Block 1 Flashcards
1
Q
pharmacology definition
A
biomedical science concerned w/study of drugs and their effects on life processes
2
Q
goal of pharmacology
A
understand mechanisms by which drugs interact w/biologic systems to enable rational use of effective agents in diagnosis & treatment of disease
3
Q
2 subdivisions of pharmacology
A
- pharmacokinetics
- pharmacodynamics
4
Q
Pharmacokinetics definition
A
study of actions of body on drug (ADME)
5
Q
Pharmacodynamics definition
A
Study of actions of drug on body
6
Q
4 domains of pharmacokinetics
A
ADME:
- Absorption
- Distribution
- Metabolism (biotransformation)
- Excretion
7
Q
dose-response relationship
A
relationship btwn concentration of drug in tissue and magnitude of tissue’s response to drug
8
Q
Most drugs produce their effects by
A
bind to protein receptors in target tissues → activate signal transduction cascade
9
Q
Toxicology definition
A
study of poisons and organ toxicity; focuses on harmful effects of drugs & mechanisms by which these agents produce pathologic changes, disease, and death
10
Q
Pharmacotherapeutics definition
A
medical science concerned with the use of drugs in the treatment of disease
11
Q
clinical trials
A
Human studies used to determine efficacy & safety of drug therapy in human subjects
12
Q
Pharmacy definition
A
science & profession concerned w/preparation, storage, dispensation, proper use of drug products
13
Q
Pharmacognosy definition
A
study of drugs isolated from natural sources, including plants, microbes, animal tissues, and minerals
14
Q
Medicinal chemistry definition
A
branch of organic chemistry that specializes in design & chemical synthesis of drugs
15
Q
Pharmaceutical chemistry / pharmaceutics definition
A
concerned w/formulation & chemical properties of pharmaceutical products, such as tablets, liquid solutions and suspensions, and aerosols
16
Q
drug definition
A
natural product, chemical substance, or pharmaceutical preparation intended for administration to human or animal to diagnose or treat a disease
17
Q
types of drugs produced by body
A
hormones, neurotransmitters, or peptides
18
Q
xenobiotic
A
synthetic or natural drug produced outside the body
19
Q
poison
A
a drug that can kill
20
Q
toxin
A
a drug that can kill and is produced by a living organism
21
Q
alkaloid definition
A
contain nitrogen groups and produce an alkaline reaction in aqueous solution
22
Q
alkaloid examples
A
morphine, cocaine, atropine, quinine
23
Q
Antibiotics
A
drugs targeted to bacteria; isolated from numerous microorganisms, including Penicillium and Streptomyces species
24
Q
structure-activity relationship
A
relationship btwn drug molecule, its target receptor, and resulting pharmacologic activity
25
crude drug preparations
obtained from natural sources; can be made by drying or pulverizing plant or animal tissue (ex: opium), or extracting substances from a natural product (ex: coffee)
26
pure drug compounds
isolated from natural sources or synthesized in lab (ex: morphine extract)
27
pharmaceutical preparations
intended for administration to patients (ex: morphine solution)
28
routes of drug administration
* enteral
* parenteral
* systemic
29
types of drugs
natural, semi-synthetic, or synthetic
30
drugs regulated by
the FDA’s Center for Drug Evaluation and Research (CDER) -- except biologics
31
CDER
FDA entity that regulates drugs (except biologics)
32
Prescription drug
aka "legend drug;" considered potentially harmful if not used under supervision of licensed health care practitioner
33
biologics
complex mixtures that are not easily identified or characterized; incl. vaccines, recombinant therapeutic proteins, and gene therapy
34
biologics regulated by
FDA’s Center for Biologics Evaluation and Research
35
CBER
FDA entity that regulates biologics
36
Controlled or scheduled drug
prescription drug whose use and distribution is tightly controlled b/c of abuse potential or risk
37
Classification of controlled drugs
Schedules CI, CII, CIII, CIV, and CV
38
Over-the-counter drugs
Do not require a prescription but still require FDA drug approval process
39
Behind-the-counter drugs
OTC drugs with restricted access (ex: sudafed)
40
regulation of dietary supplements
FDA’s Center for Food Safety and Applied Nutrition
41
What to consider when Choosing a Drug for Your Patient
benefit vs risk
42
STEPS Approach to Evaluating and Comparing Drugs
* S – Safety
* T – Tolerance
* E – Efficacy
* P – Price
* S – Simplicity
43
medication nonadherence
At least 50% of patients do this
44
percentage of adults \> 65 years old who take more than 5 drugs
42%
45
top 3 therapeutic classes of prescriptions
1. antihypertensives
2. mental health
3. pain
46
top 3 prescriptions (number prescribed)
1. levothyroxine
2. acetominophen/hydrocodone
3. lisinopril
47
how many phases of clinical testing
4
48
Clinical Testing Phase 1
safety, PK, dose range, 20-80 subjects
49
Clinical Testing Phase 2
test hypothesis of effectiveness, controlled trial, 100-300 subjects
50
Clinical Testing Phase 3
randomized, blinded, placebo controlled trials for specific indications
51
Clinical Testing Phase 4
post-marketing surveillance
52
FDA Drug Development and Approval Process
* Pre-clinical research (animals)
* Investigational New Drug Application (IND)
* Phases 1-3 of clinical testing New Drug Application (NDA) filed
* FDA subcommittee review and approval
* Phase 4 of clinical testing
53
drug patent length
20 years; can be extended 5 years but total life of patent cannot go beyond 14 years after NDA approval
54
chemical drug name
based on chemical structure
55
generic drug name
public nonproprietary name; United States Adopted Names (USAN); Standards set by US Pharmacopeia (ex: sildenafil citrate)
56
trade drug name
exclusively owned by manufacturer (ex: Viagra)
57
most common formulation of drugs is for what kind of administration
oral
58
most common preparations for oral administration
tablets and capsules
59
benefits of tablets and capsules
suitable for mass production; stable and convenient to use; can be formulated to release drug immediately after ingestion or over a period of hours
60
Variations in rate and extent of tablet disintegration and drug dissolution can give rise to
differences in the oral bioavailability of drugs from different tablet formulations
61
drug in tablet must do what to reach circulation
dissolve in gastrointestinal fluids
62
Enteric coatings
* don't disintegrate in gastric acid
* break down in basic pH of intestines
* protect drugs that would otherwise be destroyed by gastric acid
* slow release & absorption when large dose given at one time (ex: fluoxetine)
63
two methods used to extend the release of a drug
1. controlled diffusion
2. controlled dissolution
64
controlled diffusion
regulated by a rate-controlling membrane
65
controlled dissolution
caused by inert polymers that gradually break down in body fluids
66
osmotic pressure can be used for
sustained release -- formulations contain osmotic agent that attracts gastrointestinal fluid at a constant rate, which then forces drug out of tablet thru small laser-drilled hole
67
benefits / downsides of solutions and suspensions
* convenient method for administering drugs to pts who can't easily swallow pills or tablets
* less convenient than solid dosage b/c liquid must be measured each time dose is given
68
sterile solutions and suspensions be administered in these ways
parenterally: needle & syringe or IV infusion pump
69
Transdermal administration
* drug slowly released for absorption thru skin **into circulation**
* most suitable for potent drugs w/lipid solubility (ex: fentanyl patch)
70
Aerosols
* inhalation thru nose or mouth
* particularly useful for respiratory disorders b/c of direct delivery
71
Nasal sprays
type of aerosol used either for drugs that have a localized effect on the nasal mucosa or that are absorbed through the mucosa and exert an effect on another organ (ex: nasal butorphanol for pain)
72
types of enteral administration
sublingual, buccal, oral, rectal
73
enteral administration definition
drug is absorbed from GI tract
74
benefits of sublingual and buccal administration
* enable rapid absorption of certain drugs
* not affected by first-pass drug metabolism in liver (ex: nitroglycerin; hyosciamine)
75
oral administration definition
medication is swallowed, and drug is absorbed from stomach and small intestine
76
Per Os (PO)
oral administration
77
benefits / disadvantages of oral administration
* convenient, relatively safe, most economical
* absorption can vary widely
* some drugs inactivated by first-pass metabolism
* not suitable for pts who are sedated, comatose, or experiencing nausea and vomiting
78
benefits / disadvantages of rectal administration
* useful when pts can't take medications by mouth (nausea, vomiting)
* can be administered for localized conditions like hemorrhoids
* undergo relatively little first-pass metabolism
79
Parenteral administration definition
administration w/needle and syringe or IV infusion pump
80
most commonly used parenteral routes
* intravenous
* intramuscular
* subcutaneous
81
benefits / disadvantages of IV administration
* bypasses absorption
* greatest reliability and control over dose reaching systemic circulation
* 100% bioavailability
* preferred for drugs w/short T1/2
* good for drugs that have to be carefully calibrated to physiologic response
* dangerous b/c potential for serious toxicity from rapid administration
82
intramuscular and subcutaneous administration suitable for these types of drug preparations
solutions and particle suspensions
83
intramuscular or subcutaneous absorbed faster?
intramuscular -- greater circulation of blood to muscle
84
solutions or suspensions absorbed faster?
