD, heroine, mescaline)
What drugs are classified in schedule II of the Controlled Substances Act?
drugs with high potential for abuse that also have an accepted medical use; very likely to produce severe psychological and/or physical dependence (amphetamine, morphine, merperidine, secobarbital, fentanyl)
What drugs are classified in schedule III of the Controlled Substances Act?
drugs with lesser potential for abuse than those in schedules I and II, have potential to produce less serious dependence than those in schedule II (acetominophen with codeine, aspirin with codeine)
What drugs are classified in schedule IV of the Controlled Substances Act?
drugs will less abuse potential than those in schedule III; have potential for moderate dependence (diazepam, phenobarbital)
What drugs are classified in schedule V of the Controlled Substances Act?
drugs with lowest abuse potential; some may be sold in a pharmacy without a prescription (diphenoxylate with atropine, guaifenesin with codeine)
What are the rules/regulations for prescribing a Schedule II drug?
must be in writing with full name and address of pt; name, address and DEA number of prescriber; written signature, date, no refills
What are the rules/regulations for prescribing a Schedule III/IV/V drug?
written or verbal; name and address of pt; name, address, DEA # and signature of prescriber; date; up to 5 refills allowed to be used within 6 months
What are the exceptions to emergency dispensing of schedule II drugs?
may be verbal if: emergency, quantity of drug for the emergency period (no more than 72 hours); a written/signed prescription is delivered to the pharmacist within 7 days
may be faxed if: pt is in hospice and drug is for intractable pain; in an emergency but must be followed in 7 days by valid signed Rx
None
What are generic drugs?
drugs reviewed and approved by FDA to be interchangable with brand name drugs, including dose, dosage form, route of administration, safety, quality, intended use and effectiveness
Why are generic drugs less expensive?
competitive market after expiration of patent drives down price, marketing costs less, research and development costs are much less since no animal or clinical studies are necessary only bioequivalence tests
What are the Hatch Waxman amendments of 1984?
allowed generic firms to rely on findings of safety and efficacy of innovator drugs after expiration of patents
What is bioequivalence?
pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered to pts or subjects at the same molar dose under similar experimental conditions; if drugs have equal bioavailability they are bioequivalent
How are bioequivalence trials performed?
use 20-40 normal, healthy adults; 2x2 crossover design with single dose of the agent and measure the AUC and Cmax; the generic's 90% confidence interval must not be 20% greater or less than that of the branded agent
What pharm reference book has information on substitutions of branded drugs with generics?
Orange book - approved drug products with therapeutic equivalence evals
What are the two therapeutic equivalence codes?
A = substitutable; B = inequivalent substitution (only 3%)
What is pharmacogenomics?
the study of how an individual's genetic inheritance affects the body's response to drugs
What is a mutation?
an alteration in DNA sequence which is present only rarely (<<<1%) in the population
What is a polymorphism?
an alteration in DNA sequence which is present commonly (>1%) in the population
Which three CyP proteins of phase I metabolism are known to have polymorphisms in the population?
CYP2D6; CYP2C9; CYP2C19
What three phase II metabolism enzymes are known to have polymorphisms in the population?
thiopurine methyltransferase; N-acetyltransferase; uridine 5'-triphosphate glucuronosyltransferases
What drug classes does CYP2D6 metabolize?
20-25 % of all drugs: debrisoquine, sparteine, tricyclic antidepressants; antiarrhythmics, beta-blockers, neuroleptics
What drug classes does CYP2C9 metabolize?
15% of all drugs: tolbutamide (hypoglycemia/anti-diabetic); warfarin; phenytoin; and NSAIDs
What drug classes does CYP3A4 metabolize?
