Download Pharmacology Test #1 Outline Lec. 1: Intro to Principles of

Pharmacology Test #1 Outline
Lec. 1: Intro to Principles of Therapeutics
Pharmacology:
 John Jacob Abel- “Father of American Pharmacology”- 1st pharm dept University
 Pharmacotherapies: use of drugs in the treatment of patients with the disease
 Pharmacognosy- study of drugs isolated from natural sources (plants, microbes,
animal tissues, minerals)
 Pharmaceutics: formulation & chemical properties of pharmaceutical products
(tablets, fluids, aerosols)
 Pharmacogenetics: unusual responses to drugs b/c of genetic differences
 Toxicity: study of poisons and organ toxicity, harmful effects of drugs, adverse
effects at therapeutic doses
 2 branches
o pharmacokinetics
o pharmacodynamics
 Drug Names
o Chemical
o Nonproprietary (Generic)- helps identify class of drug, most often used,
USAN
o Proprietary (trade/brand)- registered trademark, belongs to drug
manufacturer
 Potency- amount of drug necessary to elicit a response (1mg of drug induces
response, it is more potent than drug that requires 10mg for same effect)
 Efficacy: ability to produce the max desired response
 Therapeutic index: margin of safety of a drug
o Ratio of dose producing undesirable effects to the dose producing the
desired therapeutic response
o Large TI: large margin of safety
o Low TI: small margin of safety (narrow therapeutic window)
 Drug Preparations
o Tablets and capsules- oral administration
 enteric coating (dissolves in intestines)
 sustained/extended release products
 undergo 1st pass metabolism
o Solutions and suspensions- oral, parenteral (IV, IM), other (ophthalmic,
otic)
o Skin Patches- transdermal use, rate controlling membrane, potent drugs
with lipid solubility penetrate skin
 Most common side effect- skin irritation from patch adhesive!!
o Ointments, crèmes, lotions- topical application to skin or mucous
membranes
 active drug incorporated into vehicle (polyethylene glycol) for tissue
adherence
 for rectal, vaginal, urethral administration
 local or systemic effects
o Aerosols
 Inhalation though the nose or mouth
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Respiratory disorders
Routes of Administration
o Enteral- drug absorbed from GI Tract
 Sublingual, buccal, rectal- readily absorbed, no 1st pass
 Oral- by mouth, per os – 1st pass metabolism
o Parental- bypasses intestines (anything using needle or syringe)
 IV: NO absorption, F=1
 IM: treatment w/ drug solution, particle suspensions (rapid
absorption from solutions, slow and sustained from suspensions)
 SC: treatment w/ suspensions and pellets, slower absorption than IV
and IM
 Intrathecal: subarachnoid space of SC
 Epidural: space above dura membranes of SC
 Intra-articular: joint space
o Transdermal: patch or ointment, bypasses 1st pass, release meds for days
o Inhalation: local or systemic effects
o Topical: body surfaces (everywhere)- localized effect
Treating Patients:
o Need to individualize patient drug therapy (increase efficacy and decrease
toxicity= therapeutic range)
o Disease Oriented Evidence: numbers, markers that the physician uses to
treat patient
o Patient Oriented evidence: 2 goals of
 Longer (mortality)
 and better (morbidity)
 outcome the patient understands
o Absolute Risk Reduction: decrease in risk of a treatment (how risky is the
treatment compared to control treatment?)
o Relative Risk Reduction: extent to which a treatment reduces a risk (How is
this treatment going to lower my risk of high blood pressure compared to
those not taking the treatment?)