Solutions are absorbed more rapidly than particle suspensions, so suspensions are often used to extend the duration of action of a drug over many hours or days.
85
Intrathecal administration
* injection of drug thru thecal covering of spinal cord and into subarachnoid space
* useful in administering antibiotics that don't cross blood-brain barrier
86
Epidural administration
targets analgesics into space above dural membranes of spinal cord
87
intraarticular administration
parenteral route used for arthritis drugs
88
intradermal administration
parenteral route used for allergy tests
89
insufflation / intranasal administration
parenteral route used for sinus medications
90
transdermal patches
* most use rate-controlling membrane to regulate diffusion
* drug intended to reach circulation
91
benefits / disadvantages of transdermal administration
* bypasses first-pass metabolism
* reliable route for drugs effective at relatively low dosage and highly soluble in lipid membranes
* controlled release possible
92
Topical administration
* application of drugs to the surface of the body to produce a localized effect
* when applied over inflamed skin, can reach circulation
93
This route of drug administration is used with potent and lipophilic drugs in patch formulation and avoids first-pass metabolism
transdermal
94
This route of administration does not have an absorption phase
intravenous
95
Which parenteral route is used to administer drug suspensions that are slowly absorbed?
intramuscular
96
An elderly patient has problems remembering to take her medication three times a day. Which one of the drug formulations might be particularly useful in this case?
extended-release
97
Which form of a drug name is most likely known by patients from exposure to drug advertisements?
trade name
98
These administration routes bypass first-pass metabolism / the hepatic portal vein
* sublingual
* buccal
* rectal
* transdermal
* parenteral
99
These administration routes bypass GI tract
* intravenous
* intramuscular
* subcutaneous
* transdermal
100
mechanisms of absorption
* Passive diffusion
* Active transport
101
passive diffusion
* drug enters cell until intracellular conc = extracellular conc
* rate depends on drug conc gradient
* **Most drugs absorbed by this method**
102
Most drugs absorbed by this method
passive diffusion
103
active transport
drugs can enter cells against concentration gradient by linking to transport proteins
104
function of Transport Proteins
Allow efficient transport of molecules across epithelial membranes in the intestine
105
OATP
* organic anion transporting proteins
* transporters that facilitate uptake
106
P-glycoprotein (Pgp)
* Efflux transporter that actively removes drugs from epithelial cells and prevents absorption
* Essential mechanism to prevent toxin absorption
* Can also lead to chemotherapeutic drug resistance
107
essential mechanism to prevent toxin absorption
efflux transporters like Pgp
108
form of drug that can cross lipid membranes
Only non-ionized form
109
pKa value of a drug tells you this
pH value at which ½ of drug is in ionic form (i.e. ½ ionized & ½ non-ionized)
110
pKa and diffusion capability of weak acids
* low pKa
* diffuse across membranes at low pH
111
pKa and diffusion capability of weak bases
* high pKa
* diffuse across membranes at high pH
112
gastric acid pH
1.4
113
plasma pH
7.4
114
weak acids do what with protons?
donate them to form anions (A-)
115
weak bases do what with protons?
accept them to form cations (HB+)
116
non-ionized form of weak acid protonated or nonprotonated?
protonated (HA)
117
non-ionized form of weak base protonated or nonprotonated?
nonprotonated (B + H+)
118
Henderson-Hasselbach eqn
* used to determine ionized:nonionized ratio
* log (prot/nonprot) = pKa - pH
119
Factors Affecting Oral Absorption
* dosage formulations (coatings, controlled-release designs)
* blood flow
* gastric motility
* first-pass effect
120
Bioavailability (F)
fraction of drug that actually enters the systemic circulation in active form
121
bioavailability = 100% for this kind of administration
parenteral
122
First pass effect
drugs absorbed from GI tract are metabolized by liver before reaching systemic circulation
123
Drugs subject to first-pass effect have this kind of extraction rate and bioavailability
* high hepatic extraction ratios
* low oral bioavailability
124
examples of drugs w/high (hepatic) extraction ratios
* oral propanalol
* morphine
* meperidine
* nitroglycerin
* verapamil
* lidocaine
125
Factors Affecting Drug Distribution
* Organ blood flow
* plasma protein binding
* lipid solubility
* molecular size
126
highly perfused organs that get faster drug distribution
* Liver
* kidney
* heart
* lungs
127
less-perfused organs that get slower drug distribution
* Skin
* fat
* bone
128
drug bound to albumin is active or inactive?
inactive -- only free drug is active and able to cross cell membranes
129
Lipid-soluble drugs distribute to a greater or lesser extent than polar and ionized molecules?
lipid-soluble have higher volume of distribution (Vd) and cross BBB
130
apparent volume of distribution (Vd)
volume of fluid in which a drug would need to be dissolved to have the same concentration as in plasma
131
can amount of drug in the body be directly measured?
no -- usually measure the conc of drug in plasma
132
Plasma concentration of drug depends on
* dose of drug
* extent of distribution into tissues
133
Vd
Vd (L) = [amount in body or dose administered (mg)] / [plasma drug concentration after administration (mg/L)]
L = mg / (mg/L)
134
Plasma volume for 70 kg Individual
* 2.8 L
* 0.04 L/kg
135
Extracellular fluid volume for 70 kg Individual
(ECF = Plasma + interstitial fluid)
* 17.5 L
* 0.25 L/kg
136
Intracellular fluid volume for 70 kg Individual
* 24.5 L
* 0.35 L/kg
137
Total body water volume for 70 kg Individual
* 42 L
* 0.6 L/kg
138
High Vd indicates...
Drug highly distributed into tissues and fat
139
Low Vd indicates...
Drug primarily in plasma
140
Importance of Vd
* Fundamental pharmacokinetic parameter for all drugs
* Useful for calculating loading dose
* Essential for determining elimination rate constant and T1/2
141
loading dose
* 1st dose of drug
* necessary to reach therapeutic serum levels quickly for drugs w/long T½
142
Calculate digoxin loading dose if
* T½ = 2 days
* Steady state plasma concentration desired (Cp) = 1.5 mcg/L
* Vd = 7.3 L/kg
* Vd = Dose / Cp
* Dose = Vd x Cp
* Dose = 7.3 L/kg x 70 kg x 1.5 mcg/L = 766.5 mcg or 0.75 mg
143
Vd formula
Vd = Dose / Cp
or
Dose = Vd x Cp
144
Drug Metabolism
* activate OR inactivate compounds
* transform compounds into easily excretable metabolites
* 2 phases
145
Drug Metabolism 1o locations
* liver
* intestinal cell lining
146
Phase I of Drug Metabolism
Addition of small polar groups to drug structure by oxidation, reduction, or hydrolysis converts lipid-soluble drugs to more polar and water-soluble metabolites (active or inactive)
147
Phase II of Drug Metabolism
Formation of highly water-soluble conjugates to create inactive and easily-eliminated compound
148
Cytochrome P450 Enzymes general characteristics & location
* Responsible for most Phase I metabolism reactions
* in all living organisms
* primarily in liver, but also in intestine, lung, brain, and placenta
149
Cytochrome P450 Enzymes structure
* bound to membranes within a cell (cyto)
* contain heme pigment (chrome and P)
* absorb light at 450 nm when exposed to CO
150
Cytochrome P450 Enzymes function
* Essential for production of endogenous compounds like cholesterol, steroids, and prostacyclins
* Necessary for detoxification of exogenous compounds like foreign chemicals and drugs
151
Cytochrome P450 Enzyme Family
* Over 50 distinct P450 enzymes in humans
* Five (1A2, 2C9, 2C19, 2D6, 3A4) metabolize 90% of drugs
152
Most drug interactions caused by this
changes in Cyt P450 metabolism
153
Pro-drug
* needs to be metabolized to become active
* parent compound usually inactive
154
When could pro-drug have little or no clinical effect?
