Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

M2 > Pharm 1 > Flashcards

Pharm 1 Flashcards

0
Q

Pharmacodynamics

A

study of how target cell responds to delivered concentration of drug.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
1
Q

what are the pharmacokinetic factors?

A 
Absorption
Distribution
Metabolism
Excretion
-factors affect concentration of drug at active site as function of time.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Lipid soluble drugs:
what do they regulate?
How long to take effect?
How long do effects last?

A

Modify gene expression
Lag period of 30 min - hours before effect
Effect lasts hours to days

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

mechanism of cytokine receptor action and receptor examples

A

JAK / STAT kinase activity
non-intrinsic
Growth Hormone, Erythropoietin, Interferon

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Transmembrane receptor activity and examples.

A

Intrinsic kinase activity (Tyrosine kinase, serine, guanylyl cyclase)
EGF, PDGF, ANP, TGFb

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Kd = ?

A

Kd = [D][R]/[DR] = k(off)/k(on)

Kd is dissociation constant

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is physiological antagonism?

A

Agonist and antagonist work at independent sites, but have opposite effects.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is chemical antagonism?

A

combination of agonist with antagonist -> inactivation of the agonist.
heparin + protamine, dimercaprol + mercuric ion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is volume of distribution (Vd)

A

Relates blood concentration to total drug in body.
Vd= amount administered / concentration at t=0

Vd is the apparent volume of plasma that would have yielded the extrapolated concentration at t=0

Low Vd: drug trapped in blood
High Vd: drug distributes readily

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What does Vd say about a drug whose target is w/in CNS?

A

Drugs w/ high lipid solubility (Vd>40) needed to cross BBB.

These drugs are eliminated via hepatic metabolism rather than renal excretion.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

probenecid

A

competitive inhibitor of tubular secretion of penecillins - prolongs effect

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Define drug metabolism

A

The process of converting lipophilic chemicals to hydrophobic chemicals that are readily excreted in the urine or bile.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is the most common cause of acute liver failure in US?

A

Acetaminophen OD

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Briefly describe Acetaminophen metabolism

A

2 main pathways -> nontoxic glucuronide (glucuronidation) and sulfate (sulfation)
When saturated, P450 enzymes -> toxic NAPQI
NAPQI can be detoxified by glutathione conjugation.
If saturated, Rxn w/ cell macromolecules -> liver cell death

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is MPTP?

A

Related to Demerol. Metabolized by MAO-B then auto-oxidized to MPP+ which interferes w/ mitochondrial respiration in DA producing cells -> Parkinson’s like symptoms in users.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is responsible for grapefruit juice’s drug interactions?

A

grapefruit juice contains furanocoumarins that inhibit CYP3A4 in the intestine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What is terfenidine?

A

Marketed as Seldane in 1985 - prodrug metabolized to fexofenadine (allegra) by CYP3A4
Inhibition of CYP3A4 -> terfenadine accumulation -> cardiotoxicity (torsades de pointes)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What pathophysiological conditions can impact drug metabolism?

A 
Liver disease
Cardiac disease (reduced CO, reduced metabolism of "flow limited drugs)
Metabolic abnormalities (obesity, infection, inflammation) -> alteration in expression of drug metabolizing enzymes.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What is Phase I drug metabolism?

A

Oxidation, Reduction, Hydrolysis

*expose or introduce a functional group

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What is Phase II metabolism?

A

Conjugation of a functional group on an endogenous molecule

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What is Phase III metabolism?

A

term not often used.

refers to transporters that “pump” xenobiotics or conjugates out of cells.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What enzymes are most responsible for metabolism of oral medications?

A

CYP2D6 and CYP3A4

over 50% of orally effective meds.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What organs contain the most xenobiotic metabolizing enzymes and transporters?

A

Liver and small intestine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What is a first pass effect?

A

metabolism in sm. intestine or liver limiting bioavailability of drug. Seen w/ orally administered meds.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Name 3 xenobiotic sensing receptors, their ligands and describe the concept.

A

Aryl hydrocarbon (Ah) receptor: aromatic and polychlorinated hydrocarbons
Pregnane X receptor (PXR): hyperforin (st. johns wort), rifampicin and others
Constitutive androstane receptor (CAR): phenobarbital and others
All receptors induce expression of metabolizing enzymes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What kind of reaction does the Cytochrome P450 family of enzymes assist with?

A

Oxidation
usually monooxidation with reducing equivalents from NADPH
R (Substrate) + O2 + NADH -> ROH + H20 + NADP+

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

Where are CYP enzymes located?

A

Mostly liver ER.

to some extent in most tissues, some in mitochondria (steroidogenic)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

How many CYPs do humans express?

A

57
18 families, 43 subfamilies
12 perform most drug metabolism
3 metabolize most : CYP3A4/5 and CYP2D6 and CYP2C8/9

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Describe Cytochrome P450 nomenclature

A 
CYP = P450 superfamily
followed by number, letter, number
1st number:  family: >40% similarity
letter: >50% similarity
2nd number:  gene #
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

List reactions carried out by P450 enzymes

A

Hydroxylation: aliphatic carbon (CYP2C9)
Hydroxylation: aromatic carbon (CYP2C19) same fam/subfam
Epoxidation
Heteroatom oxidation (S- oxidation, N-oxidation)
Heteroatom dealkylation (CYP2D6)
1. hydroxylation of methoxy carbon 2. rearrangement -> loss of carbon as formaldehyde (HCHO)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What are the 3 most prevalent CYP enzymes?

A

CYP3A4/5
CYP2D6
CYP2C8/9

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

How are azo and nitro reductions usually carried out?

A

Via intestinal flora

Occasionally P450 or others.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

Protonosil : why important and how metabolized

A

Discovery led to first sulfa drug (sulfanilamide) and effective antimicrobial therapies
Azo reduction of protonosil -> sulfanilamide

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

What are two important enzymes that participate in hydrolysis of xenobiotics?

A 
Carboxylesterases (CE1, CE2)
Epoxide hydrolases (microsomal mEH, soluble sEH)
	-detoxify electrophilic epoxides that could otherwise interact with proteins and nucleic acids
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

why are mEH and sEH often expressed in same cells as P450?

A

detoxify esters produced by oxidative metabolism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

What are flavin monooxygenases? How are they similar to P450?

A

catalyze oxidation of N, S, and P heteroatoms
Similar to CYP: require NADPH and O2, but do not need additional protein
5 mammalian flavin monooxygenases.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

What reaction do epoxide hydrolases carry out?

A

trans addition of water to alkyl epoxides and arene oxides

-> trans 1,2 dihydrodiols

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

In general, are conjugated metabolites more or less polar than original substrate?

A

Usually more polar

Usually pharmacologically inactive and easily excreted, but not always.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

What are 6 major conjugation reactions?