~50% of all drugs, inhibited by grapefruit juice (bioflavonoids and furanocoumarins)
What drug classes does N-acetyltransferase 2 (NAT2) metabolize?
isoniazid (peripheral neuropathy); hydralazine (lupus); sulfonamide (hypersensitivity rxns)
What is phase I of clinical drug testing?
determine the pharmacodynamic parameters of a drug: test on small sample of healthy humans to assess safety and dosage
What is phase IIA of clinical drug testing?
test the desired clnical effect and safety of the drug tested on small sample of humans with the disease the drug is intented to treat
How can pharmacogenomics improve clinical trials?
determine who would be good responders, smaller clinical trials necessary, reduce the # of failed trials, greater chance of obtaining statistically significant results
How could pharmacogenomics improve the treatment of schizophrenia?
by being able to determine who would be a good candidate for use of clozapine and ensure avoidance of the fatal side effect of agranulocytosis
Where is the location of the Abl gene?
on chromosome 9q34
Where is the location of the Bcr gene?
on chromosome 22q11
What disease results from the translocation t(9,22) of the bcr-abl genes?
chronic myelogenous leukemia (CML) forming the philadelphia chromosome (short chromosome 22)
What drug is used to treat chronic myelogenous leukemia?
imatinib (Gleevec) inhibits the Bcr-Abl tyrosine kinase and reduces the proliferation of cancerous white blood cells
What is the Her2-Neu gene?
human epidermal growth factor receptor 2 which is amplified in 25-30% of breast cancer pts
What drug is used to treat breast cancer patients with Her2 amplification?
transtuzumab (Herceptin) which is a humanized monoclonal antibody directed against Her2
What is the use of erythropoeitin (Epogen)?
used to treat chronic kidney failure and stimulate RBC production; contraindicated in pts with uncontrolled HTN
What is the use of tissue plasminogen activator (Activase)?
thrombolytic agent used in pts who have had a heart attack or stroke; risk of excessive bleeding
What is the use of tumor necrosis factor alpha (Etanercept)?
used to treat rheumatoid arthritis
What is the use of nerve growth factor (NGF)?
attempted in the treatment of alzheimer pts, but developed neuropathies
What is the use of trastuzumab (herceptin)?
is a humanized monoclonal antibody against epidermal growth factor receptor 2 (HER2/Neu) expressed in 25-30% of breast cancers, slows the dz progression and improves survival
What is the use of cetuximab (Erbitux)?
chimeric MAb against epidermal growth factor receptor (EGFR), used to treat solid tumors associated with colorectal cancer
What is the use of bevacizumab (Avastin)?
humanized MAb against vascular endothelial growth factor (VEGF), used in treating colorectal and lung cancers, reduces tumor angiogenesis and growth
What are the advantages and disadvantages to use of adenovirus as a viral delivery vector?
advantage: can be readily generated, infects most cells; disadvantage: very immunogenic causing inflammation, infection only for a few months, virus doesn't integrate into genome
What are the advantages and disadvantages to use of adeno-associated virus (AAV) as a viral delivery vector?
advantage: small, infects many cell types, no immune response, persists in vivo, may integrate into genome; disadvantage: difficult to generate sufficient for infection
What are the advantages and disadvantages to use of retrovirus as a viral delivery vector?
advantage: generated at high titer, readily integrates into dividing cells, long lasting effects; disadvantage: only integrates into dividing cells, unpredictable integration
What are the advantages and disadvantages to use of lentivirus as a viral delivery vector?
advantage: infects nearly all cell types even neurons, transgene expression persists; easy to generate; harmful HIV genes removed; disadvantage: site of integration is upredictable
What are the advantages and disadvantages to use of herpesvirus as a viral delivery vector?
advantage: infects neurons; disadvantage: large and difficult to use
What are two gene silencing treatment techniques?
Antisense oligonucleotide (ASO) and RNA interference (RNAi)
How do antisense oligonucleotides (ASO) function?
single stranded DNA like molecule complementary to selected mRNA binds to it and promotes its degradation
How does RNA interference (RNAi) function?
in cells double stranded RNA is recognized and degraded by an enzyme DICER and the pieces are used by RNA inducing silencing complex (RISC) to bind to complementary mRNA and degrade it. Short double stranded RNA is delivered via virus vectors to silence desired mRNAs
What is LD50?
the dose of a substance that kills 50% of the subjects
What are the major routes of toxic exposure?
oral (#1). Inhalation, dermal
What are some factors which will affect dose-response relationship with a toxin?
route of exposure, biotransformation, health/nutritional state, age, genetics
How is therapeutic index calculated?