when it depends on a P450 enzyme that isn't functioning b/c:
* in short supply (poor metabolizer)
* inhibited by something else
155
Examples of pro-drugs
* Hydrocodone → hydromorphone (pain relief)
* Tramadol (Ultram) → metabolite 33x more active (pain relief)
* Enalapril → enalaprilat (HTN)
* Vyvanse (lisdexamfetamine) → dextroamphetamine in gut (prevent intravenous abuse)
156
Examples of Active Metabolites of Old Drugs Developed as New Drugs
* Zyrtec (cetirizine) from Atarax (hydroxyzine)
* Allegra (fexofenadine) from Seldane (terfenadine)
* Clarinex (desloratidine) from Claritin (loratidine)
* Invega (paliperidone) from Risperdal (risperidone)
* Pristiq (desvenlafaxine) from Effexor (venlafaxine)
* Trilipix (fenofibric acid) from fenofibrate
157
Biliary excretion
* Conjugated drug metabolites and large molecular weight compounds
* Drug may be reabsorbed by enterohepatic cycling
* requires active center
158
Renal excretion
Most drugs eliminated this way, either as parent compound or as inactive metabolite formed in liver
159
Most drugs eliminated this way
renal excretion
160
Glomerular filtration depends on
extent of protein binding
161
3 methods of renal excretion
1. Glomerular filtration
2. Active tubular secretion
3. Passive tubular reabsorption
162
Passive tubular reabsorption depends on
* lipid solubility
* ionization
163
Clearance (Cl) definition
* Volume of plasma from which drug is eliminated per unit time (L/hr or ml/min)
* Summation of clearance of drug metabolized by liver and excreted by kidney
* Does not indicate how much drug is removed
164
Clearance calculation
Elimination rate (mg/hr) = Clearance [Cl] (L/hr) x Plasma conc [Css] (mg/L)
165
Creatinine Clearance (ClCr)
* allows estimation of GFR
* need accurate estimate of renal function to dose drugs eliminated by kidney
* most dosage adjustments for renally excreted drugs based on estimate of ClCr
166
Creatinine
* metabolic byproduct of muscle
* constant rate of formation
* elimination almost exclusively by GFR
167
Formula name for estimating Creatinine Clearance
* Cockroft and Gault formula widely used
* Need to know sex, age, ideal body weight, and Scr
168
Cockroft and Gault formula
* ClCr = [(140 - age) x IBW in kg] / (Scr in mg/dl x 72)
* multiply ClCr by 0.85 for women
169
Zero-Order Elimination
* aka capacity-limited or nonlinear elimination
* Elimination rate constant and independent of plasma concentration
* Cl inversely proportional to drug concentration (toxic levels can be reached quickly)
* Very few drugs eliminated by this method
170
Drugs eliminated by Zero-Order Elimination
* phenytoin (Dilantin)
* aspirin at high doses
* ethanol
171
First-Order Elimination
* At normal doses, rate of drug elimination is proportional to plasma drug concentration
* if drug concentration increases, so does clearance
* most drugs eliminated by this method
172
most drugs eliminated by this method
First Order Elimination
173
Elimination Rate Constant (Ke)
* a fraction of drug eliminated over a set period of time
* ex: Ke = 0.25/hr → 25% of drug remaining in body is removed each hour
174
Calculating Ke
Ke = Cl (L/hr) / Vd (L)
175
Mathematical Relationship btwn K and T½
T½ = 0.693 / k
176
Relationship btwn Ke and Half-Life
T½ = 0.7 / Ke
177
Relationship btwn Vd, Cl, and Half-Life
T½ = 0.7Vd / Cl
178
Steady state
drug administration rate = elimination rate
179
time it takes for a drug to reach steady state is dependent on...
T½ of drug
180
It takes about how many half-lives to reach steady state after starting drug (no loading dose)?
5
181
It takes about how many half-lives for elimination of drug after last dose?
5
182
Therapeutic Drug Monitoring
* Usually for drugs with narrow therapeutic index
* Drug needs to be at steady state, otherwise lab result may lead to dosage error
* Depending on drug, may need peak level, trough level, or both
183
Examples of Drugs Requiring Therapeutic Monitoring
* Aminoglycoside antibiotics (Gentamicin, tobramycin, amikacin)
* Clozapine (atypical antipsychotic)
* Digoxin (antiarrhythmic)
* Theophylline (bronchodilator)
* Vancomycin (antibiotic)
* Warfarin (anticoagulant)
184
Summarize the 5 important pharmacokinetic equations
* Vd (L) = Drug in body (mg) / Plasma drug concentration or Cp (mg/L)
* Loading Dose (mg) = Vd x Cp
* Ke = Cl (L/hr) / Vd (L)
* T½ = 0.7 / Ke
* T½ = 0.7Vd / Cl
185
what protein can lead to chemotherapeutic drug resistance
Pgp
186
examples of Pgp inhibitors
amiodarone, erythromycin, propranolol
187
acidic drugs generally bind to what in plasma?
albumin
188
basic drugs generally bind to what in plasma?
glycoproteins and β-globulins
189
conjugation
* attachment of polar groups
* often allows for faster excretion
190
microsomal P450 monooxygenase reaction requires what?
* CYP (a hemoprotein)
* NADPH-dependent CYP reductase
* membrane lipids in which the system is embedded
191
Most drug biotransformation is catalyzed by which three CYP families?
* CYP1
* CYP2
* CYP3
192
which CYP subfamily catalyzes more than half of all microsomal drug oxidations?
CYP3A
193
polymorphism
individual variation in the genes coding for drug-metabolizing enzymes
194
examples of polymorphisms that affect drug metabolism
* SA phenotype:
* slow acetylators -- reach toxicity of certain drugs faster
* CYP2D6 and CYP2C19 differences:
* altered enzymatic rxn rates (codeine; omeprazole)
195
enterohepatic cycling
* drug excreted in bile
* bile empties into intestines
* fraction of drug may be reabsorbed into circulation and eventually return to liver
196
biliary excretion eliminates substances from the body only to the extent that...
some of the excreted drug is not reabsorbed from the intestine
197
one-compartment model
drug undergoes absorption into blood according to rate constant Ka, and elimination from blood with rate constant Ke
198
two-compartment model
drugs are absorbed into central compartment (blood), distributed from central compartment to peripheral compartment (the tissues), and eliminated back from central compartment
199
how to accelerate rate of excretion of weak acid?
* alkalinize urine via NaHCO3 administration
* particularly useful for
* aspirin overdose
* salicylate overdose
* phenobarbital overdose
* 2,4-dichlorophenoxyacetic acid (herbicide) poisoning
200
how to accelerate rate of excretion of weak base?
* acidify urine
* has been largely abandoned b/c does not significantly increase elimination of these drugs and poses serious risk of metabolic acidosis
201
when is manipulation of the urine pH worthwhile for accelerated excretion?
when drug is excreted to a large degree by kidneys
202
Parameters of plasma drug concentration curve
* maximum concentration (Cmax)
* time needed to reach maximum (Tmax)
* minimum effective concentration (MEC)
* duration of action
203
area under the curve (AUC)
measure of total amount of drug during time course
204
formula to determine oral bioavailability of a particular drug
dividing the AUC of an orally administered dose of the drug (AUCoral) by the AUC of an IV-administered dose of the same drug (AUCIV)
205
Pharmaceutical factors that can affect bioavailability
* rate and extent of tablet disintegration
* drug dissolution
206
Biologic factors that can affect bioavailability
* food, which can sequester or inactivate a drug
* gastric acid, which can inactivate a drug
* gut and liver enzymes, which can metabolize a drug during absorption and first pass through the liver
207
indication that drug has reached intracellular fluid?
Vd = total body water
208
drugs w/renal clearance close to ClCr...
eliminated primarily by glomerular filtration, w/little tubular secretion or reabsorption
209
drugs w/renal clearance higher than ClCr...
undergo tubular secretion
210
drugs w/renal clearance lower than ClCr...
are highly bound to plasma proteins or undergo passive reabsorption from renal tubules
211
hepatic clearance
usually determined by multiplying hepatic blood flow by arteriovenous drug concentration difference
212
why is hepatic clearance difficult to determine?
hepatic drug elimination includes biotransformation and biliary excretion of parent compounds
213
What does graph of first-order kinetics look like?
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214
Compare graphs of first-order and zero-order kinetics
215
What does graph of Vd look like?
216
How is plasma concentration affected by intermittent vs continuous administration?
* intermittent will accumulate to a steady state at the same rate as a drug given continuously
* but the plasma concentration will fluctuate as each dose is absorbed and eliminated
217
maintenance dose
given to establish or maintain the desired steady-state plasma drug concentration
218
what does graph of drug accumulation to steady state look like?
219
In first-order kinetics, a drug’s half-life and clearance are constant as long as...
physiologic elimination processes are constant
220
What does the graph of steady-state plasma drug concentration and dosage look like?
221
What does the graph of steady-state plasma drug concentration and half-life look like?
222
What does the graph of steady-state plasma drug concentration and intermittent vs continuous infusion look like?
223
What does the graph of steady-state plasma drug concentrations after intermittent oral administration (affected by the rates of drug absorption, distribution, and elimination) look like?