A 
Glucuronidation
Sulfation
Glutathione conjugation
Acetylation
Methylation
Amino Acid conjugation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

Describe glucouronidation

A

Transfer of glucuronic acid from co-factor UDP-glucuronic acid to nucleophilic heteroatom on substrate.
Enzyme: UGT

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

Where are UGTs located?

A

Microsomal (ER)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

What enzyme metabolizes morphine?

A

UGT2B7

morphine -> morphine 6-glucuronide (active metabolite)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

What is a sulfonation reaction? What enzyme?

A

Transfer of sulfonate group from co-factor 3-phosphoadenosine-5’-phosphosulfate (PAPS) to available substrate group
substrates: aliphatic alchol, phenol, amine, N-oxides, N-hydroxyls, NOT CARBOXYLIC ACIDS!!
Enzyme: cytosolic sulfotransferases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

Describe acetylation reaction and enzyme involved

A

Transfer of acetyl group from acetyl co-A to amino group on amine substrate
Enzyme: N-acetyltransferases (NAT-1 and NAT-2 in cytosol)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

Describe methylation reaction and enzyme involved.

A

Transfer of methyl group from cofactor to substrate
Cofactor: S-adenosylmethionine (SAM)
Substrates: phenol, catechol, aliphatic and aromatic amines, sulfhydryl compunds, some metals
Enzyme: methyl transferases : COMT, POMT, PNMT, HNMT, NNMT, etc.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

What are first order and zero order processes?

A

rate = constant * [drug]^n (n=kinetic order)
First order: are directly dependent on drug concentration : elimination - constant fraction or percent lost per unit time

Zero order: not dependent on concentration - constant rate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

Is normal drug metabolism zero or first order?

A

First order

Plasma concentrations of most drugs are below Km, so rate is dependent on concentration.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

What order kinetics is alcohol metabolism?

A

Zero order
consumed in large quantity (g vs mg) so metabolizing system is easily saturated.
First order when when blood levels <10mg/dl.
10mg/dl -100mg dl is transitional bet. zero and first.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

What is the relationship between ke and t(1/2)?

A

Inverse
ke=0.7/t(1/2)

ke=elimination rate constant =~amount of drug lost / unit time

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

How do you calculate the rate of drug output?

A

rate of output = X(ke)
X = amount of drug in body, ke= elimination rate constant.

BUT - X changes. X = C(Vd) C=serum conc.
So: **rate of output = C * Vd * ke

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

What is the steady state equation?

A 
Input = output
f(D/T) = Css * Vd * ke = Css * Vd * (0.7/t(1/2))

f(D/T)=Css * Clearance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

How long does it take for a drug concentration to reach steady-state?

A

4t(1/2)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

What is a loading dose, how is it calculated and how is it administered?

A

Dose needed to immediately reach steady state
Loading Dose = Css * Vd
Usually given in two doses separated by time to avoid idiosyncratic adverse responses.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

What is a maintenance dose and how is it calculated?

A

Dose needed at regular intervals to maintain steady state.

Maintenance Dose = Clearance * Css

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
54
Q

How is drug clearance calculated?

A 
Clearance = Vd * ke = Vd * (0.7/t(1/2))
Clearance = (metabolism + excretion)/[drug]plasma

Clearance is additive across systems. Total body clearance = CL(liver) + CL(kidney) + CL(other)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
55
Q

What classes of drugs are most often involved in predictable adverse events?

A

Cardiovascular agents, Analgesics, hypoglycemics

accounted for 86.5% of adverse effects in quoted study.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
56
Q

What is an example of an direct chemical interaction?

A

Ca++ in dairy along with Tetracycline inhibiting tetracycline absorption
Tetracycline is a Ca++ chelator and is not absorbed w/ bound Ca++

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
57
Q

cimetidine inhibiting CYP3A4 leading to toxic accumulation of CNS drugs is what kind of drug-drug interaction?

A

parmacokinetic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
58
Q

A patient taking OTC decongestant that causes vasoconstriction while taking a antihypertensive vasodilator is what kind of drug-drug interaction?

A

negative pharmacodynamic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
59
Q

What is meant by additivity in terms of drug-drug interactions?

A

2 drugs given together have additive effects
A -> increases HR by 10 bpm
B -> increases HR by 9 bpm
A+B -> increases HR by 19bpm

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
60
Q

What is meant by potentiation in terms of drug-drug interactions?

A

use of two drugs together has an enhanced effect. AKA supra-additivity
A -> increased HR by 10bpm
B -> increased HR by 9bpm
A + B -> increased HR by 25 bpm

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
61
Q

What is a subadditive effect in terms of drug-drug interactions?

A

2 drugs given together have a less than additive effect
A -> increased HR by 10bpm
B -> increased HR by 9 bpm
A + B -> increased HR by 13 bpm

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
62
Q

What is synergism in terms of drug-drug interaction?

A

drugs work together to common effect. Often used interchangeably with additive and supra-additive

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
63
Q

What is a quantal response?

A

All or nothing response.

Relief of headache. Partial relief would be non-response.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
64
Q

What is a therapeutic index?

A

TI = LD50 / ED50

Estimates separation of dose between effective and toxicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
65
Q

What is the certainty of safety factor?

A

TD1 / ED99

Larger ratio = less toxicity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
66
Q

What is a polymorphism?

A

Variation in DNA sequence present in at least 1% of population
-some polymorphisms can impact drug metabolism and -> adverse effects and death.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
67
Q

6-mercaptopurine: what and what is a relevant genetic variation?

A

6-MP: used to treat childhood acute lymphoblastic leukemia

1: 300 kids has mutation in thiopurine methyltransferase -> inability to metabolize 6-MP -> drug accumulation -> potential fatality
* * patients always tested before being given 6-MP**

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
68
Q

What are two ways to test for CYP2C19 poor metabolizers?

A

Genotype: test DNA for presence of specific polymorphisms
Phenotype: administer probe that is degraded by CYP2C19 (s-mephenytoin) and measure for metabolites

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
69
Q

What are two methods of determining the fraction of phenotypic variability in drug metabolism attributable to genetics?

A

Twin studies: monozygotic vs. dizygotic

Multigenerational kindred studies: interfamily vs. intrafamily

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
70
Q

What have twin studies revealed about drug metabolism?

A

Drug metabolism is highly heritable.

more drug metabolism similarities between monozygotic twins than dizygotic twins.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
71
Q

Poor metabolism by CYP2D6 is what kind of trait?

A

Autosomal recessive.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
72
Q

Poor metabolism by CYP2C19 is what kind of trait?

A

codominant

herozygotes exhibit intermediate phenotype.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
73
Q

What are 3 major types of polymorphisms?