LD50 or TD50/ ED50; the larger the value the safer the drug
What are some drugs which are known to be teratogenic?
thalidomide, tetracycline, cyclophosphamide, phenytoin, cocaine, ethanol
What are the most common causes of death due to acute poisoning?
airway obstruction, aspiration, respiratory arrest, hypotension, cellular hypoxia, hyperthermia, and seizures
When treating a possible acute poisoning what sure the initial considerations be?
airway, breathing, circulation, dextrose (ABCDs); cervical spine protection
What toxics are often the cause of cholinergic or anticholinesterase syndrome?
organophosphate and carbamate insecticides
What are symptoms of cholinergic or anticholinesterase syndrome?
Muscarinic overstimulation leading to parasympathetic overdrive: bradycardia, miosis, abdominal cramps, incontinence, hypotension etc; Nicotinic overstimulation initial muscle cramps, later weakness and paralysis, respiratory distress
What toxins are often the cause of anticholinergic syndrome?
atropine, scopolamine, tricyclic antidepressants, antihistamines, jimson weed
What are symptoms of anticholinergic syndrome?
block of muscarinic receptors leading to sympathetic overdrive: mydriasis, tachycardia, hyperthermia, abdominal distention, urinary retention etc. and nonspecific central effects
What toxins are often the cause of hemoglobinopathy syndromes?
carboxyhemoglobinemia: inhalation of excessive CO or methylene chloride; methemoglobinemia: oxidation of ferrous 2+ iron of hemoglobin to ferric state
What are symptoms of hemoglobinopathy syndromes?
hypoxia, headache, coma, nausea, cardiac disfunction, acidosis, death
What are symptoms of and drugs which produce narcotic overdose ?
pinpoint pupils, respiratory depression and hypotension due to heroine, oxycodone, morphine, merperidine; IV naloxone given to counteract effects
What are symptoms of and drugs which produce sympathomimetic excess?
nervousness, agitation, tremor, dehydration, hypertension, tachycardia, and seizures; cocaine, amphetamines, MAOI's
What are physical signs of opiate withdrawl syndrome?
mydriasis, piloerection, rhinorrhea, and lacrimation; not associated with seizures
What are physical signs of non-opiate withdrawl syndrome?
hallucinations, tachycardia, hyperpyrexia, seizures
What drugs produce the toxic sign of AV block?
digitalis glycosides
What drugs produce the toxic sign of sinus bradycardia?
digitalis, beta-blockers, calcium channel blockers
What drugs produce the toxic sign of metabolic acidosis?
aspirin, methanol, ethylene glycol
What drugs produce the toxic sign of GI dysfunction?
iron poisoning
What drugs produce the toxic sign of seizures?
intoxications, withdrawls, CNS infections,
What drugs are given to acutely control seizures?
diazepam and lorazepam, not phenytoin
What is an antidote for iron?
deferoxamine
What is an antidote for acetaminophen?
acetycysteine
What is an antidote for atropine and organophosphates?
2-PAM chloride
What is an antidote for opiates?
naloxone
What is an antidote for carbamates?
atropine
What is an antidote for anticholinergic poisoning?
physostigmine
What are the 5 steps involved in neurotransmission?
1. Neurotransmitter synthesis, 2. vesicular storage, 3. synaptic release, 4. binding of NT to receptor, 5. termination of NT action
What are the pre-synaptic mechanisms by which drugs can enhance or decrease neuronal transmission?
inhibition of enzymes in production of NTs, inhibition of vesicular transport of NTs, inhibition or promotion of NT vesicular release, pre-synaptic (type I) augmentation of NT reuptake
What are the post-synaptic mechamisms by which drugs can enhance or decrease neuronal transmission?
agonistic or antagonistic binding to post-synaptic NT receptors, modification of enzymatic metabolism of the NT in the synapse, post-synaptic (type II) augmentation of NT reuptake
Are drugs that act pre-synaptically or post-synaptically more selective in their effects? Why?
post-synaptic drugs because they mimic or inhibit the effects of the NT at a single receptor rather than affecting the many other pathways and receptor interactions my affecting pre-synaptically.