224
If food decreases the rate but not the extent of the absorption of a particular drug from the GI tract, then taking the drug with food will result in a smaller...
maximal plasma drug concentration
225
If a drug exhibits first-order elimination, then the rate of elimination is proportional to...
the plasma drug concentration
226
After a person ingests an overdose of an opioid analgesic, the plasma drug concentration is found to be 32 mg/L. How long will it take to reach a safe plasma concentration of 2 mg/L if the drug’s half-life is 6 hours?
24 hours. The half-life is the time required to reduce the plasma drug concentration 50%. In this case, it will take four drug half-lives, or 24 hours, to reduce the plasma level from 32 to 2 mg/L.
227
What dose of a drug should be injected intravenously every 8 hours to obtain an average steady-state plasma drug concentration of 5 mg/L if the drug’s volume of distribution is 30 L and its clearance is 8 L/hr?
320 mg. The dose required to establish a target plasma drug concentration is calculated by multiplying the clearance by the target concentration and dosage interval. In this case, it is 5 mg/L × 8 L/hr × 8 hr = 320 mg.
228
If a drug is is more ionized inside cells than in plasma, then its Vd will be...
greater.
When a drug is more ionized inside cells, the drug becomes sequestered in the cells and the Vd can become quite large. This is called ion trapping.
229
ion trapping
When a drug is more ionized inside cells, the drug becomes sequestered in the cells and the volume of distribution can become quite large.
230
Hierarchy of Evidence
1. Randomized, double-blind, controlled studies (meta-analysis, Cochrane review)
2. Randomized, controlled studies
3. Cohort studies
4. Case control studies
5. Case series
6. Case reports
7. Ideas, editorials, opinions
8. Animal research
9. In vitro research
231
Relative risk reduction (RRR) equation
RRR = (CER - EER) / CER
232
Absolute risk reduction (ARR) equation
ARR = CER - EER
233
Numbers needed to treat (NNT) equation
NNT = 100 / ARR
or NNT = 100 / (CER - EER)
234
Numbers needed to harm (NNH) equation
NNH = 100 / ARI
or NNH = 100 / (EER - CER)
235
Number needed to harm (NNH) definition
tells number of pts that must be treated for 1 to have a serious adverse rxn
236
Numbers needed to treat (NNT) definition
A NNT of 20 means that you would need to treat 20 patients with drug M to prevent a migraine from recurring in 1 patient.
237
Absolute risk increase (ARI) equation
ARI = (EER - CER)
238
The CLASS Study
Study on GI Toxicity of Celecoxib vs NSAIDs
239
the VIGOR Study
Study on GI Toxicity of Rofecoxib vs Naproxen
240
benefits & drawbacks for RRR
* Cannot discriminate large risks and benefits from small ones
* Useful for marketing purposes
241
benefits & drawbacks for NNT
* Can estimate degree of benefit or risk
* Easy method to use
* Significant # depends on outcome, alternative treatments, risk, and cost
242
P value
* probability that observed result is due to **chance**
* Usually findings are “statistically significant” if P \< 5% (P\<0.05)
243
Confidence Interval (CI)
* range of plausible results (**precision**)
* Usually reported as 95% CI (range of true result in 95% of studies if repeated many times)
* If 95% CI includes no difference between study groups, then P \> 0.05
244
Schedule I Controlled Drugs
have no currently accepted medical use in the United States, a lack of accepted safety for use under medical supervision, and a high potential for abuse.
245
Examples of Schedule I Controlled Drugs
heroin, LSD, marijuana, peyote, methaqualone
246
Schedule II Controlled Drugs
high potential for abuse which may lead to severe psychological or physical dependence
247
Examples of Schedule II Controlled Drugs
hydromorphone, methadone, meperidine, oxycodone, fentanyl, morphine, opium, codeine
248
Schedule III Controlled Drugs
potential for abuse less than substances in Schedules I or II and abuse may lead to moderate or low physical dependence or high psychological dependence
249
Examples of Schedule III Controlled Drugs
Vicodin, Tylenol with Codeine
250
Schedule IV Controlled Drugs
low potential for abuse relative to substances in Schedule III
251
Examples of Schedule IV Controlled Drugs
alprazolam, carisoprodol, clonazepam, clorazepate, diazepam, lorazepam, midazolam, temazepam, and triazolam.
252
Schedule V Controlled Drugs
low potential for abuse relative to substances listed in Schedule IV and consist primarily of preparations containing limited quantities of certain narcotics.
253
Examples of Schedule V Controlled Drugs
cough preparations containing not more than 200 milligrams of codeine per 100 milliliters or per 100 grams (Robitussin AC®, Phenergan with Codeine®), and ezogabine
254
Pt overdoses on adderall (amphetamine, weak base w/pKa 9.9). How do you minimize further GI absorption and enhance urinary excretion?
Acidify GI tract and urine
255
2 types of drug action
* receptor-mediated
* non-receptor-mediated
256
Receptors definition
Cell molecules, usually proteins, that initiate a series of biochemical events resulting in a physiological response when stimulated by an agonist
257
Affinity
tendency of a drug to bind to a receptor
258
Efficacy
ability of a drug to initiate effect by activating receptor once bound
259
Agonist
* Drug w/receptor affinity and efficacy
* Can be full (maximal response) or partial (submaximal response)
260
Antagonist
* Drugs w/receptor affinity but no efficacy
* Can be competitive (reversible) or non-competitive (irreversible)
261
5 major transmembrane signaling mechanisms to bypass lipid membrane barrier
1. Intracellular receptors for lipid soluble drugs
2. Transmembrane enzyme receptors
3. Transmembrane cytokine receptors
4. Ligand-gated ion channels
5. G Proteins and second messengers
262
Intracellular receptors
* MOA for lipid soluble drugs (steroid hormones, thyroid hormone, vitamin D)
* Receptors on nucleus stimulate gene transcription via diffusion thru cell membrane
263
Signaling MOA for steroid hormones, thyroid hormone, vitamin D
Intracellular receptors
264
Transmembrane enzyme receptors
* MOA of insulin & growth factors
* Usually a tyrosine kinase that phosphorylates upon activation
265
Signaling MOA of insulin
Transmembrane TK receptor
266
Transmembrane cytokine receptors
* MOA for regulators of growth and differentiation (growth hormone, erythropoetin, interferon)
* Activate Janus-kinase enzymes which phosphorylate STAT molecules
267
Signaling MOA for regulators of growth and differentiation
Transmembrane Janus-STAT cytokine receptors
268
Ligand-gated ion channels
* MOA of many drugs that mimic the action of natural NTs (Ach, 5-HT, GABA, glutamate)
* Regulate ion flow thru channel by changing transmembrane electrical potential
269
Signaling MOA of drugs that mimic NTs
Ligand-gated ion channels
270
G Proteins and second messengers
* MOA for many drugs, including sympathomimetics
* Variety of G-protein subtypes determine 2nd messenger response
* 3 separate components:
* Serpentine cell-surface receptor
* G protein on cytoplasmic side of membrane changes enzyme or ion channel activity
* 2nd messenger (cAMP, PLC)
271
3 components of G protein-second messenger signaling
1. Serpentine cell-surface receptor
2. G protein on cytoplasmic side of membrane that changes enzyme or ion channel activity
3. 2nd messenger (cAMP, PLC)
272
Signaling MOA for sympathomimetic drugs
G Proteins and second messengers
273
What do intracellular signals look like?
274
what does extracellular signaling look like?
275
what does tyrosine kinase signaling look like?
276
what does ion channel signaling look like?
277
what does G protein signaling look like?