A

SNP (single nucleotide polymorphism) - ~1 every few hundred - 1,000 bps. ~10 million in genome.

InDel (insertion/deletion) - less common than SNP

CNV (copy number variation) - caused by genetic rearrangement - duplication, deletion, inversion. occurs in ~10% of human genome
-CYP2D6 ultra-rapid metabolism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
74
Q

3 types of SNPs

A
  • nonsynonymous (missense) - change -> different AA
  • synonymous (sense) - change -> same AA
    • may contribute to phenotypic trait: slower translation -> altered folding -> altered membrane insertion (C3435T SNP in ABCB1 transporter: P-glycoprotein efflux pump for many drugs)
  • nonsense - change -> stop codon
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
75
Q

What effects can SNPs in non-coding regions of DNA produce?

A
  • alteration of elements that determine mRNA translatability
  • promoter/ enhancer regions - may change transcription
  • near exon/intron boundary - may change splicing or introduce a premature stop codon
  • intergenic regions - may change DNA tertiary structure interaction with chromatin, topoisomerase, or DNA replication
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
76
Q

What is gene linkage?

A

The extent to which two genotypes found at two loci are indepent of each other:

  1. linkage equilibrium: independence
  2. linkage disequilibrium: not independent, varying degrees - in complete disequilibrium, two genotypes always occur together - SNP at one point -> SNP in second Locus
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
77
Q

What factors influence the clinical importance of gene polymorphisms?

A
  • frequency and penetrance of allele
  • narrowness of TI / sharpness of dose response curve - will small change -> toxicity or ineffectiveness of drug?
  • limited availability of alternate clearance pathways
  • availability of alternative drugs.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
78
Q

Polymorphisms in UGT1A1 cause what?

A

hyperbilirubinemia
UGT1A1 involved in metabolizing bilirubin. >50 polymorphisms -> inheritable hyperbilirubinemia
Crigler-Najjar Syndrome types I and II
Gilbert’s Syndrome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
79
Q

Acetylation polymorphism

A

Alteration in rate of acetylation of drugs (n-acetyltransferases)
NAT-1 and NAT-2 (2 is primarily polymorphic - metabolism of procainamide, caffeine, 4-aminobiphenyl (bladder carcinogen))
ethnic variation: 90% of others.
Coded @ 4 alleles @ 1 locus on chrom 8. 3 slow, 1 fast. Fast dominant. Must have 2 slow to display slow acetylation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
80
Q

Effects of acetylation polymorphism

A

Slow: 1. prone to polyneuropathy during isoniazid treatment
2. likelihood of hemolytic anemia w/ sulfa drugs
3. elevated incidence of bladder cancer w/ arylamine carcinogens
Fast: need higher doses for effect.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
81
Q

Outline ETOH metabolism

A

ETOH -(ADH)-> acetaldehyde -(ALDH)-> acetic acid -> acetyl CoA

acetaldehyde is toxic - accumulation -> flushing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
82
Q

Alcohol Dehydrogenase polymorphism

A

ADH: 7 enzymes, 5 classes
faster action -> rapid accumulation of acetaldehyde -> increased flushing
ADH21 - B1B2 - 95% caucasians Vmax = 9
ADH22 - B2B2 - most Chinese, Japanese, Korean Vmax = 400
ADH2*3 - B3B3 - 15% Africans Vmax = 300

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
83
Q

Length of time before a poison’s effects are seen is determined by:

A

Dose
Age
Personal habits
Genetics

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
84
Q

What is meant by acute, subacute, and chronic exposure?

A

Acute : single or multiple exposures over 24 hrs
Subacute : multiple exposures 24 hrs - 3 mos
Chronic: multiple exposures over 3 mos

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
85
Q

What are the differences between non-cumulative and cumulative poisons?

A

Non-cumulative: total dose doesn’t matter w/ small individual doses. Easily excreted, cleared by body. No permanent irreversible damage at low dose.

Cumulative: Total dose important. Accumulates or causes irreversible damage.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
86
Q

In the case of OD or poisoning is drug elimination 1st or zero order?

A

Zero order - some process is saturated.

** increase in dose -> disproportionate increase in blood level**

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
87
Q

Aspirin metabolism

A

Acetylsalicylic acid -> salicylate by plasma esterases (t1/2 = 15min
Salicylate -> conjugated to glycine -> salicyluric acid
** this step saturates @ ~1g aspirin. Saturated w/ 3 tabs.
Very high dose : zero order
Lower dose: mixed
Low dose: first order

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
88
Q

How do heavy metals exert toxicity?

A

Combine w/ key amino acid residues on proteins

  • active sites
  • key residues of structural proteins

Heavy metals are not metabolized - may persist for long periods.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
89
Q

Symptoms of acute inorganic Pb poisoning

A

Acute GI distress
Progression to CNS abnormalities
Often looks like pancreatitis, ulcer, appendicitis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
90
Q

What is the basis for lead’s toxicity?

A

It is a bivalent cation and interferes with Ca++ dependent processes.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
91
Q

Symptoms of chronic inorganic Pb poisoning

A

Weakness, nervousness, tremor, GI distress, anorexia, weight loss, headache
Recurrent abdominal pain, extensor muscle weakness w/o sensory deficit (wrist drop is characteristic)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
92
Q

What is the usual cause of organic lead poisoning? What are the symptoms?

A

tetraethyl or tetramethyl Pb in gasoline - highly volatile - easily inhaled, lipid soluble - easily absorbed
Acute CNS disorders, few hematologic abnormalities
rapid progression - hallucinations, insomnia, headache, irritability

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
93
Q

How is Pb poisoning tested for?

A 
Standard screening:  FEP - free erythrocyte protoporphyrin test
Also:
Pb in blood
24hr urine test for Pb
Abnormalities of porphyrin production:  
delta-ALA and Coproporphyrin III.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
94
Q

What is the t1/2 of Pb in blood and bone?

A

Blood: 1-2 mos. Steady state in 6 mos.
Bone: 20 yrs.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
95
Q

How does Pb distribute in the body?

A

First to soft tissues - kidney and liver, then to teeth, hair and bones
Pb in blood is assoc. w/ RBCs
Eventually 95% will deposit in bone
Excreted in urine and feces

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
96
Q

What are some biochemical effects of Pb?

A

Inhibition of SH containing enzymes in heme biosynthesis
Inhibition of ferrochelatase (heme production)
produces hypochromic microcytic anemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
97
Q

Pb poisoning treatment

A

Remove source
Treat seizures w/ diazepam
Treat cerebral edema with mannitol and dexamethosone
Maintain fluid and electrolyte balance
Chelation therapy: Dimercaprol w/ Edetate Calcium Disodium (CaNa2 EDTA) then D-Penecillamine for long-term

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
98
Q

3 forms of mercury

A 
Elemental (Hg)
Inorganic salts (HgCl2)
Organic mercuruials (methyl mercuric chloride)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
99
Q

After absorption where are the highest concentrations of Hg found?