What neurotransmitters are in the biogenic amines class?
dopamine, serotonin, norepinephrine, epinephrine, acetylcholine
What neurotransmitters are in the amino acid class?
glutamate, glycine, GABA
What neurotransmitters are in the peptide class?
SP, Ang II, LHRH, FSH, vasopressin, oxytocin, neuropeptide Y
What neurotransmitters are in the nucleotide class?
ATP, ADP
What neurotransmitters are in the gas class?
NO, CO
What are the 4 main therapeutic manipulations of cholinergic transmission?
1. interfere with vesicular release SNARE (botox); 2. post-synaptic receptor agonism and antagonism; 3. block NT degradation with acetylcholinesterase inhibitors; 4. presynaptic receptor inhibition of synaptic release
What are the 8 main therapeutic manipulations of adrenergic transmission?
1. competition for synthetic enzymes (Metyrosine); 2. inhibition of storage (Reserpine); 3. inhibition of synaptic release (Guanethidine); 4. receptor agonists/antagonists (phenylephrine); 5. autoreceptor agonists; 6. reuptake inhibitors (cocaine); 7. NT releasers (ephedrine); 8. inhibition of degradating enzymes (MAO inhibitors)
What is the effect of the drug Metyrosine?
competes with tyrosine for tyrosine hydroxylase, preventing tyrosine in adrenergic neurons from being transformed to DOPA and decreases the production of catecholamines
What is the effect of the drug reserpine?
blocks the vesicular dopamine transporter and results in the depletion of catecholamines in adrenergic neurons
What is the effect of the calcium channel blockers in adrenergic neurons?
prevent the signalling of the AP to be converted to a release of vesicles
What is the effect of the drug guanethidine?
prevents the SNAREs on vesicles from binding with the pre-synaptic membrane and catecholamine release
What is the effect of cocaine in adrenergic neurons?
inhibits reuptake of monoamines such as norepinephrine, dopamine, and serotonin.
What is the effect of tricyclic antidepressants in adrenergic neurons?
block the reuptake of monoamines
What is the effect of monoamine oxidase inhibitors (MAOIs)?
inhibit the degradation of monoamines in the pre-synaptic cytoplasm and increase catecholamine and other monoamine release
What are the three elements of the enteric nervous system?
sensory neurons that monitor the tension of the gut wall and chemical environment; motor neurons to control the muscles, vasculature, and secretions; interneurons to communicate btw sensory and motor
What are the two interconnected ganglia of the enteric nervous system?
submucosal (meissner's); myenteric (auerbach's)
What autonomic projections can modify the enteric nervous system function?
parasympathetic pre-ganglionic neurons; sympathetic post-ganglionic neurons
What three currents contribute to the SA membrane potential?
inward calcium current, inward funny current (induced by hyperpolarization); outward K+ current
Alpha-1: What tissue does this receptor distribute and what are its actions?
most vascular smooth m.(contracts causing increased vascular resistance), pupillary dilator m. (contracts causing mydriasis)
Alpha-2: What tissue does this receptor distribute and what are its actions?
adrenergic and cholinergic nerve terminals (inhibits transmitter release); some vascular smooth m. (contracts)
Beta-1: What tissue does this receptor distribute and what are its actions?
Heart (stimulates rate and force of contraction); justaglomerular cells (stimulates renin release)
Beta-2: What tissue does this receptor distribute and what are its actions?
respiratory, uterine, and vascular smooth m. (relaxes); liver (stimulates glycogenolysis); pancreatic B cells (stimulates insulin release); somatic motor nerve terminals (causes tremor)
Beta-3: What tissue does this receptor distribute and what are its actions?
fat cells (stimulates lipolysis)
Dopamine-1: What tissue does this receptor distribute and what are its actions?
renal and other splanchnic blood vessels (relaxes, reduces resistance)
Dopamine-2: What tissue does this receptor distribute and what are its actions?
nerve terminals (inhibits adenylyl cyclase and vesicular release)
What is the Alpha-1 adrenergic receptor signaling pathway?