278
Gs receptor for
ß-adrenergic amines, glucagon, histamine, serotonin, other hormones
279
Gs signaling pathway
INcrease in Adenylyl Cyclase → INcrease in cAMP
280
Gi receptor for
a2-adrenergic amines, muscarinic Ach, opioids, serotonin
281
Gi signaling pathway
DEcrease in Adenylyl Cyclase → DEcrease in cAMP → open cardiac K+ channels → decrease in HR
282
Golf receptor for
odorants (olfactory epithelium)
283
Golf signaling pathway
INcrease in Adenylyl Cyclase → INcrease in cAMP
284
Gq receptor for
muscarinic Ach, bombesin, serotonin
285
Gq signaling pathway
Increase in PLC → Increase in IP3, DAG → increase in cytoplasmic Ca2+
286
Gt receptor for
photons (rhodopsin & color opsins in retina)
287
Gt signaling pathway
INcrease in cGMP phosphodiesterase → DEcrease in cGMP (phototransduction)
288
4 Types of Drug AGonists
1. Agonists of cell surface receptors
2. Nuclear receptor agonists
3. Enzyme activators
4. Ion channel openers
289
Examples of cell surface receptor agonists
* Alpha-receptor agonists -- epinephrine
* Beta-receptor agonists -- albuterol inhaler
* Opioid analgesics -- morphine and hydrocodone
* NT agonists -- levodopa for Parkinson’s
290
Examples of Nuclear receptor agonists
* Estrogens
* Corticosteroids -- prednisone
291
Examples of enzyme activators
nitroglycerin
292
Examples of ion channel openers
* ethanol
* benzodiazepines
293
5 Types of Drug ANTagonists
1. Antagonists of cell surface receptors
2. Antagonists of nuclear receptors
3. Enzyme inhibitors
4. Ion channel blockers
5. Neurotransmitter inhibitors
294
Examples of cell surface receptor ANTagaonists
Beta-receptor antagonists (β-blockers) -- atenolol
295
Examples of nuclear receptor ANTagaonists
Estrogen receptor antagonists -- tamoxifen for breast cancer
296
Examples of enzyme inhibitors
* ACE inhibitors for hypertension and heart failure
* HMG-CoA Reductase inhibitors (statins) for hypercholesterolemia (remember: HMG-CoA reductase catalyzes a rxn early in the cholesterol synthesis pathway)
297
Examples of ion channel blockers
Ca2+-channel blockers for hypertension and angina
298
Examples of NT inhibitors
Selective serotonin reuptake inhibitors (SSRIs) for depression
299
8 Types of Non-Receptor-Mediated Drug Mechanisms
1. Enzyme action
2. Chemical reaction
3. Binding free molecules
4. Nutrient supplementation
5. Physical reactions
6. Antigens
7. Vaccines
8. Antibiotics
300
Equation for determining drug level at any time after administration
Cp = (Cp0)(e-ket)
* Cp = plasma conc at time t
* Cp0 = initial plasma conc
301
example of enzyme action drug mechanism
Streptokinase for thrombolysis after acute MI
302
example of chemical reaction drug mechanism
antacids
303
examples of binding free molecules drug mechanism
* Drugs for heavy metal poisoning
* monoclonal antibodies
304
example of nutrient & supplementation drug mechanism
vitamins & minerals
305
example of physical reaction drug mechanism
osmotic laxatives
306
example of antigen drug mechanism
vaccines
307
Potency
concentration of drug required to produce a particular effect
308
Median effective dose (ED50)
Dose that produces 50% of maximal response
309
Median lethal dose (LD50)
Dose that causes death in 50% of subjects
310
Therapeutic Index (TI)
* Ratio of LD50 to ED50
* higher TI = safer drug
311
A safer drug has a high or low TI?
High
312
Dose-Response Relationship
Relationship btwn concentration of drug at receptor site and magnitude of response
313
Graded dose-response curve
Tracks percent of maximum response vs dose
314
Quantal dose-response curve
Tracks percent of subjects with response vs dose
315
what does a graded dose-response graph look like?
316
In this graded dose-response curve, which drugs are full agonists?
R and S
317
In this graded dose-response curve, which drugs are partial agonists?
T
318
For this graded dose-response curve, rank the drugs in order of potency.
R \> S \> T
319
In this graded dose-response curve, what do X, Y, and Z represent?
X = agonist
Y = agonist w/competitive antagonist
Z = agonist w/noncompetitive antagonist
320
In this graded dose-response curve, which letter represents agonist alone?
X
321
In this graded dose-response curve, which letter represents agonist in presence of competitive antagonist?
Y
322
In this graded dose-response curve, which letter represents agonist in presence of noncompetitive antagonist?
Z
323
What does a quantal dose-response graph look like?
324
What does another kind of quantal dose-response graph look like?
325
What does TI look like on a graph?
326
Tolerance
Same dose of drug given repeatedly loses its effect → Greater doses needed to provide previously obtained effect
327
Tachyphylaxis
Acute tolerance -- decrease in response after single exposure
Ex: Oxymetazolone (Afrin) for nasal congestion; ethanol
328
Pharmacodynamic tolerance
**down**regulation of **receptors** (decreased synthesis)
ex: morphine
329
Pharmacokinetic tolerance
* *up**regulation of **metabolic enzymes** (increased synthesis)
ex: Carbamazepine for seizure control
330
2 types of enantiomer designations
1. *dextro-* or *levo-* (rotation of polarized light R or L)
2. *rectus-* or *sinister-* (molecular config)
331
stereoisomers and enantiomers are
non-superimposable mirror images
332
Isomerism effects on drug activity
Isomers can have/be:
* identical efficacy and toxicity, but different potency
* full pharm activity vs essentially inactive
* *ex: S-warfarin 5x more active than R-warfarin*
* both pharm active, but different therapeutic and toxic effects
* metabolized by different pathways
* *ex: S-warfarin by CYP2C9 / R-warfarin by CYP1A2 and 3A4*
333
Examples of New Drugs Developed from Older Drug Isomer Mixtures
* Escitalopram (Lexapro) for depression: S-isomer of citalopram (Celexa)
* Levalbuterol (Xopenex) for asthma: R-isomer of albuterol
* Esomeprazole (Nexium) for GERD/ulcers: S-isomer of omeprazole (Prilosec)
* Levofloxacin (Levaquin) for bacterial infections: S-isomer of ofloxacin (Floxin)
* Dexmethylphenidate (Focalin) for ADHD: D-isomer of methylphenidate (Ritalin)
* Levocetirizine (Xyzal) for allergies: L-isomer of cetirizine (Zyrtec)
* Dexlansoprazole (Kapidex) for GERD/ulcers: D-isomer of lansoprazole (Prevacid)
334
Factors that can cause variability in drug response
* Behavior (compliance)
* Body weight
* Body surface area
* Age
* Gender
* Health status
* Placebo effect
* Genetics
335
Pharmacogenetics
study of the genetic basis for variation in drug response
336
Pharmacogenomics
use of tools to assess multigenic determinants of drug response
337
polymorphic alleles
code for various amounts of protein resulting in various phenotypes
338
Genetic variations (alleles) exist for which Cytochrome P450 enzymes?
* 1A2
* 2C9
* 2C19
* 2D6
339
wild type allele
most common
340
variant allele
usually codes for reduced or no enzyme activity
341
extensive metabolizer
normal metabolizer homozygous for wild type allele
342
intermediate metabolizer
heterozygous for wild type and variant allele
343
poor metabolizer
homozygous for variant alleles
344
ultrarapid metabolizer
multiple copies of wild type allele
345
types of adverse drug reactions (ADRs)
* Allergic (hypersensitivity reactions)
* Toxic
* Ideosyncratic
* Alterations of biological or metabolic systems
346
partial agonist
produces submaximal response
347
Autonomic
“automatic” – regulated by brain stem
348
Somatic
voluntary – skeletal muscle innervation activated by motor cortex
349
Primary NTs in autonomic and somatic nervous systems:
* Acetylcholine
* Norepinephrine
* Epinephrine – from adrenal gland
350
Steps in Synaptic Transmission
1. NT synthesis
2. Cell Depolarization
3. Activation of Ca2+ channel
4. Fusion of vesicle with membrane, NT release
5. NT binds to ion channel receptor or G protein-coupled receptors
6. NT degraded by enzyme
7. NT Reuptake
8. Enzyme termination of signal
351
Neurotransmitter Receptors
Molecule on neuron or other cell surface that accepts NT and activates a specific response
352
Most autonomic drugs do what?
activate or block receptors
353
direct acting drugs
activate or block receptors; most autonomic drugs
354
Acetylcholine receptors are
cholinergic
355
location of muscarinic Ach receptors
neuroeffector junctions
356
location of nicotinic Ach receptors
all autonomic ganglia and somatic neuromuscular junctions
357
Norepinephrine and epinephrine receptors are
adrenergic
358
types of adrenergic receptors
α-adrenergic receptors
β-adrenergic receptors
359
parasympathetic ganglion location relative to target
ganglion very close to target
360
sympathetic ganglion location relative to target
ganglion far from target
361
preganglionic sympathetic neurons release what NT at what kind of receptor?
Ach, nicotinic
362
postganglionic sympathetic neurons release what NT at what kind of receptor?
NE or EPI, adrenergic
363
preganglionic parasympathetic neurons release what NT at what kind of receptor?
Ach, nicotinic
364
postganglionic parasympathetic neurons release what NT at what kind of receptor?
Ach, muscarinic
365
somatic neurons release what NT at what kind of receptor?
Ach, nicotinic
366
adrenal gland releases what NT?
Epi
367
SNS organization
* Nerves arise from thoracic and lumbar regions of spinal cord
* Ganglia adjacent to spinal cord
* Discharges as unit producing diffuse activation of target organs
368
principal post-ganglionic neurotransmitter released by SNS neurons
NE
369
SNS produces what kind of response
fight or flight
370
PNS organization
* Nerves arise from cranial and sacral region of spinal cord
* Ganglia in organ systems, not spinal cord
* Can discretely activate target tissues
371
principal postganglionic neurotransmitter released by PNS neurons
Ach
372
PNS produces what response
rest and digest (smooth mm contraction)
373
Baroreceptor Reflex
* Stretch receptors in aortic arch and carotid sinus activated with increased arterial pressure
* brainstem vasomotor center receives impulse
* Vagal/PNS response causes decreased HR
374
Drugs affecting blood pressure can stimulate what reflex?