A

Renal proximal tubules

w/in a few hours of absorption

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
100
Q

What is the basis of Hg’s toxicity?

A

Binds SH groups (cysteinyl residues of structural proteins and enzymes, SH of glutathione)
Precipitates protein on contact -> corrosive

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
101
Q

How is Hg excreted?

A

Usually through urine - most over 1 week period.

kidneys and brain retain for longer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
102
Q

Symptoms of acute Hg intoxication

A

Acute: Chest pain, SOB, metallic taste, nausea, vomiting, acute kidney damage 2nd, severe gingivitis and gastroenteritis on 3rd-4th days. Most severe cases - muscle tremor and psychopathology

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
103
Q

Symptoms of chronic Hg intoxication

A

GI complaints, renal insufficiency, gingivitis, loose teeth, discolored gums, enlarged salivary glands, tremors in fingers, arms and legs, ocular changes (deposition of Hg in lens)
Personality changes - fearfulness, inability to concentrate, irritability,

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
104
Q

Treatment for Hg poisoning

A

remove source
chelation: dimercaprol (3-5mg/kg IM every 4hr for 48 hr, then every 12 hrs for 10 days)
dialysis w/ renal damage
Chronic poisoning: oral penicillamine (200-500mg 4x/day for 10 days), also DMSA

105
Q

What is the major source of arsenic poisoning?

A

Industry
Coal plants, ore facilities
Contaminates water supply.

106
Q

What are the important forms of arsenic (As)?

A

inorganic
organic
elemental
arsine gas (AsH3)

107
Q

Current medical uses of As

A

Treat certain tropical diseases

2nd line treatment for leukemias (Arsenic trioxide and all-trans retinoic acid)

108
Q

Non-medical uses of As

A

herbicides, insecticides, fungicides, algicide, wood perservative

109
Q

What is the basis of As toxicity?

A

As3+ reacts w/ SH groups - inhibits enzymes
PDH system: lipoic acid forms 6 member ring

As5+ uncouples mitochondrial oxphos: competes with POi in formation of ATP

110
Q

Treatment for As poisoning

A

remove source, stabilize patient

chelate with dimercaprol and follow with penicillamine

111
Q

Main sources of cadmium poisoning

A

Pollution: <5% of Cd is recycled
Cigarettes: 2ug / cig (1 pack/day = 1mg/ year)

112
Q

t1/2 for Cadmium in the body

A

10-30 years

** prone to accumulation**

113
Q

Treatment for Cd poisoning?

A

????
no effective treatment, but dimercaprol is CONTRAindicated - mobilizes Cd -> kidneys -> more damage

Edetate Calcium Disodium - maybe, questionable utility

114
Q

What is required of a chelation agent for pharmacological use?

A

2 or more electronegative groups that can form stable coordinate covalent bonds with a cationic metal atom (less-toxic than metal)
water solubility, resistance to metabolism, ability to distribute to metal location, excretable, greater affinity for ligand than endogenous metals.

115
Q

Dimercaprol

how administered, what for, contraindicators, adverse effects

A

colorless, oily, offensive odor. Usually dispensed as 10% mixed w/ peanut oil.
IM injection - readily absorbed, metabolized, and excreted w/in 4hrs.
Contraindicated in presence of severe liver or kidney disease.
Adverse effects: HTN, tachycardia, headache, nausea, vomiting

116
Q

Conjeners of dimercaprol

A

DMSA
DMPS
more water soluble, fewer side effects

117
Q

Edate Calcium Disodium (CaNa2 EDTA)

Uses, contraindicators, toxicity

A

Chelates di and trivalent metals
Pb, An, Cr, Cu, Ni, Cd
NOT Hg
Chelates essential Ca++ - limits usefullnes, but calcium disodium salt helps
Kidney toxicity w/ prolonged use - contraindicated w/ renal disease.

118
Q

Penicillamine

A

Degradation product of penicillin (D-form preferred to more toxic L-form)
Chelates: copper, lead, iron, mercury
Used in Wilson’s disease (hepatic degen. due to Cu poisoning)
Chronic use: acute allergic rxn, leukopenia, eosinophilia, nephrotoxicity

119
Q

Carbon Monoxide toxicity

A

Binds Hb - 200x greater affinity than O2

Inhibits cytochrome oxidase - disrupting ETC

120
Q

CO poisoning symptoms and treatment

A

Headache, nausea, vomiting, weakness, loss of muscular control, LOC, death

Treatment: pure O2, hyberbaric O2

121
Q

What % blood saturation of CO is fatal?

A

70-80%

60-70% - coma, depressed cardiac and pulmonary function and possible death

122
Q

Sources of Cyanide poisoning

A

Industry: metal cleaners, fumigants, synthetic rubber synth and chemical synth
Fires in which N-containing plastics burn
Home: silver polish, insect and rodenticides, fruit seeds

123
Q

Fatal dose of HCN

A

50-200 mg

124
Q

Mechanism of cyanide poisoning

A

CN- binds oxidized Fe in cytochrome oxidase

inhibits cellular respiration

125
Q

Treatment for cyanide poisoning

A

Speed is essential
introduce large pool of Fe3+ to compete for CN
administer amyl nitrite or sodium nitrite - produces metHb (contains Fe3+) - binds CN-
administer O2

126
Q

Symptoms of methanol poisoning

A

Initially similar to ETOH
GI cramps, vomiting
blurred vision, dilated pupils, no reaction to light
acidosis
Cardiac depression (MeOH and formic acid - cardiotoxic)

127
Q

Toxicity of MeOH

A

End products of metabolism: Formic Acid and Formaldehyde
Formaldehyde -> blindness - damage to retinal cells
Forimic Acid -> cardiotoxicity and acidosis - control of acidosis is key to survival

128
Q

Treatment of MeOH poisoning

A

Protect eyes from light
NaHCO3 - correct acidosis
Admin EtOH: outcompetes MeOH for ADH

129
Q

Ethylene Glycol toxicity

A

Metabolized by ADH -> oxalate -> oxalate crystaluria
Oxalate -> kidney damage
Formic Acid -> acidosis

130
Q

Treatment for Ethylene Glycol poisoning

A

Gastric lavage - remove poison
ETOH
NaHCO3
hemodialysis may be needed

131
Q

Fatal dose of Acetaminophen

A

25g or more (300mg/kg)

132
Q

Symptoms of Acetaminophen poisoning

A

24-48 hrs: pallor, nausea, vomiting - no other abnormal physical signs
2-4 days: hepatic and renal damage

133
Q

t1/2 of Acetaminophen

A

1-3 hrs

134
Q

Treatment for Acetaminophen poisoning

A

Administer SH containing compounds - alternate target for hydroxylated APAP metabolite and GSH source
oral N-acetylcysteine (mucomist) - ASAP sulfur amino acid source

135
Q

What vitamins are most commonly associated with toxicity?