o Numbers Needed to Treat: prevent one adverse outcome
o Numbers needed to harm: incur one adverse outcome
Pharmacokinetics (Lectures 2,3,4,5)
 pharmacokinetics: what the body is doing the drug
o focuses on changes in drug plasma concentration
o ADME
o Influenced by blood flow, passage out of vasculature, rate of entry into the
cell
Absorption: movement of drug into the bloodstream
 Movement across a biological membrane (active transport or passive diffusion)
o Carrier Mediated Transport: transports large, hydrophilic, ionized species
(saturation limit, competitive inhibition)
 facilitated diffusion: requires carrier molecule, NO E used
 Active Transport: requires E to pump drug against concentration
gradient (kidney, biliary excretion, CNS, choroid plexus, ciliary body)
o Passive Transport
Endocytosis
Passive Diffusion
 Fick’s Law
 flux= (C1-C2) (Area x Permeability)/ Thickness of the
membrane
 physiochemical properties determine permeability
o ionized acids/bases will NOT cross membrane
o weak acid: when protinated, not ionized (HA)
o weak base: when protinated, ionized (BH+)
o used dissociation constant (Ka) to determine
distribution of drugs to cross membrane
o pKa: pH when half of the drug is ionized
o pka-pH= log [protinated]/[unprotinated]
Bioavailability (F): amount of extravascular administered drug that reaches
systemic circulation (due to incomplete absorption and 1st pass effect/metabolism
in liver )
Rate of absorption: fastest (IVIMSC) slowest
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Distribution
 Drug can stay in blood and begin elimination or
 Distribute to other organ/tissue
 Barriers to distribution: BBB b/c of tight jxns, only small hydrophobic drugs (gases)
can cross, requires active transport
o Quaternary ammonium (always charged, never going to get into the
brain)
 Distribution and Elimination phases
o After drug is distributed though body, will reach equilibrium and will enter
plasma again or get eliminated from body (1st order kinetics)
 Volume of distribution (Vd): amount of drug in body compared to amount in
plasma
o Vd= D/C
o Use to determine amount of drug that will go into tissue vs plasma
o Vd= distribution in tissues/fluids
o Vd= limited drug distribution (blood)
o used to calculate loading dose (LD) to achieve steady state conc. (Css)
 LD= Css x Vd
 If LD is not IV, divide by bioavailability
 LD used to get therapeutic effect quick (emergency)
 LD does not change based on liver or renal disease
 Plasma Protein Drug Interactions
o Albumin most common, binds drugs, makes them unable to reach target site
o Drugs that bind plasma proteins have Vd (remain in plasma)
 One-compartment model:
o used w/ drugs that distribute to tissue instantaneously following IV
injection or stay in plasma and elimination begins instantly (ke- elimination
rate constant),
o follows first order kinetics
o One compartment: all body tissues and fluids (has own Vd)
o Used most commonly for clinical dose adjustments
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Two-compartment model:
o Central compartment (initial distribution volume)
o Final compartment (distribution volume following EQ)
o Used w/ drugs that distribute to tissue more slowly (extrapolate backwards
to get Co)
o 2 compartments, drug moves between compartments, then reaches EQ
 Multi-compartment model: drugs that distribute into multiple tissues at different
rates
o fast (vessel richmuscleadipose) slow
Metabolism
 3 Types
o Phase 1: oxidation/reduction
 Adds or exposes polar fxnal groups (OH, NH2)
 Oxidases
 Heme Protein Oxidases- Cytochrome P450
o Microsomal mixed function oxidases
o 75% of all drugs
o 95% of all oxidation biotransformations
o 36% in CYP3A 4/5 Isoforms
o requires O2, NADPH, H+
o hydroxylates drug
o CYP450 Induction: increases transcription
 own metabolism, increase active metabolite
o PYP450 Inhibition: inhibiting metabolism
 Can lead to active drug levels of substrate
(competitive, can be irreversible)
 Non-CyP450 oxidation (ADH)
 Monoamine oxidase (catecholamines/tyramine)
o Phase II: Conjugation/Hydrolysis
 Conjugation
 Products more polar, water soluble, and inactive (can be
more readily excreted via kidneys/bile)
 Glucuronidation most common conjugation rxn
 Acetylation (N-acetyltransferase- NAT)
 Glutathione (UDP-glucouronosyltransferase)- UGT- not
active in newbies (jaundice)
o Phase III: transport
 Multidrug resistance protein 1 (MDR 1) or P-glycoprotein 1, or
ABCB1)
 Transports drugs back into GI tract, or brain, or into proximal tube
for excretion
 Substrates: Antiretrovirals, antifungals, macrolides,
chemotherapeutic agents
 Bind P-glycoprotein 1 and remove from target tissues, bad in
treating bacterial infections, cancer
Excretion
 Drug compounds now more hydrophilic and can be excreted
 Renal Excretion: 25% of blood flow
Typically only free, unbound, drug is filtered though glomerulous (passive