Baroreceptor -- cause reflex bradycardia or reflex tachycardia
375
types & locations of Cholinergic Receptors
* Muscarinic – at neuroeffector junctions
* Nicotinic -- at all autonomic ganglia
376
Types & locations of muscarinic receptors
* M1 – CNS and autonomic ganglia
* M2 – cardiac muscle
* M3 – smooth muscle and glandular tissue
* M4 and M5 – CNS
377
nicotinic receptor actions
* At (all) autonomic ganglia – leads to postganglionic NT release at neuroeffector junctions
* At somatic neuromuscular junctions leads to skeletal mm contraction
378
examples of Cholinergic Response at Muscarinic Receptors
* Heart SA node - bradycardia
* Heart AV node - slow conduction
* blood vessels - vasodilation
* GI tract - increased tone & secretions, sphincter relaxation
* Eye iris - miosis
* Eye ciliary mm - accommodation/contraction
* urinary bladder - detrusor contraction, sphincter relaxation
* lungs - bronchoconstriction, increase in secretions
* exocrine glands - increase in tears, sweat, saliva
379
examples of Cholinergic Response at Nicotinic Receptors
* ganglia - SNS & PNS responses
* adrenal medulla - EPI & NE release
* skeletal mm - end plate depolarization
380
Classification of Cholinergic Receptor **Ag**onists
* Direct-acting
* Indirect-acting
* Reversible
* Irreversible
381
Classification of Cholinergic Receptor **Ant**agonists
* muscarinic
* nicotinic
382
Direct-acting cholinergic receptor agonists
* Directly stimulate cholinergic receptors
* Choline esters
* Plant alkaloids
383
Indirect-acting cholinergic receptor agonists
Increase Ach at synapse by inhibiting acetylcholinesterase
* Reversible
* Irreversible
384
Direct-acting choline esters
* Ach: no therapeutic use
* Methacholine: muscarinic, longer duration
* carbachol: predom nicotinic
* bethanechol: predom muscarinic
385
Ach as direct-acting agent
* choline ester w/no therapeutic use
* nonselective
* short duration
386
Methacholine
* direct-acting cholinergic (muscarinic)
* longer duration
* asthma stress test
387
Carbachol
* direct-acting cholinergic (nicotinic)
* topical agent for glaucoma
388
Bethanechol
* direct-acting cholinergic (muscarinic)
* used to stimulate bladder or GI tract w/o cardiac effects
389
Muscarine
* direct-acting plant alkaloid cholinergic
* from poisonous mushrooms
390
Nicotine
* direct-acting plant alkaloid cholinergic
* from tobacco
* oral, nasal, or transdermal to assist in smoking cessation
391
Pilocarpine
* direct-acting plant alkaloid cholinergic (muscarinic -- M1)
* from small shrub
* topical agent for glaucoma
* oral agent for xerostomia (dry mouth)
392
Therapeutic Uses for Direct-Acting Cholinergic Agonists
Relatively few primary uses
393
Cevimeline (Evoxac)
* synthetic direct-acting cholinergic agonist for xerostomia and xerophthalmia
* use after radiation treatment or for pts with **Sjögren’s** syndrome
394
Primary Open Angle Glaucoma
* Elevated IO pressure due to narrowing of anterior chamber angle and decrease in aqueous humor outflow
* Can result in irreversible optic nerve damage
395
2 Topical Drug Tx Goals for Primary Open Angle Glaucoma
* Increase aqueous humor outflow
OR
* Decrease aqueous humor production
396
Drugs to Increase aqueous humor outflow
* Muscarinic receptor **ag**onists
* Prostaglandin analogs
397
Drugs to Decrease aqueous humor production
* α2-receptor **ag**onists
* β-receptor **ant**agonists
* Carbonic anhydrous inhibitors
398
Pilocarpine mechanism in eye
* direct-acting M1 agonist
* Contracts ciliary muscle
* Miosis
* Thickens lens
* Causes **near** vision
399
Atropine mechanism in eye
* M1 **ant**agonist
* Relaxes ciliary muscle
* Mydriasis
* Thinner lens
* Causes **far** vision
400
Neostigmine
* Reversible Cholinesterase Inhibitor
* Quaternary amine – poor penetration of CNS
401
Edrophonium (Tensilon)
* Reversible Cholinesterase Inhibitor
* Neostigmine analog with shorter duration of action
* Dx Myasthenia Gravis
402
Physostigmine
* Reversible Cholinesterase Inhibitor
* Alkaloid from alabar bean
* Tertiary amine – can penetrate CNS
403
Myasthenia gravis
* autoimmune disease
* antibodies to nicotinic receptors in skeletal mm → severe muscle weakness
* Dx: Edrophonium
* Tx: Neostigmine, Pyridostigmine (cholinesterase inhibitors)
404
Rx myasthenia gravis
Neostigmine, Pyridostigmine
* Quaternary amines -- do NOT cross BBB
* Antidote for neuromuscular blockers such as d-tubocurarine
Contraindications:
* Intestinal or bladder obstruction
* Asthma
405
Neostigmine & pyridostigmine
* Tx myasthenia gravis
* Quaternary amines → do not cross BB barrier
* Antidote for neuromuscular blockers (d-tubocurarine)
* Contraindications:
* Intestinal or bladder obstruction
* Asthma
406
diseases associated w/decreased Ach production in brain
Dementia and Alzheimer’s Disease
407
Reversible Cholinesterase Inhibitors for Alzheimer’s Disease
* **Donepezil** (Aricept) – once daily
* Galantamine (Rizatidine)
* Rivastigmine (Exelon)
* These easily cross BBB
* Higher doses can cause typical cholinergic adverse effects (GI and bladder fx)
408
Examples of Irreversible cholinesterase inhibitors
* Organophosphates -- pesticides, sarin
* Malathion -- Inactivated by hydrolysis in mammals and birds, but not insects
409
Signs & Symptoms of Organophosphate Toxicity
* Muscarinic: bradycardia, hypotension, salivation, sweating, lacrimation, miosis
* Nicotinic: mm fibrillation, fasciculation, paralysis
* CNS: confusion, ataxia, coma, respiratory paralysis
410
Organophosphate Toxicity Acronym
* S – salivation
* L – lacrimation
* U – urination
* D – diarrhea
* G – gastric
* E - emptying
411
Examples of Muscarinic receptor **ant**agonists
* Belladonna alkaloids
* Semisynthetic and synthetic antagonists
412
Examples of Nicotinic receptor **ant**agonists
* Ganglionic blocking agents
* Neuromuscular blocking agents
* Nondepolarizing
* Depolarizing
413
Most common of the cholinergic drugs
* Anticholinergic drugs aka muscarinic receptor antagonists
* Most are competitive antagonists (reversibly bind to same site as Ach)
414
Atropine
* muscarinic **ant**agonist
* belladonna alkaloid
* widely distributed
* T1/2 = 2 hours
* eye effect \> 72 hours
* blocks **M1, M2,** and **M3**
415
Scopolamine
* muscarinic antagonist
* greater CNS effects than atropine
416
Expected Response to Anticholinergic Agents
* Eye mydriasis, paralysis of accommodation
* Sweating blocked, increased body temp
* Drying effect on secretions generally
* Bronchodilation, reduced secretions
* Increased HR
* Decreased GI motility
* Bladder atonia, urinary retention
417
Atropa belladonna
* Nightshade
* Source of belladonna alkaloids (atropine)
418
Belladonna Alkaloids
* Atropine (IV)
* Hyoscyamine: L-isomer of atropine
* Scopolamine (Transderm Scop)
419
Hyoscyamine complications
GI spasms
420
Toxicity profile for belladonna alkaloids
* Dry mouth
* blurred vision
* tachycardia
* palpitations
* urinary retention
* delirium
* hallucinations
421
Relative contraindications for belladonna alkaloids
* Glaucoma
* prostatic hyperplasia
* dementia
* delirium
422
Examples of Synthetic and Semisynthetic Muscarinic Receptor Antagonists
* Ipratropium (Atrovent) and tiotropium (Spiriva): Inhaled agents for asthma and COPD
* Dicyclomine (Bentyl): For irritable bowel disease
* Tropicamide (Mydriacyl): Topical agent to facilitate eye exams (short T ½)
* Benztropine (Cogentin): For drug-induced Parkinsonian (extrapyramidal) symptoms from antagonism of dopamine receptors
423
Drugs used for overactive bladder
* Oxybutinin (Ditropan)
* Tolterodine (Detrol)
* Solifenacin (VESIcare)
424
drugs that antagonize muscarinic receptors to some degree, even though this is not their primary mechanism of action
* 1st generation sedating antihistamines -- diphenhydramine
* Antidepressants -- amitriptyline
* Antipsychotics -- olanzapine
* Muscle relaxants -- carisoprodol
425
Anticholinergic risk scale examples
* 3 points:
* Chlorpheniramine
* Diphenhydramine
* 2 points:
* Loratidine
* 1 point:
* Carbidopa-levodopa
426
Anticholinergic risk scale
* ranks medications for anticholinergic potential on a 3-point scale
* 0 -- no or low risk
* 3 -- high anticholinergic potential
* ARS score for a patient is the sum of points for his or her # of medications.