A

A and D

assoc. with long term use and megadoses.

136
Q

What do dendrites lack in terms of AP conduction

A

voltage gated Na channels

137
Q

What is the main excitatory NT in the brain? What are its receptors?

A

Glutamate
Acts via binding 2 classes of ligand-gated ion channels (Na/Ca)
NMDA
AMPA

138
Q

What are the inhibitory NTs of the brain/CNS?

A

GABA and glycine

hyperpolarization via movement of Cl- down its gradient.

139
Q

What effect will colchicine have on axonal transport

A

Inhibitory - interferes w/ microtubule assembly

140
Q

Ionotropic vs. Metabotropic receptor

A

Ionotropic: NT binding opens channel, changes membrane permeability to ions

Metabotropic: NT binding activates intracellular signaling cascade, often G prot. mediated, results in opening of a channel

141
Q

What class of NT are the primary excitatory and inhibitory NTs of the CNS?

A

Amino Acids
glutamate and aspartate - excitatory
glycine and GABA - inhibitory

142
Q

What class of NT are the primary modulators of the CNS?

A

Biogenic amines

NE, Epi, Dopamine, Serotonin, Histamine

143
Q

Cholera and Pertussis toxins target what class of molecule?

A

G-protein

144
Q

Effect of NE on B adrenergic receptors

A

Increased adenosine cyclase activity via Gs

145
Q

Effect of NE on alpha 1 receptors

A

Increased activity of PLC via Gq

146
Q

Effect of NE on alpha 2 adrenergic receptors

A

decreased adenylate cyclase activity via Gi

147
Q

Effect of ACh on types 1,3,5 muscarinic receptors

A

Increased PLC activity via Gq

148
Q

Effect of ACh on types 2 and 4 muscarinic receptors

A

Decreased activity of Adenylyl cyclase via Gi

149
Q

What is the usual course for single source divergent neurons?

A

Originate in a nucleus in the brainstem, terminate on thousands of neurons - usually in cerebral cortex

150
Q

Describe autonomic innervation of the eye

A

Sympathetic: alpha1: contract radial and circular muscles (mydriasis)
Beta: relaxation of of ciliary muscle
Parasympathetic: M3: contract ciliary muscle (myosis)

151
Q

Describe autonomic innervation of the heart

A

Sympathetic
Sinoatrial node: B1,B2: accelerate conduction, increase contractility
Parasympathetic
Sinoatrial node: M2: decelerate, decrase contractility

152
Q

Autonomic innervation of autonomic smooth muscle

A

Sympathetic: B2 - relaxation
Parasympathetic: M3 - contracts

153
Q

B1 receptors in the kidney have what effect

A

Renin release

154
Q

Where does somatic central control originate?

A

Motor cortex via corticospinal tracts

155
Q

Where does central control of the autonomic nervous system originate?

A

Hypothalamus, limbic system and brain stem

156
Q

Output of the cranial nerves and sacral spinal cord make up what portion of the autonomic nervous system?

A

Parasympathetic

157
Q

Output of thoracic and lumbar portions of the spinal cord comprise what portion of autonomic nervous system?

A

Sympathetic

158
Q

What is the enteric nervous system?

A

In walls of GI system. modulated by SS (inhibitory) and PS (excitatory) inputs.
Contains many non-adrenergic, non-cholinergic (NANC) fibers - NT are peptides and other substances

159
Q

Thermal sweat glands and arterioles of skeletal muscle have what unique innervation?

A

Cholinergic sympathetic

preganglionic origin is within SS (T1-L2), but ACh is NT.

160
Q

What class molecule is choline?

A

quaternary amine

161
Q

What determines the rate of ACh synthesis?

A

Choline Transfer Pump

Availability of extracellular choline is rate limiting.

162
Q

What effect does Mg++ have on NT release?

A

Antagonizes - interferes w/ membrane permeability to Ca++

163
Q

What are the prototypical agonists / antagonists of muscarinic and nicotinic receptors

A

Muscarinic: agonist - muscarine, antagonist - atropine

Nicotinic: agonist - nicotine, antagonist d-tubocurarine

164
Q

What are the subdivisions of Muscarinic receptors?

A

M1 - neuronal
M2 - heart
M3 - secratory

165
Q

Basic structure of a muscarinic receptor

A

Single peptide chain that transverses membrane 7x
N-terminus: extracellular
C-terminus: intracellular

166
Q

Effect of ACh on the heart (M2 receptors)

A

activation of Gi -> increased K+ conductance -> hyperpolarization -> decreased rate of contraction
Gi-> decrease in AC activity

167
Q

What class of receptor are presynaptic ACh receptors usually?

A

M2.
inhibitory.
blocked by atropine -> increased ACh release

168
Q

What class of drugs blocks the presynaptic sodium dependent choline transporter?

A

Hemicholinium (no therapeutic use)

169
Q

What does the vessicle associated transporter (VAT) do and what inhibits it?

A

Pumps ACh from cytosol into vessicle (H+ exchange)

Blocked by vesamicol (no therapeutic use)

170
Q

How does black widow spider venom work?

A

Promotes sustained release of ACh from presynaptic terminal.

May have systemic effects: sweating, abdominal cramping, bradycardia.

171
Q

Describe depolarizing blockade at NMJ and applicable drugs

A

excessive stimulation of nicotinic receptors at NMJ -> depolarization at motor end plate and muscle paralysis

Succinylcholine - therapeutic use
Nicotine, organophosphates - toxic effect

172
Q

How are tertiary and quaternary amines preferentially administered?

A

Tertiary generally administered orally

Quaternary generally directly to appropriate site (topical, aerosol) - requires very large oral dose for effect.

173
Q

What is atropine?

A

Muscarinic antagonist - on of most prescribed drugs
alkaloid - absorbed well orally, topically, parenterally
widely distributed to all body compartments
metabolized in liver, some urinary excretion
CNS effects - hallucinations, delirium only at toxic levels. Death may follow.

174
Q

How does the action of scopolamine differ from atropine?

A

Primarily in CNS.
Scopolamine: 100x greater depressing effect as atropine
may induce hallucinations and delerium at therapeutic levels.
Hypnotic and amnesia action - used preop or in childbirth
Has been used for sleep / sedation (OTC - low dose, not very effective)
Very effective anti motion sickeness (patch) - blocks in brainstem - between semicircular canals and emetic center.

175
Q

What is benztropine?