diffusion)
o excretion rate by filtration, renal blood flow, GFR, plasma protein
binding
o proximal tubule uses active transport to remove drug and concentrate them
into proximal tubule, can remove protein bound drugs
Biliary Excretion
o Metabolites from liver via common bile duct enter small intestine (if
lipophilic enough, drug will get reabsorbed into liver w/ bile salts)
o Other bile salts excreted in bile
Rate of Elimination (v)
o V=max rate of drug elimination x Conc. of drug in plasma/ Km + C
o MM graph, 1st order
o V=CssCL (steady state conc x clearance)
o Faster rate of infusion does NOT change time needed to achieve steady state
(only conc. changes)
1st order kinetics
o most drugs
o clearance process NOT saturable
o rate of drug elimination proportional to plasma drug concentration
o half life and clearance of drug remain constant
o Km>>C
o Linear kinetics
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Zero order kinetics:
o Carrier mediated elimination (enzyme saturation)
o Rate is independent of drug concentration (elimination is constant)
o Km<<C (seen with large drug dosages)
o Aka: non-linear kinetics (MM kinetics)
o V=Vmax (rate stays the same when you concentration)
o Serum conc. change more or less than expected w/ change in dose
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Clearance
o Rate of elimination relative to conc. of drug in plasma
o CL= v/Css
o CL total: total clearance from body of all organs
o Determines Css for a given dosage rate
o 2 major sites of elimination: kidneys and liver
o can change based on disease states or enzyme inducing/inhibiting drugs
o Maintenance dosing: used to maintain Css
 Rate of drug going in=rate of drug going out
 MD= CL x Css / F
Organ clearance (extraction)
o Ca: drug entering organ
 Ca= dose x absorption
o Cv: drug leaving organ
 Cv= dose x bioavaiibility
o Extraction ratio (E)= (Ca-Cv)/ Ca
o Cl (organ)= blood flow though organ (Q) x E (extraction ratio)
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Elimination Rate Constant (ke)- single compartment model, follows 1st order
kinetics
Half-Life
o Time taken for a drug to be reduced to half it’s value
o T1/2 = 0.693 / ke or ln2/ke
o 1st order half life: independent of drugs concentration
 (1st order kinetics)
 half life does not change w/ increase of plasma concentration
 time to eliminate all of drug does increase
 ke is slope of line
o Zero order half life: does  when plasma conc.
 Time to eliminate all of drug also increases w/conc.
o Half time determines time to reach Css and dosing interval
 Css usually achieved after 4-5 half lives
 T1/2= 0.693 X Vd / CL
 AUC= area under the curve (once Clearance is constant, AUC directly
proportional to dose administered)
 LDs and MD’s based on a desired Css w/in therapeutic range (4-5
half lives)
 Can calculate new dose (desired Css)
 Xnew=Xold (Css, new/ Css, old)
o Factors Affecting Half Life
 Age (half life)
 Obesity (half life)
 Pathologic fluid (half life)
 CYP450 induction (half life)
 CYP450 inhibition (half life)
 Cardiac, hepatic, renal failure ( half life)
Individualizing Drug therapy
 PK parameters can be altered by
o Age
 Neonates:
 biotransformation/elimination
 oxidative and glucoronate conjugation
 renal excretion
 mg/kg dosing
 Elderly:
 Vd for fat-soluble drugs (less learn muscle)
 Lower rate of oxidative metabolism
 Conjugation is okay
 Renal excretion
o Gender: women more vulnerable than men to alcohol-induced liver, heart
damage
o Weight:
 Fat-soluble drugs
 Vd w/ obesity
 Vd w/ cachexia
 Multiply TBW by 0.4 to get adjusted body weight
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Disease States
 Renal Disease
 Cockroft-Gault eqn used to estimate creatinine clearance
(Clcr)
 Clcr= (140-age) IBW/SCr x 72
 Females: multiply 0.85 (140-age)
 For drugs mainly eliminated via kidney:
o If Clcr is 30-60 minor dose adjustment
o If Clcr is 15-30 moderate dose adjustment
o If Clcr is <15 major dose adjustment
 (Drug not being cleared well by kidneys)
 Hepatic Disease
 No test to estimate liver drug metabolism
 Indicators of poor metabolism in liver: serum bilirubin,
serum albumin, prolonged prothrombin, cirrhosis
 Heart Failure
 CO which liver blood flow
 Decrease initial doses by 25-50% in moderate to severe HF
Genetics
 Polymorphism-individual variation in the genes coding for drugmetabolizing enzymes
 N-acetyltransferase- slow acetylators- higher levels of certain
drugstoxicity
Transport Proteins
Interactions w/ other drugs/foods
Specific Drugs to use PK on
 Aminoglycosides: nephro, ototoxicity at toxic levels
o Gentamicin, tobramycin, amikacin (antibiotics)
o Cleared renally
o Hartford nomogram (ODA)- concentration dependent killing and postAntibiotic effect of the drugs
 Can change the interval, NOT the dose
 Vancomyocin: very toxic
o Time dependent bacterial killing, min conc. is important!!