Gq protein coupled to Phospholipase C (PLC) which forms DAG (activates PKC) and IP3 (releases stored calcium from SR)
What is the Alpha-2 adrenergic receptor signaling pathway?
Gi protein coupled to adenylyl cyclase inhibits cAMP formation preventing the activation of PKA which cannot phosphorylate N-type calcium channels (reducing vesicular release of NT) or MLCK (allowing it to remain active and promote smooth m. contraction)
What is the Beta-1 adrenergic receptor signaling pathway?
Gs protein coupled to adenylyl cyclase increases cAMP, which activates PKA to phosphorylate calcium channels (increasing calcium current in SA node and in the cell membrane and SR of myotomes)
What is the Beta-2 adrenergic receptor signaling pathway?
Gs protein coupled to adenylyl cyclase increases cAMP, which activates PKA to phosphorylate and inactivate MLCK (prevents smoot m. contraction)
What are the relative potencies of the direct acting sympathomimetics on Alpha-1 receptors?
Epi > NE >> Isoproterenol
What are the relative potencies of the direct acting sympathomimetics on Alpha-2 receptors?
Epi > NE >> Isoproterenol
What are the relative potencies of the direct acting sympathomimetics on Beta-1 receptors?
Isoproterenol > Epi >> NE
What are the relative potencies of the direct acting sympathomimetics on Beta-2 receptors?
Isoproterenol > Epi = NE
What are the cardiovascular effects of Epinephrine?
at low doses: beta receptors predominate causing peripheral vasodilation and ↓ diastolic BP (B2), ↑ CO, systolic BP, HR (B1); with higher doses alpha 1 predominates ↑ vascular resistance and total BP
What are the cardiovascular effects of Norepinephrine?
stimulates alpha-1 (↑TPR, diastolic BP); stimulates beta 1 (↑ HR, inotropy, systolic BP); rise in BP leads to barometric ↓HR
What are the cardiovascular effects of Dopamine?
stimulates D1 receptors at low conc (↓TPR); at medium conc stimulates B1 (↑inotropy, HR); at high conc stimulates A (↑BP, TPR)
What are the cardiovascular effects of Isoproterenol?
stimulates B2 (peripheral vasodilation, ↓diastolic BP); B1 (↑inotropy, HR, systolic BP); reflex tachycardic response to B2 receptor activation
What are two ways indirect acting sympathomimetic agents can increase the concentration of endogenous cateholamines?
release of stored catecholamines; blockade of reuptake transporters
What are two main types of drug interactions?
Homergic (2 drugs produce the same response, additively, supra-additively, or infra-additively) or Heterergic (only one drug of the pair produces the response, synergistically or antagonistically)
What is the interaction between thiazide diuretics and digitalis?
thiazide diuretics lead to the excessive loss of potassium in the urine and can cause hypokalemia this makes the heart more sensitive to digitalis and can make a normal dose of digitalis toxic and cause cardiac block and death
What is the interaction between warfarin and phenytoin?
warfarin blocks the metabolism of phenytoin at its CYP450 leading to increased phenytoin levels
What do barbituates do to CYP450s?
they cause an increase in the production of CYP450s by enzyme induction and increase the metabolism of many drugs
What are the two types of nicotinic receptors and where are they located?
Nn - in autonomic ganglia; Nm - on membranes of skeletal muscles at neuromuscular junctions
What are the three types of muscarinic receptors and where are they located?
M1 (myenteric plexus); M2 (heart SA node; adrenergic neurons innervating the heart); M3 (pupillary sphincter, ciliary muscle, bronchiolar, GI, uterine, bladder, GI glands)
What are the two types of cholinesterases and where are they found?