427
Ganglionic blocking agents
* Block nicotinic receptors at ganglia
* Only useful for **research** b/c block all autonomic outflow – potential toxicity
428
Neuromuscular blocking agents
* Inhibit neurotransmission at skeletal neuromuscular junction (nicotinic antagonists)
* Cause mm weakness and paralysis
429
Majority of available nicotinic blocking agents use this mechanism
nondepolarizing
* presynaptically by preventing NT release (Botulinum)
* postsynaptically by blocking receptor (tubocurarine)
430
Nondepolarizing Neuromuscular Blocking Agents
* Competitive Ach antagonists
* Highly polar and only given IV or IM
* Prototypical drug: d-tubocurarine
* Used for **muscle relaxation** during surgical procedures
431
d-tubocurarine
* prototypical nondepolarizing Neuromuscular Blocking Agent
* First isolated from arrow poisons
* **Not used** b/c more adverse effects than newer agents
432
nondepolarizing Neuromuscular Blocking Agent mechanism of mm relaxation
Competitive Ach anatagonist:
* first paralyzes small, rapidly moving muscles
* then paralyzes larger limb mm
* finally paralyzes mm necessary for breathing
433
Only Depolarizing Neuromuscular Blocking Agent
Succinylcholine
434
Succinylcholine
* Only depolarizing Neuromuscular Blocking Agent
* Binds to nicotinic receptor, causes persistent depolarization → sustained mm paralysis
* 5-10min duration
* Commonly used in ER setting
* **No pharmacologic antidote exists**
* Can cause clinically significant **hyperkalemia**
435
what are the catecholamines?
* Epinephrine
* Norepinephrine
* Dopamine
436
what do the catecholamines do?
Endogenous adrenergic receptor agonists
437
how are catecholamines metabolized and taken up?
* Rapidly metabolized by:
* Monoamine oxidase (MAO)
* Catechol-O-methyltransferase (COMT)
* Taken up into presynaptic nerves by
* NET transporter
* DAT transporter
438
how are catecholamines administered as drugs?
Parenterally
* Inactive by oral route
439
rate-limiting step of catecholamine synthesis
tyrosine → DOPA
by tyrosine hydroxylase
440
steps in catecholamine synthesis
441
α2 receptor located where in synapse?
pre-synaptic
442
α1 receptors location and action
* smooth muscle
* contraction/vasoconstriction
443
α2 receptors location and action
* mostly SNS postganglionic neurons
* feedback inhibition of NT release (inhibitory autoreceptor)
* Clonidine
444
β1 receptors location and action
* Cardiac tissue
* Increase HR, contraction force, conduction speed
* (1 heart)
445
what receptor does clonidine act on? stopping suddenly can cause what?
* α2
* stopping → hypertensive crisis
446
β2 receptors location and action
* lungs
* bronchodilation
* be careful giving β2 blockers to asthmatic!
* also smooth mm relaxation
* (2 lungs)
447
β3 receptors location and action
* fat cells
* activation of lipolysis
448
autonomic drug that can be used to help organophosphate poisoning
atropine -- blocks Ach receptors, which helps b/c organophosphates are Ach-esterase inhibitors (→ increased Ach)
449
D1 receptors location and action
* smooth muscle
* dilation of **renal** blood vessels
450
D2 receptors location and action
* nerve endings
* Modulation of NT release in CNS
451
Adrenergic Receptor Agonist Classification
* Direct-acting
* Indirect-acting
* Mixed-acting
452
Adrenergic Receptor Antagonist Classification
* Nonselective α-blockers
* α1-blockers
* Nonselective β-blockers
* β1-blockers
* α- and β-antagonists
453
sympathomimetic drugs
Adrenergic Receptor Agonists
454
Direct-acting adrenergic receptor **ag**onists action
* Bind to and activate adrenergic receptors
* May be selective or non-selective for α and β receptors
* Catecholamines & Non-catecholamines
455
duration of action of catecholamines as Direct-acting Adrenergic Receptor agonists
short -- metabolized rapidly by endogenous enzymes MAO and COMT
456
characteristics of Non-Catecholamines as Direct-acting Adrenergic Receptor agonists
* not metabolized by MAO and COMT
* can be given orally
* longer duration of action
457
Indirect-acting Adrenergic Receptor agonist action & mechanism
Increase NE concentration at synapse by several different mechanisms
458
Mixed-acting adrenergic receptor agonist action
Combination of direc and indirect action
* bind to receptors
* increase NE conc at synapse
459
Epinephrine as Adrenergic Drug
* Direct-Acting **Nonselective** (α + β) Adrenergic Agonist
* Endogenous catecholamine given IV or SC
* **Low** doses: **β** effects predominate
* **High** doses: **α1** effects predominate
* Uses: anaphylactic shock, cardiac arrest, topical vasoconstriction
* Adverse effects: tremor, palpitations, headache, arrhythmias
460
Norepinephrine as adrenergic drug
* Direct-Acting **Nonselective** Adrenergic Agonist
* Endogenous catecholamine given IV
* Receptor affinity: α1 = α2 ; **β1 \>\> β2**
* Greater peripheral vascular resistance (PVR) than EPI
* Uses: hyp**o**tension
* Adverse effects: similar to EPI
461
Isoproterenol
* Direct-Acting **β**-Adrenergic Agonist
* Synthetic catecholamine given IV
* Uses: potent vasodilator & inotropic agent
* Adverse effects: tachycardia, arrhythmias
462
what do the effects of catecholamine drugs on the CV system look like?
463
Dobutamine
* β1-agonist
* Synthetic catecholamine given IV
* Uses: acute heart failure – potent inotropic agent
* Adverse effects: HTN, tachycardia
464
diphenhydramine, a 1st-gen sedating antihistamine, can exacerbate what condition?
Alzheimer's / Dementia -- b/c has anticholinergic properties and Ach is decreased in these conditions
465
examples of β2-agonists
* Albuterol
* Levalbuterol (Xopenex)
* Salmeterol (Serevent)
* Terbutaline
466
Albuterol
* β2-agonist
* Inhaled: bronchodilation for asthma and COPD
467
Levalbuterol (Xopenex)
* β2-agonist
* Inhaled: bronchodilation for asthma and COPD
468
Salmeterol (Serevent)
* β2-agonist
* Inhaled: bronchodilation for asthma and COPD
469
Terbutaline
* β2-agonist
* PO – bronchodilation for asthma (but more systemic effects)
* IV – relaxation of uterus in late pregnancy to delay premature labor
470
Examples of Selective α1-adrenergic agonists
* Phenylephrine
* Oxymetazoline (Afrin)
471
Phenylephrine
* α1-agonist
* Vasoconstriction w/increased vascular resistance and BP
* IV – for hypotension and shock
* PO – popular OTC decongestant
472
Oxymetazoline (Afrin)
* α1-agonist
* Nasal decongestant
* Causes acute rebound congestion (tachyphylaxis) if used for more than several days
473
Examples of Selective α2-adrenergic agonists
* Clonidine
* α -methyldopa
474
Clonidine
* α2-agonist
* Centrally-acting anti-HTN agent
* Also used for attenuating substance withdrawal symptoms
* Given orally or as transdermal patch
475
α-methyldopa
* α2-agonist
* Centrally acting anti-HTN
* Useful during pregnancy
476
Examples of Indirect Acting Adrenergic Agonists
* Amphetamine and methamphetamine
* Ephedrin
* Methylphenidate (Ritalin)
* Cocaine
* Tyramine
477
Amphetamine and methamphetamine
* Indirect Adrenergic Agonists
* Stimulate NE & dopamine release
* Very lipid soluble and easily enter CNS
* Stimulant effects on mood/alertness, heart
* Appetite depressant
* Peripheral vasoconstriction
478
Methylphenidate (Ritalin)
* Indirect-Acting Adrenergic Agonist
* Amphetamine derivative with similar action
479
Cocaine
* Indirect-Acting Adrenergic Agonist
* Inhibits NE, dopamine, 5-HT reuptake -- blocks NET and DAT transporters (like antidepressants)
* Peripheral vasocontriction
* Cardiac stimulant
* Effects like amphetamine but shorter acting and more intense
* Also has local anesthetic effects (used in ocular surgery)
480
what does the mechanism of action of amphetamines look like?