o Use Matzki nomogram
 Digoxin: long half life (40 hrs)
o Used for afib and HF
o Cleared renally
o Narrow therapeutic index
o Calculate Clcr, calculate Vd, calculate LD
 Phenytoin: large amount of patient variability (unpredictable)
o Anticonvulsant
o Non-linear kinetics (half time  as MD )
o Approximate new concentrations after dose adjustment by assuming linear
kinetics and adding/subtracting 15-33%
Drug Interactions Lec. 6-7
Mechanisms of Drug Interactions
 Pharmaceutical interactions (Drug incompatibilities)
o A chemical rxn between drugs PRIOR to administration (combo of drug
solutions- IV, are incompatible, pharmacist concern
 Pharmacodynamic interactions
o Effects on tissues, organ system, microbes, tumor cells
o Additive: add up to the sum to individual drug effects
o Synergistic: > sum of individual drug effects
 Sildenafil (Viagra) and Nitroglycerin: hypotension risk
o Antagonistic: affecting same fxn w/ opposing effects
 Pharmacokinetic interactions
o Altered Drug absorption
 Altered gut motility or secretion
 Binding or chelation of drugs
 Divalent cations (Ca+2, Al+2 in antacids bind
drugs(fluoroquinolones, tetracyclines)
 Competition for active transport (p-glycoprotein)
 OATP Fruit Juice Interaction
 Organic anion transporting peptide, transports drugs into
cells, absorption
 Fruit juices inhibit OATP, absorption
o Altered Drug distribution
 Can displace drugs from plasma proteins, resulting in greater “free”
drug, increasing the effects (as conc. increases, so does clearance)
 Liver disease: albumin (unbound drug concentrations)
o Altered Biotransformation
 CYP450 Enzymes
 CYP3A4- responsible for over 50% of drugs, most
important for drug interactions!!
 CYP 450 Enzyme induction
 metabolism, clearance, half life, pharmacologic action
 Barbituates, Carbamazepine, Rifampin, tobacco smoke
 CYP 450 Enzyme inhibition: metabolism, clearance, half life,
pharmacologic action
 “azole” antifungals- notorious CYP450 inhibitors
o itraconazole inhibits CYP3A4, conc. of HMG-CoA
reductase inhibitors (simvastatin)
 “
ketoconazole
o Altered Drug Excretion
 Change in renal pH
 Competition for active transport in renal tubules
 Probenecid  conc. of certain antibiotics
 biliary clearance
 Nephrotoxicity
 Change in renal blood flow (NSAIDS, ACE inhibitorsPG inhibitors,
renal blood flow)
o Drug-Food interactions
 Absorption (dairy products Ca+2 bind drugs, absorption
(tetracyclines, fluoroquinolones)
Metabolism- Flavonoids in Grapefruit juice (CYP3A4 inhibitor, conc.
and effects of simvastatin/statins)
o P-glycoprotein: drugs can induce or inhibit P-gp
 St. John’s Wort: bioavailability of many drugs, induces P-gp
Can use drug interactions to our advantage (additive effect)
Clinically Significant Drug Interactions
o Drugs w/ low therapeutic indices (potential for significant medical
interactions!!)