A

AChR antagonist - used for Parkinson’s and to treat Parkinson’s like symptoms produced by anti-psychotics.

176
Q

What are the primary targets of muscarinic agonists and antagonists in the eye?

A

Agonist: Sphincter Pupillae
Antagonist: Ciliary Muscle

Action at other site is primary source of side effects

177
Q

What is pilocarpine?

A

Direct Muscarinic agonist, tertiary amine
used in opthamology - miotic action
-pressure reduction in anterior chamber - drainage via canal of Schlemm - Glaucoma treatment (2nd line compared to B-adrenoreceptor antagonist)

178
Q

What is carbachol?

A

Muscarinic agonist (some nicotinic activity), quaternary amine
Not degraded by Acetylcholinesterase
Used in eye surgery - lens replacement

179
Q

What is tropicamide?

A

Muscarinic antagonist
Used for myadriatic effect (dilated pupil) - eye exam for corrective lenses -> focus fixed at a distance (flattened lens)

180
Q

What is muscarinic action on the heart?

A

Directed at SA, AV and atria (not ventricles) via M2 receptors
Negative chronotropic
Negative inotropic
Negative dromotropic (AV conduction)

181
Q

What is the action of muscarinic agonists on the vascular system

A

Vasodilation via M3 receptors on endothelium -> release of EDRF (NO)
Most prominent effect w/ IV admin of ACh.
NO -> vasodilation -> decreased peripheral resistance -> baroreceptor increases sympathetic tone to heart -> tachycardia

182
Q

What is the effect of direct ACh injection to coronary artery during diagnostic angiography?

A 
Normally vasodilation (via M3, EDRF)
Patient w/ vasospastic angina pectoris -> vasospasm of coronary artery
183
Q

What is commonly administered after MI for treatment of bradycardia?

A

Atropine

blocks all vagal input -> increased HR

184
Q

What is the effect of muscarinic agonists on GI tract?

A

Increased tone and motility of all visceral smooth muscle from lower esophagus to rectum. Most sphincters relax (activation of enteric nervous system, other NTs) except lower esophagus contracts
Mostly M3 receptors
*can cause epigastric distress, cramping, vomiting, involuntary defacation,

185
Q

What is Bethanecol?

A

synthetic quaternary amine - acts mostly on GI and urinary bladder when admin orally or subQ.
Resistant to hydrolysis by AChesterase and pseudo.
Used to treat stasis of GI and bladder after gen an. or postpartum

186
Q

What is propantheline?

A

Muscarinic antagonist - quaternary amine
used to treat gastric hypermotility and for detrussor stimulation
has some ganglionic blocking activity (all quaternary amines)

187
Q

What drugs are most selective for detrussor stimulation?

A

Muscarinic agonists Bethanecol and Neostigmine (indirect)

-also have prominent GI effects

188
Q

What cholinergic drugs are used to affect the uterus?

A

Uterus is mostly unresponsive to stimulation / inhibition of its M3 receptors

189
Q

What is methacholine and what is it mostly used for?

A

Quaternary amine, muscarinic agonist, slow metabolism by AChE, not metabolized by pseudo.
No longer used to treat atrial tachycardia
Used to diagnose bronchial airway hyperreactivity - use in setting w/ support for acute respiratory distress.

190
Q

Ipratropium and tiotropium

A

Both quaternary amines, admin as aerosol to treat COPD
tiotropium (Spiriva) - newer w/ less M2 antagonizing activity -> decreased inhibition of feedback regulation. has longer t1/2

Neither reduce mucociliary clearance (other mAChR antagonists might

191
Q

Nicotine

A

Tertiary amine, lipid soluble - naturally occurring alkaloid. crosses placenta, secreted in milk
Toxicity: intense ganglionic PS activation, CNS excitation w/ convulsions followed by depression, eventual skeletal muscle paralysis.

192
Q

Varenicline

A

Partial nAChR agonist
Minimal metabolism - urinary excretion
minimizes pleasurable effects and cravings for tobacco
negative neuropsychiatric effects - suicide.

193
Q

What is the half-life of d-tubocurarine, and how is it metabolized?

A

3.8 hours in plasma

partially metabolized - 40% excreted unchanged in urine

194
Q

What is the most significant side-effect of d-tubocurarine?

A

Rapid transient fall in blood pressure

  • ganglionic blockade decreases sympathetic tone to heart
  • histamine release via direct action on mast cells.

may precipiate asthmatic reaction in bronchial tree.

195
Q

Cisatracurium

A

synthetic agent related to atracurium (no longer used)
competitive antagonist of nAChR
mild hypotensive action via histamine (compare to tubo)
spontaneous breakdown (blood pH) 20 min. half-life - safe for use in cases of hepatic and renal failure
Laudanosine - product of breakdown, crosses BBB -> seizures (very rarely)

196
Q

Pancuronium

A

steroid based competitive nAChR antagonist
long duration of action - renally eliminated
Also M2 blockade -> tachycardia
used in lethal injection
prolonged use in ICU -> prolonged muscle weakness

197
Q

Vecuronium

A

steroid based. one tertiary, one quaternary amine
Good selectivity for nAChR at nmj - no cardiac effect, no histamine
30 mins of action
85% elim unchanged in bile, 15% elim renally

198
Q

Rocuronium

A

Steroid based - fastest onset of non-depolarizing nAChR blocking agents
can be used in series with succinylcholine for intubation - prevents fasiculations seen w/ sux.
excreted in bile, little cardiac effect, rare allergic rxns.

199
Q

Competitive neuromuscular blocking agents are potentiated by what?

A

General anesthetics: halothane, methoxyflurane, enflurane
aminoglycoside antibiotics: streptomycin, neomycin, gentamicin, kenamycin
electrolyte imbalance (high Mg++)
Polypeptice antibiotics: polymyxins, colistin, linomycin
Advanced age

200
Q

Succinylcholine

A

Nicotinic agonist at NMJ - depolarizing blockade
Extremely fast - less than one minute and 5 minute duration
Not metabolized by AChE, but by pseudo
Liberates histamine, but also ganglionic stimulation - masks
significant K+ released into blood can lead to cardiac arrest
Children: only in emergencies (immediate intubation)

201
Q

What are Phases I and II of nAChR depolarizing blockade?

A

Phase I: gradual depolarization of motor end plate avoids firing of AP -> skeletal muscle paralysis No antagonist available - OD treated w/ supportive breathing
Fasiculations often seen - avoided with pre-treatment of rocuronium (higher dose of Sux then needed)
Phase II: w/ continuous dosing 20 mins or more - repolarization, but maintenance of paralysis - mechanism unclear. partially Reversible w/ neostigmine or edrophonium

202
Q

What class of molecule are all of the nAChR skeletal muscle relaxants?