481
what does the mechanism of action of cocaine look like?
482
Tyramine
* Indirect-Acting Adrenergic Agonist
* Increases NE release
* Naturally occurring amine found in **fermented products** (cheese, sausage, beer); red wine, bananas, avocados, canned meats, yeast supplements
* Levels can increase if foods taken w/MAO inhibitors (used for depression)
* Can cause hypertensive crisis w/**MAO inhibitors**
483
Examples of Mixed Acting Adrenergic Agonists
* Dopamine
* Ephedrine
* Pseudoephedrine (Sudafed)
484
Dopamine as adrenergic drug
* Mixed-Acting Adrenergic Agonist
* Endogenous catecholamine given IV
* Dose-related activation of D, β1 , α1 receptors; NE release
* Low doses: D receptor → **increases renal blood flow**
* Medium dose: D + β1 receptors activated
* High doses: D + β1 + α1 receptors activated
* Uses: cardiogenic shock, acute renal failure
* Adverse effects: similar to NE at high doses
485
Ephedrine
* Mixed-Acting Adrenergic Agonist
* Natural product found in ma-huang
* α + β receptor agonist, plus enhances NE release
* High doses: similar effects to EPI
* In 2006, sale of ephedrine-containing dietary supplements was prohibited in the US
486
sale of dietary supplements containing what drug is prohibited in the U.S.? what does it do?
ephedrine -- mixed α + β receptor agonist that also enhances NE release
487
Pseudoephedrine (Sudafed)
* Mixed-Acting Adrenergic Agonist
* Popular OTC decongestant
* also 1o ingredient for illegal meth manufacture
* Most non-restricted OTC brands now contain phenylephrine (PE)
* Avoid in pts w/HTN or cardiomyopathy
488
Types of Adrenergic Receptor **Ant**agonists
* Nonselective α-blockers
* Selective α1-blockers
* Nonselective β-blockers
* Selective β1-blockers
* α- + β-adrenergic antagonists
489
Examples of Nonselective α-Blockers
* Phenoxybenzamine
* Phentolamine
490
Phenoxybenzamine
* Nonselective α-Blocker (α1 \> α2)
* Non-competitive antagonist
* Irreversible receptor blockade – lasts 4 days
* Use: catecholamine excess (ex: pheochromocytoma)
* Adverse effects: postural hypotension, reflex tachycardia
491
Phentolamine
* Nonselective α-Blocker
* Competitive antagonist
* Uses:
* Pheochromocytoma
* Reversal of ischemia from extravasation or injection of adrenergic agonists (EPI)
* Adverse effects: same as phenoxybenzamine
492
Examples of Selective α1-Blockers
* Prazosin (prototype drug)
* Terazosin (Hytrin)
* Doxazosin (Cardura)
* Tamsulosin (Flomax)
493
Prazosin; Terazosin (Hytrin); Doxazosin (Cardura)
* α1-Blockers
* Relax smooth mm in vessels, bladder neck, prostate
* Uses:
* BPH
* 3rd line for HTN (b/c increased morbidity compared to others)
* Adverse effects:
* 1st dose syncope -- must use small doses and have pt lie down
* Reflex tachycardia
494
Tamsulosin (Flomax)
* α1-Blocker -- specifically prostate α1A receptor
* Causes less vasodilation than other α1-blockers
* Use: decreasing urinary obstruction from BPH
* Little effect on BP at normal doses
495
Examples of Nonselective β-Blockers
* Propranolol
* Nadolol (Corgard)
* Timolol
* Pindolol
496
Propanolol
* prototype nonselective β-Blocker
* Highest lipid solubility – more CNS penetration
* High 1st pass effect: oral dose \>\> IV dose
* Negative inotropic and chronotropic effect
* Bronchoconstriction and decreased glycogenolysis
* Uses: HTN, arrhythmias, angina, migraine headache, essential tremor
* Adverse effects/cautions: bradycardia, insomnia, heart failure, asthma, diabetes
497
Nadolol (Corgard)
* Nonselective β-Blocker
* Low lipophilicity - fewer CNS adverse effects than propranolol
* Renal excretion
* Long T ½
498
Timolol
* Nonselective β-Blocker
* Used primarily as topical agent for glaucoma
499
Pindolol
* Nonselective β-Blocker
* Also partial β-agonist
* Intrinsic sympathomimetic activity – causes less bradycardia
500
Examples of Selective β1-Blockers
* Metoprolol
* Atenolol
* Bisoprolol (Zebeta)
* Esmolol (IV only)
* Acebutolol
501
Metoprolol
* Prototype β1-Blocker
* aka cardioselective β-blocker
* Selectivity lost w/higher doses!
* Use: HTN (higher doses), heart failure (lower doses), angina
* Safer for asthma & diabetes than nonselective β-blockers but still must use caution
* T ½ = 3 to 8 hrs dep. on CYP 2D6 phenotype
502
Atenolol
* β1-Blocker
* Low lipophilicity - fewer CNS adverse effects than propranolol
* Renal excretion
* Long T ½
503
Bisoprolol (Zebeta)
* β1-Blocker
* Moderate lipophilicity
504
Esmolol
* β1-Blocker
* IV only
505
Acebutolol
* β1-Blocker
* also partial β1-agonist
* Intrinsic sympathomimetic activity
506
Examples of α- and β-Adrenergic Blockers
* Labetalol
* Carvedilol (Coreg)
507
Labetalol
* α- and β-Blocker
* Receptor affinity: β1 = β2 ; **α1** \> α2
* More pronounced vasodilation than other β-blockers due to α1 blockade
* Given IV, PO
* Same cautions as nonselective β-blockers
* Useful for rapid BP reduction
508
Carvedilol (Coreg)
* α- and β-Blocker
* Receptor affinity: β1 = β2 ; α1 \> α2
* More pronounced vasodilation than other β-blockers due to α1 blockade
* Given IV, PO
* Same cautions as nonselective β-blockers
* Useful for heart failure
509
Criteria to consider in Choosing β-Blockers
* Receptor selectivity
* Note selectivity tends to be lost at higher doses
* Lipid solubility
* If too high, can have CNS adverse effects
* Half-life
* Determines doses per day
* Elimination route (renal vs liver)
510
This route of administration has the fastest absorption
inhalation
511
narrow therapeutic index means
small margin between sub-therapeutic, therapeutic, and toxic drug concentrations
512
Increasing the dose of a particular drug decreases its clearance. What kind of elimination does this drug undergo?
Zero-order
513
Increasing the dose of a particular drug increases its clearance. What kind of elimination does this drug undergo?
First-order
514
M1 receptor locations
CNS and autonomic ganglia
515
M2 receptor locations
cardiac muscle
516
M3 receptor locations
smooth muscle and glandular tissue
517
M4 and M5 receptor locations
CNS
518
Tensilon Test
Edrophonium used for Dx Myasthenia Gravis
519
what drug can increase renal blood flow at low doses and what receptor does it work on?
Dopamine stimulating D1 receptor
520
which adrenergic agonist could cause reflex bradycardia?
NE
521
which adrenergic agonist causes a widening of pulse pressure?
EPI -- increase in systolic + decrease in diastolic
522
drug safe for Rx HTN in pregnancy
* Methyldopa
* Labetolol
523
potential side effects of alpha-1 blockers
* 1st dose syncope
* reflex tachycardia (b/c Rx HTN also)
524
drugs w/variable T1/2 based on CYP 2D6 phenotype
* metoprolol
525
beta-blocker w/highest lipid solubility
propanolol
526
contraindications for beta-blockers
* asthma
* diabetes
527
beta-blocker safer to give to pt w/asthma or diabetes
selective beta-1 blockers
528
two mechanisms for treating glaucoma
* increase aqueous humor outflow
* decrease aqueous humor production
529
types of drugs that increase aqueous humor outflow
* muscarinic agonists
* prostaglandin analogs
530
types of drugs that decrease aqueous humor production
* alpha-2 agonists
* beta-blockers
531
describe graph of cardiovascular effects of catecholamines
532
Antidote for neuromuscular blockers
effects of d-tubocurarine, for example, can be treated with cholinesterase inhibitors like neostigmine and pyridostigmine
533
Atropine Man
* **Can't see** (mydriasis, decreased lacrimation, ciliary mm relaxation)
* **Can't pee** (detrusor relaxation, int sphincter contraction)
* **Can't spit** (decreased salivation)
* **Can't sh\*t** (decreased GI motility)
* Toxicity: Hot (decreased sweating) and Delirious