Acetylcholinesterase (NM junction, cholinergic synapse; RBCs); Butyrylcholinesterase (plasma, glial cells, liver)
What does inhibition of cholinesterases cause?
increased Ach at all cholinergic synapses resulting in agonism of: muscarinic actions at autonomic effector targets and CNS; nicotinic actions at autonomic ganglia and motor end plates (these are very toxic bc of the wide spread effects)
What are the symptoms of irreversible cholinesterase inhibitors?
Salivation, Lacrimation; Urination; Diaphoresis (sweating); Gastrointestinal motility; Emesis (SLUDGE)
What is the treatment of severe organophosphate poisoning (irreversible cholinesterase inhibitors)?
1. artificial respiration; 2. suction of tracheal secretions; 3. anti-muscarinic agent (atropine); 4. reactivation of acetylcholinesterase with Pralidoxime Chloride (2-PAM)
What are the symptoms of atropine poisoning?
dry mouth, difficulty swallowing, flushed, mydriasis, blurred vision, tachycardia, high BP, hallucinations, psychosis
What is the treatment of atropine poisoning?
1. gastric lavage; 2. maintenance of circulation and resp; 3. lower body temp; 4. catherization; 5. mitotics; 6. barbituates for sedation;
What are the common routes of ocular pharmacological administration?
Topical; subconjuctival, retrobulbar; intraocular; intravitreal; oral; intravenous
What type of sympathetic/parasympathetic receptors are on the corneal epithelium of the eye?
β2 and M
What type of sympathetic/parasympathetic receptors are on the corneal endothelium of the eye?
β2 and undefined
What type of sympathetic/parasympathetic receptors are on the iris radial muscle of the eye?
α1 (dilation)
What type of sympathetic/parasympathetic receptors are on the iris sphincter of the eye?
M3 (miosis)
What type of sympathetic/parasympathetic receptors are on the trabecular meshwork of the eye?
β2
What type of sympathetic/parasympathetic receptors are on the ciliary epithelium of the eye?
α2/β2 (aqueous production)
What type of sympathetic/parasympathetic receptors are on the ciliary muscle of the eye?
β2 (relaxation); M3 (accommodation)
What type of sympathetic/parasympathetic receptors are on the lacrimal gland of the eye?
α1 (secretion); M2, M3 (secretion)
What type of sympathetic/parasympathetic receptors are on the retinal pigment epithelium of the eye?
α1/β2 (water transport)
Non-selective β-blockers
Propanolol; Nadolol; Timolol
Cardio selective β1 blockers
Metoprolol; Atenolol; Esmolol
Partial Agonist β-blocker
Pindolol
Non-selective α-blockers
Phenoxybenzamine (non-competititve); Phentolamine (competitive)
Selective α1 blockers
Prazosin; Doxazosin; Terazosin;
Non-selective β-agonist
Isoproterenol
Direct Sympathomimetics
Epinephrine (α1, α2, β1, β2); Norepinephrine (α1, α2, β1); Dopamine (α1, α2, β1)
β1- agonist
Dobutamine
Selective β2 Agonists
Albuterol; Turbutaline
Selective α1 Agonist
Phenylephrine
Selective α2 Agonist
Clonidine
Indirect acting Sympathomimetics
Amphetamine, Methamphetamine; Methylphenidate; Ephedrine; Pseudoephedrine
Nicotinic Agonists
Nicotine; Succinylcholine
Non-selective Cholinergic Agonists
Acetylcholine, Carbachol
Muscarinic Agonists
Methacholine; Bethanechol; Muscarine; Pilocarpine
Reversible Cholinesterase Inhibitors
Physostigmine; Neostigmine; Edrophonium; Tacrine; Galatamine; Rivastigmine
Irreversible Cholinesterase Inhibitor
Echothiophate
Acetylcholinesterase reactivator
Pralidoxime
Muscarinic Antagonists
Scopolamine; Atropine; Glycopyrrolate
What is the order from fastest to slowest route of elimination: organ/mechanism?
Plasma cholinesterase; Liver; Kidney
What is the order of muscles first affected by non-depolarizing drugs?
small muscles first (extraocular, hands, feet, head, neck) followed by larger muscles of limb and trunk (abdomen, extremities, diaphragm); recovery is in the reverse