A

Quaternary amines - must be administered parenterally

203
Q

What are two ganglionic blockade drugs, what do they do, what are they used for, and problems?

A

Hexamethonium and Mecamylamine (secondary amine)
Early anti-hypertensive meds. Sometimes used in surgery.
Block PS and SS via nAChR at ganglionic synapse.
Orthostatic Hypotension
also effects of autonomic blockade.

204
Q

Physostigmine

A

Reversible cholinesterase inhibitor. (Poor AChE substrate)
Tertiary amine methyl carbamate. metabolized by ester hydrolysis in plasma.
Works at nicotinic and muscarinic receptors.
used for glaucoma - miotic
systemic to reverse OD of atropine or tricyclic ADs - can cause seizures

205
Q

Neostigmine

A

Reversible AChE inhibitor (poor substrate). Has some nAChR agonist activity.
Quaternary amine
1. Augmentation of GI motility
2. Reversal of skeletal muscle blockade by competitive agonists
3. Treatment of myasthenia gravis (do not use w/ GI obstruction)

206
Q

Edrophonium

A

Competitive AChE inhibitor. Potent nAChR agonist - specific to motor end plate. Very short acting (5 mins)
Quaternary amine.
Diagnostic agent in Myasthenia Gravis

207
Q

Pyridostigmine

A

Long acting inhibitor of AChE (poor substrate)
Used for chronic treatment of myasthenia gravis
similar to neostigmine, but longer acting

208
Q

What is cholinergic crisis?

A

Accumulation of ACh due to OD of AChE inhibitor coupled with direct action of neostigmine / pyridostigmine at nAChR
-> Depolarizing Blockade and muscle weakness.

** must discern between cholinergic and myasthenic crisis by edrophonium dose**

209
Q

Tacrine

A

Competitive AChE inhibitor
Alzheimers med - high dosage needed and many side effects, not often used
hepatotoxic

210
Q

Donepezil

A

Competitive AChE inhibitor
Alzheimer’s med - limited effectiveness, longer lasting than Tacrine
CYP2D6 / 3A4 - no hepatotoxicity, but potential for drug interactions

211
Q

Rivastigmine

A

Poor substrate for AChE - carbamate
used for Alzheimers
not bind plasma protein - low risk for drug interaction

212
Q

How do irreversible AChE inhibitors work?

A

Phosphorylation of serine OH at active site
Isopropyl radical - no hydrolysis can occur - new enzyme must be made
Methyl or Ethyl substitutions - very slow hydrolysis - half lives of several hours

213
Q

Echothiophate

A

Irreversible AChE inhibitor
atypical organophosphate - polar and stable in water
Used to produce sustained miosis (3+ days)
chronic use -> lens clouding

214
Q

Symptoms of anti-AChE toxicity

A

Increased GI motility - pain, nausea, vomiting, involuntary defacation
Hypotension and bradycardia, lower peripheral resistance (M3 EDRF/NO)
Depression of CNS vasomotor center
Bronchial constriction and increased secretion
CNS- first stim w/ convulsions, then depression and coma w/ severe respiratory depression
NMJ - fasiculations then depolarizing blockade including respiratory paralysis

215
Q

Treatment of organophosphate poisoning

A

Heroic doses of atropine
Pralidoxime (2-PAM): releases sarin from AChE as oxime-phosphate complex, regenerating AChE
hydrolysis of sarin-AChE by water -> ‘aged’ enzyme - inactive
Benzodiazepine - for seizures

216
Q

NE is moved down an axon by fast transport. What drugs block?

A

Colchicine
Vinca-alkaloids - vinblastine and vincristine

inhibit polymerization of microtubules and microfilaments.

217
Q

How is NE stored in vessicles?

A

4 molecules NE electrostatically bound to 1 ATP for unknown reasons

218
Q

What is VMAT? Classes?

A

Vessicular Monoamine Transporter - voltage and pH dependent
Requires Mg++ and ATP as cofactors
Moves NE and DA into vessicles
VMAT1: in periphery (mostly endocrine cells)
VMAT2: CNS

219
Q

3 pathways that synaptic NE can follow

A
  1. diffusion: blood/ lymph -> liver (COMT and MAO catabolism)
  2. extraneuronal uptake (uptake2 - inhibit w/ estrogen or corticosteroid): catabolized by COMT -> normetanepherine -> diffuse to blood -> liver
  3. Reuptake by NET (uptake1): 70% of NE taken up by neuron that released it by NE Transporter. blocked by cocaine and tricyclic antidepressants.
220
Q

Distribution of NE and EPI degrading enzymes.

A

COMT: effector cells and liver (cytosol)
MAO: nerve terminals (mito OM). plentiful in brain, liver and intestinal mucosa

Primary pathway for NE released from cells: COMT first, then MAO in liver

221
Q

How does dopamine elicit cardiovascular response?

A
  1. Induces release of NE from adrenergic neurons
  2. Interaction w/ alpha and beta receptors
  3. Interaction w/ specific DA receptors.

High DA: increase HR, contractility and CO via NE on Breceptors

222
Q

What happens w/ B1 activation in cells of SA node?

A

More rapid depolarization -> increased HR
K+ leak is accelerated -> shorter duration of AP, increase in HR

*** may be overridden by Vagus stim if amine increases BP

223
Q

What effect do catecholamines have on Cardiac Efficiency?

A

Decrease:

CE = work / O2
Catecholamines: work increases, O2 demand greatly increases, efficiency decreased.

224
Q

What is the predominant adrenergic receptor of the kidney?

A

alpha1
EPI, NE -> vasoconstriction
ISO -> vasodilation (via B1)

225
Q

What adrenergic receptors are found in skeletal muscle vascular beds and what effect do different catecholamines have?

A

a1 and B2
NE: only vasoconstriction (a1)
EPI: early vasodilation (B2) then constriction (a1) w/ higher concentration and saturation of B2
ISO: only dilation (B2)

226
Q

Effect of catecholamines on coronary vasculature

A

Vasodilation

  • B2 activation (EPI and NE)
  • decreased CE -> increased ATP breakdown -> increased adenosine -> vasodilation
227
Q

Effect of catecholamines on pulmonary vasculature

A

Mosty alpha receptors - some Beta.

Vasoconstriction, but comparatively weak.

228
Q

Effect of catecholamines on Pancreas

A

Alpha cells - B2 receptors -> secrete glucagon

Beta cells - alpha receptors -> INHIBITION of insulin secretion

229
Q

What adrenergic receptors are in the GI tract and what do they do?

A

a1 and B2 - both relax smooth muscle

a1: hyperpolarizatoin -> inability to reach threshold for AP

230
Q

What adrenergic receptors in uterus?