 Digoxin
 Lithium
 Warfarin
o Multiple meds-polypharmacy
o Drugs w/ bioavailability (F<10%)
o Concomitant illness
o Genetic Polymorphisms
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“Red” Flag Drugs
 Azole Antifungals
 H2 blockers (cimetidine)
 Griseofulvin
 Macrolide antibiotics (erythro, clarithryomyocin)
 Omeprazole
 Paroxetine & fluoxetine
 Phenytoin
 Probenecid
 Ritonavir
 Theophylline
 Warfarin
 Smoking
 Antacids (Omeprazole)
 Carbamazepine
 Diltiazem- HR: inhibits metabolism of simvastatin (simvastatin conc)
 Grapefruit Juice
 MAOIs
 Phenobarbitol
 Quinidine
 Rifampin/rifabutin
 St. Johns Wort
 Valproic acid
 Verapamil
Clinical Cases:
 Clopidogrel: omeprazole (antacid) reduces clipidogrel’s antiplatelet effect, but
research is debatable. Treatment: weaker Cyp2C19 inhibitors (Pantoprazole)
 Itraconazole (azole antifungals) are CYP3A4 inhibitors, can decrease the metabolism
of drugs (warfarin)
 Ibuprofen (PG inhibitor,  renal blood flow) can decrease the elimination of lithium
(eliminated by kidneys)
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Antacids fluoroquinolone antibiotic absorption by binding the drug
o “Take your quin “alone” – don’t take you quinolone antibiotics w/ anything
Diltiazem inhibits metabolism of simvastatin, conc. muscle pain, myopathy
Pharmacodynamics (Lec 8,9,10)
 What the drug does to the body (Mechanism of Action)
 Sites of Drug Action
o Drug Action NOT involving specific protein/receptor
 Physical Actions (lipid soluble anesthetic agents, osmotic diuretics
(mannitol), osmotic cathartics
 Chemical Actions (Antacids, chelating agents (removes Lead, copper)
o Drug action involving specific protein/receptor
 Enzymes: Act directly (mimic substrate, and inhibit enzyme’s
activity)
 Competitive and Noncompetitive
 Selective Toxicity though inhibition of a unique metabolic
pathway
 Selective toxicity though species different in enzyme
selectivity
 Incorporation of a drug into a macromolecule (produces
desired response)
 Inhibitors of enzyme activity in specialized cells
o Inhibitors of the synthesis/degradation of NT
 Stoichiometric and irreversible inhibition
o Cyclooxygenase inhibitors (aspirin) permanently
binds enzyme, have to make more enzyme to make
more platelets
 Carrier molecules
 Carry polar and non-lipid soluble molecules across cell
membranes
 Ex: SSRI (serotonin uptake)
 Specific physiological tissue/cellular receptor
 Receptor is physiological target for drugs,  transduction
 Specificity: selective attachment or influence of one substance on another
(interaction w/ drug on receptor)
o Determined by drug/receptor structure, chemical forces of interaction, drug
solubility, cellular fxn of receptor
 Selectivity: ability to achieve the desired therapeutic effect while minimizing
unwanted effects
o Determined by cell type specificity of receptor and specificity of the binding
out receptor-effector
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Response by a Drug
o Initial stimulus (drug + receptor)
 Binding forces
 Attractive Forces
o Covalent bonds (irreversible w/o catalyst)
o Ionic Bonds
H bonds
Van der Waals: significant role in determining
relative affinity
o Hydrophobic Effect: attraction between two apolar
groups in an aqueous environment
 Repulsive forces
o Ionic and dipole repulsions
o Steric hinderance
Transduction, modulation, or amplification
 Agonist: binding causes change in the activity of the target
 Full: max activation (Agonist and allosteric activator)
 Partial: agonist alone
 Inverse: agonist and allosteric inhibitor
 Antagonist: inhibit the ability of their targets to be
activated/inactivated by agonist
 Competitive or Noncompetitive
 Drug Receptor Types
 Ion Channels
o Ligand gated: binds ligand,voltage sensitive (nicotinic
receptors)
 Excitatory amino acid receptors
 Inhibitor amino acid receptors
o Voltage gated (can fxn w/o endogenous ligand)
 Activated w/ change in transmembrane
potential, ion can flow though (Na, Ca, K)
 Drug can directly block channel (anesthetic)
 Drug can bind integral part of channel,
modulate receptor (Ca+2 channel blockers)
o Second messenger regulated
 Ion channels can be modulated by G protein
receptor activation
 G protein coupled Receptors
o G isoforms
 Gs (activates Ca+ channels, activates AC)
 Gi (activates K channels, inhibits AC)
 Gq (activates PLC)
 G12/13 (activates Rho)
o  subunits
o GDPGTP (subunits interact w/ effectors)
 Adenylate Cylase (AC): cAMP
 Phospholipase C (PLC): cleaves PIP2DAG
and IP3
o Effectors interact w/ second messenger (cAMP)
 Amplification of response by cAMP
 IP3 increases intracellular Ca+2
 DAG activates PKC (binds Ca+2)
o GTPGDP (subunit deactiation, subunits return
 cAMP inactivated 5’AMP (via
phosphodiesterases- PDE)
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Transmembrane enzymatic Receptors
o Cysolic domainsdimers, multisubunit complexes
o Fxns: kinase (major player), phosphatase
o 5 major classes
 Tyrosine kinase- major player (insulin)
 Tyrosine phosphatases
 Tyrosine kinase-assicated (JAK)
 Serine/threonine kinases
 Guanylyl cyclases
 ANP-Atrial Natiuretic factor,
enterotoxion bind membrane
 NO binds intracellular enzyme
 cGMP- 2nd messenger
o Receptors linked to Guanylyl cyclase
 Intracellular Receptors
o Intracellular enzymes
o Transcription factors: steroid hormones
o Structural proteins (antibiotics target ribosomes)
o Nuclear Receptors
o Generation of an effect
 Regulation of Drug-Receptor Interactions
o Tachyphylaxis: repeated administration of the same dose of a drug
results in a reduced effect of the drug over time (rapid tolerance
buildup)
o Desensitization: decreased ability of a receptor to respond to
stimulation by a drug or ligand
 Homologous (same receptor)
 Heterolgous (2> receptor types)
Occupancy Theory
 Ligand-receptor binding: once a sufficient number of receptors are bound on/in a
cell, a response occurs (L+RLR response)
o Dissociation constant Kd=koff/kon
 Dose-Receptor Relationship
o If receptors remain constant (Ro)
o Percent bound/binding affinity = LR/Ro
o Kd=50 when 50% of receptors bound
o Drug with lowest Kd has highest affinity (binds to receptor)
o Dose Receptor binding curve:
 Dose Response Relationship
o Relationship between the dose and the response of the organism (measures
drug effectiveness), usually mirrors drug-receptor binding
o DR/Ro= dose response/max response
o EC50- where you have half of your max efficiency
o Dose Response Curve- goes from no response, to minimal effective dose to
graded response (dose dependent) to max effect
o
Quantal: relationship between dose of the drug and % of pop who have
defined response (all or nothing)
 ED50: median effective dose
TD50: median toxic dose
LD50: medial lethal dose
Therapeutic window: range between the ED50 and beginning of
TD50 curve
 Therapeutic index: TD50/ED50
o Graded (effect on individual, therapeutic window-looking at potency and
efficacy)
 EC50-potency, left shift
 Emax (efficacy)- higher curve
Agonist: 2 state model (active/inactive)
o 4 possible states in EQ (D+R, D+R*, DR, DR*)
o Partial Agonist
o Inverse Agonist: effect on constitutively active receptors
o Spare Receptors
Antagonist
o Inhibits the action of the agonist
o No effect on its own, requires agonist
o Competitive: binds to active site on receptor, reversible, stabilizes receptor
in an inactive state (shifts dose response curve to the right)kd of agonst,
potency
o Noncompetitive: antagonist binds irreversible to active site of receptor
 Binds allosteric site, or active site (irreversible)
 Shift the dose-response curve downward (efficacy of the agonist)
o Nonreceptor:
 chemical antagonist: binds agonist before it can work (neutralizes)
 physiologic antagonist: opposite effect but at different receptor
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