A

a1 and B2
NE and EPI cause contractions (a1)
Specific B agonists -> relax (ritodrine, terbutalin)

231
Q

What are phenylethylamines and how do they work?

A

indirectly acting adrenergics: Tyramine, Amphetamine, Ephederine
Induce release of NE from sympathetic neurons
Ca++ incependent, non-exocytotic - physical chemical displacement
Other contents of synaptic vessicles not released.

232
Q

Tyramine

A

phenylethylamine
taken up by NET, causes release of NE from vessicles
Natural product found in wine, cheese (decarboxylation of Tyr)
Normally oxidized by MAO
If on MAO inhibitor effects are potentiated - may be dangerous

233
Q

Amphetamine and Ephederine

A

phenylethylamines - can cross BBB
Cause release of NE and DA in CNS
Substrate for MAO, but not metabolized - slow oxidation of NE and DA
ephederine - minor direct effect on adrenergic receptors

234
Q

Alpha methyl tyrosine

A

Tyrosine Hydroxylase inhibitor - antihypertensive
Inhibits formation of DOPA
No longer used in USA
pheochromocytoma - high doses -> crystals in renal tubules -> renal damage.

235
Q

Reserpine

A

Antihypertensive
Blocks VMAT, inhibits transport of NE into vesicles
MAO metabolizes -> NE deficiency
in CNS inhibits transport of DA -> NE deficiency and DA depletion
Can cause emotional distress (suicide) and tremors
PS unopposed and corresponding side-effects
Not used much, but cheap. low dose (.05-.1mg/day) + diuretic sometimes.

236
Q

Guanethidine

A

Antihypertensive
taken up by NET and blocks NE exocytosis (Ca++ independent)
lowers BP, HR, and renin secretion - severe postural hypotension
1. enters SNS neurons and blocks exocytosis
2. blocks NET
3. chronically reduces NE stores
not used in US any more

237
Q

Clonidine

A

Antihypertensive
a2 agonist (highly selective)
via a2 and imidazoline receptor (rostral ventrolateral medulla) activation -> reduce SNS outflow, lower BP
Withdrawal -> SNS overactivity -> life threatening hypertensive crisis

238
Q

Methyldopa

A

Antihypertensive
metabolized to alpha-methyl-NE and stored in synaptic vessicles.
Has high affinity for a2 receptors (not imidazoline) @ NTS -> reduces SNS outflow, reduces BP, reduces renal vascular resistance.

239
Q

Tricyclic Antidepressants - what and how do they work?

A

Imipramine, Desipramine (most potent), Amitryptyline (least potent)
Block NET -> enhance activity of NE
Amitryptyline also blocks 5HT transporter (serotonin)
no longer first line of antidepressants since SSRI
side effects: block other NTs, tremor, insomnia, blurred vision, ortho hypotension

240
Q

Cocaine

A

Completely blocks NET- no uptake of NE or EPI
Blocks uptake of DA - enhanced response to all
CNS stimulation
Local anesthetic (30 - 100x concentration)

241
Q

Is isoproterenol used for asthma?

A

No - non-specific B agonist -> risk of cardiac stimulation

242
Q

Dobutamine

A

Racemic mixture of L and D isomers
L: alpha agonist and weak B1 agonist
D: a1 antagonist and B1 agonist
Selective B1 agonist - used for CHF to improve CO

243
Q

What cells produce erythropoietin?

A

Proximal tubular cells of kidney epithelium

Small amount in the liver

244
Q

What is the most prevalent side effect of erethropoietin therapy?

A

Associated with increase in red cell mass
HTN and thrombotic phenomena
Hematocrit should be raised slowly to avoid these effects

245
Q

How does cobalt effect erythropoietin production?

A

Cobalt lowers O2 use by tissues, increases production of EPO

246
Q

What treatments are available for sickle cell anemia?

A

hydroxyurea - ill defined pathway -> increased HbF which interferes with polymerization of HbS
Also, analgesic, antibiotic, blood transfusion, pneumococcal vaccine

247
Q

What form of iron is given orally?

A

Ferrous Sulfate

248
Q

What drug is used to treat pheochromocytoma as well as clonidine withdrawal or tyramine / MAOi interaction?

A

Phentolamine

non-selective competitive alpha blocker - imidazoline class

249
Q

prazosin

A

a1 antagonist - quinazoline class
1000x affinity for a1 compared to a2
used for CHF - reduce preload and afterload
antihypertensive

250
Q

propranolol

A

non-selective B-blocker, no agonist activity
Little intrinsic effect on heart or CV system
profound blockade with sympathetic activation
B1: decrease HR and CO, slow cardiac conduction, inhibit renin release
B2: increase peripheral resistance

251
Q

list specific B1 blockers

A 
Acebutolol
Atenolol
Betaxolol
Esmolol
Metoprolol
252
Q

Bystolic

A

Selective B1 antagonist
no membrane stabilizing
Reduces HR, force of contraction, vasodilates, reduces TPR

253
Q

Labetelol

A

a + B blocker (B:a is 3:1 PO, 7:1 IV)
partial agonist, membrane stabilizing
little presynaptic a2 activity
**Lowers TPR w/o major change in HR or CO
HTN, HTN + angina, pre-op for pheochromocytoma

254
Q

In the case of a poisoned patient with AMS, what should be given?

A

Oxygen
Naloxone (unless known to be opioid dependent
Thiamine
Glucose or Dextrose bolus - prevent Wernikes

255
Q

What is flumazenil?

A

Competitive benzodiazepine antagonist - binds GABA receptor

  • given to benzo OD, not recommended for unkown OD
  • may precipitate withdrawal syndrome
  • may unmask seizure disorder.
256
Q

What is Anion Gap? Normal value?

A

AG = [Na+] -([HCO3-] + [Cl-])
12 +/- 4 is normal

Anion gap elevated by things that induce acidosis (MUDPILES)
decreased by Li and Br

257
Q

Calculate osmolality and osmolal gap

A

Osm = 2 Na + (glucose / 18) + (BUN / 2.8) N= 285
Osm gap = measured - calculated
should be <10
Elevated by: MeOH, EtOH, isopropanol, ethylene glycol, acetone, osmotic diuresis

258
Q

What is the gold standard for toxin ID in a lab?

A

gas chromatography - mass spectrometry

259
Q

What toxic substances appear radioopaque?

A

CHIPES

chloral hydrate, heavy metals, iodine, phenothiazenes / TCAs, enteric coated, solvents (chlorinated)

260
Q

How does absorption change w/ aging?

A

Most drugs: little to no change

Decreased: B12, Ca, Fe, Thiamine

261
Q

Calculate creatinine clearance

A

CrCl = ((140-age) * wt / ([Cr]*72)) * 0.85 (for women only)

Units: mL/min/1.73m^2

M2 (19 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions