Exam 1 Flashcards
(164 cards)
1
Q
Inadivir
A
HIV drug, St. Johns wart INCREASES metabolism via induction of CYP3A4
2
Q
What are the three Xenobiotic receptors?
A
Aryl hydrocarbon (AhR), The pregnane X receptor (PXR), The constitutionally active receptor (CAR)
3
Q
Most phase 1 rxns are performed by what?
A
CYP450 system
4
Q
What CYP isoform is responsible for 30% of enzymes in the liver?
A
CYP450, CYP3A4 metabolizes approximately 50%
5
Q
How many families of CYP450 proteins are there?
A
In humans there are 18 families
6
Q
Of the 18 families of CYP450 proteins which are responsible for xenobiotics?
A
Families 1-3, others are mainly endogenous
7
Q
Which three drugs are enzyme inducers for CYP450 enzymes?
A
Phenobarbital, Rifampin, Carbamazepine all INCREASE the synthesis of P450 isoforms
8
Q
What induces the Xenobiotic receptor AhR? 2
A
PAH’s and TCDD
9
Q
What induces the Xenobiotic receptor PXR? 5
A
Steroids, Hyperforlin, rifampin, phenobarbital and mifepristone
10
Q
What induces the Xenobiotic receptor CAR? 2
A
Phenobarbital, phenytoin
11
Q
Warfarin question for exam, what drug was give from 5 that would decrease plasma concentration via enzyme induction
A
look up
12
Q
Indinavir
A
HIV drug, increased metabolism by induced CYP3A4 with St. Johns wort
13
Q
Amiodarone
A
Anti arythmic, Inhibit CYP450
14
Q
Cimetidine
A
HRT burn, Inhibit CYP450
15
Q
Ketoconazole
A
Antifungal, Inhibit CYP450
16
Q
Erythromycin
A
Antibacterial, inhibit CYP450
17
Q
Cloremphenicol
A
Antibacterial, inhibit CYP450
18
Q
Grapefruit juice has what effect on drug metabolism?
A
Inhibits CYP450 AND P-glycoprotein in the small intestine. Statin is an example, drinking grapefruit juice while taking statins can cause increased plasma levels of statins. Same effect with Felodipine (anti-hypertensive).
19
Q
some drugs are actively transported back into the intestinal lumen by the P-glycoprotein, what two drugs are examples of this?
A
Digoxin-Hrt Failure
HIV-1 protease inhibitors
20
Q
What is P-glycoprotein?
A
A drug transporter that can transport Digoxin and HIV-1 protease inhibitors to the intestinal lumen
21
Q
What can inhibit the P-glycoprotein?
A
Macrolide antibiotics, resulting in increased serum levels of Digoxin
22
Q
What is an example of a macrolide antibiotic?
A
Clarithromycin, results in inhibition of P-glycoprotiens and subsequent increased levels of Digoxin
23
Q
What is the N-acetyltransferase 2?
A
NAT2 catalyzes the acytlation of isoniazid and other drugs, polymorphisms are present and pts treated with isoniazid can be either FAST (low blood levels) acetylators or slow (high blood levels) which are homogenous for AR allele of the enzyme.
24
Q
What are Slow acetylators (NAT2 polymorphism) prone to?
A
Toxicity of drugs that are inactivated by acetylation
25
Felodipine
Anti hypertensive, Grapefruit juice decreases metabolism=high serum levels
26
Aromatic hydrocarbons in cigarette smoke, Cruciferous vegetables and chared foods and pesticides all have what effect of drug metabolism?
Induce enzyme metabolism.
27
Plasma concentration of a drug is determined by what three things?
Rate of" Input, distribution and elimination
28
What are the three most important Pharmacokinetic parameters?
Volume of Distribution, Clearance, Bio-availability
29
How do you define Volume of distribution?
amount of drug in body/Plasma concentration
conceptual volume of drug that would be needed to contain all of the drug in the body at the same concentration as in the blood.
30
What is the main purpose of Vd?
To determine the loading dose needed to quickly reach your target plasma concentration.
We know the dose we want to achieve by the therapeutic window
31
What is Clearance?
Rate of elimination of drug(amount/time)/Plasma drug concentration (amount/volume)
Total body clearance is the SUM of all clearance in the body
clearance is a constant for drugs that follow first order kinetics, and is directly proportional to the drug concentration.
32
What is rate of elimination?
CL x Conc. First order elimination
33
What is the equation for t1/2?
t1/2=(0.693xVd)/CL
34
How many half life's to achieve steady state and eliminate the drug?
4 half lifes to reach steady state and another 4 to eliminate the drug.
35
What effect does doubling the infusion rate have?
It doubles the steady state concentration but DOES NOT change the half life, or the fact that we need 4 half lifes to reach steady state concentration Css
36
What three drugs exhibit zero order Kinetics?
Aspirin in high doses, Ethanol and Phenytoin, Only Phenytoin has clinical significance
37
What is needed for a rational dosage regimen?
Min therapeutic and min toxic conc. of a drug, Clearance, Vd of the drug
38
What is the therapeutic window?
The useful window between the min therapeutic conc. and the min Toxic conc. of the drug.
The peak must be below the toxic level and the trough above the therapeutic level
39
What is dosing rate at steady state?
At steady state, dosing rate is equal to rate of elimination which is equal to (CLxC)/F
40
How is maintenance dose calculated?
Maintenance dose= Dosing rate x Dosing interval
41
What is the equation for drug accumulation? (accumulation factor AF)
AF=1/Fraction lost in one dosing interval
| AF predicts the ration of the Steady state to the peak concentration after the first dose.
42
When a drug is administered every half life what will the Css be?
The first peak times 2 and the trough at Css will equal the peak initially given. This means the AF is 2xthe first peak
43
What is the equation for loading dose with intermittent dosing?
LD= Maintenance dose x Accumulation factor
44
What is the time course effect?
The drug effect Vs Time
45
Enalopril
ACE inhibitor, popular for Hrt failure and hypertension
46
What are the examples of inhibitors of CYP450?
Cimetidine, Ciprofloxin, Ketoconazole, Clarithromycin, quinidine, Grapefruit juice
47
What are some exaples of INDUCERS of CYP450?
Rifampin (biggest), Phenobarbital, dexamethasone, carbamazepine, and Tobacco
48
What drug should not be given with sidenifil (viagra)?
Sidenifil should never be given with Nitroglycerin, since Sidenifil inhibits PDE5 preventing the breakdown of cAMP and Nitroglycerin increase Guanylate cyclase activity resulting in increased production of cAMP, when taken together the effect is remarkable.
49
What is the No effect dose?
Maximum dose at which specified toxic dose is not seen
50
What is a schedule 1 drug?
No accepted use, never can be used in clinical study.
51
What is schedule 2?
high potential for abuse but can be used and prescribed, no over the phone refills
52
What is schedule 3?
still potential for abuse but used and prescription must be re-written after 6 months or 5 refills
53
Schedule 4?
still potential for abuse but used and prescription must be re-written after 6 months or 5 refills. Difference from 3 is punishment if fund in illegal possession.
54
Schedule 5?
Same as any non-opioid drug, may be dispensed without prescription, unless state laws differ.
55
What are the three leading causes for Otitis Media?
H. influenzae, S. pneumonea, Moraxella cataralis
56
What are the most common cause of sinusitis and the types of presentations?
H. influenzae, S. pneumonea and
Acute 12 wks
recurrent acute 4 or more acute epis. in a yr
57
What is a clinical diagnosis of acute sinusitis?
* purulent nasal discharge ,
* nasal congestion + or facial pain or pressure
* bacterial infection suspected after 7 days if symptoms of purulent discharge, maxillary pain persist or symptoms worsen after initial improvement.
58
Pneumonia by exposure, Birds, Farm animals, ground water?
* Exposure to psittacine birds-Psittacosis (Chlamydophila psittaci)
* Exposure to parturient animals or birth products-Q fever (Coxiella burnetii)
* Exposure to water vapor and soil -Legionnaire’s (Legionella pneumophila)
59
Common bacterial causes of pneumonia
–Streptococcus pneumoniae (most common)
–Haemophilus influenzae (Non typable, COPD)
–Staphylococcus aureus including CA
-MRSA
–Chlamydophila pneumoniae (elderly)
–M. pneumoniae (crowding, child, yng adults)
–Legionella pneumophila (contaminated water soil disruption)
–Klebsiella pneumoniae (alcoholics)
–Pseudomonas aeruginosa
(immunosuppressed, chronic structural lung
damage → cystic fibrosis, bronchiectasis)
60
What are the laboratory findings of Legionares?
L. pneumophila 80% of human disease
–Aerobic gram negative rod
–Won’t grow in lab on routine media. Use buffered charcoal yeast extract.
–3 to 5 days to grow
•Attaches to respiratory alveoli and macrophage cells by pili
and is phagocytosed to enter cell.
•Intracellular pathogen than inhibits phagosome–lysosome fusion and evades destruction
61
What are the clues to diagnosing Lenionella?
```
•Clues to diagnosis
–High fever > 39oC
–Confusion
–Diarrhea
–Sputum findings on gram stain (3+ WBC no organisms)
–Hyponatremia, hematuria
–Failure to respond to Beta lactams
```
62
What are the charecteristics of Chlamydia and chlymidophila? Chlamydophila is the respitory one
–Obligate intracellular bacteria
–No peptidoglycan in cell wall
–2 distinct forms in growth cycle
•Elementary body= infectious particle and survives in extracellular environment. Entry into the cell is by phagocytosis
•Reticulate body is form in which multiplication occurs and lives in a membrane bound inclusion.
63
What is the most common org. for CAP?
Pseudomonas Aeriginosus.
| –Non fermentive Gram negative aerobe, grows easily in lab. Green pigment and grape like odor. Oxidase positive.
64
Which are the Cholinergic fibers? What does that mean?
The cholinergic fibers are fibers that release AcH. They include:
All preganglionic fibers
All Parasympathetic post ganglionic fibers
All Somatic motor fibers to skeletal muscle
65
What are the adrenergic fibers?
They synthesize and release NE, they are most post ganglionic sympathetic fibers
66
What are the exceptions to the rule that most post ganglionic sypathetic fibers are adrenergic?
The sympathetic fibers supplying the sweat glands release AcH Not NE (basically a sympathetic cholinergic fiber whihc is very rare)
The Adrenal medulla releases NE and Epi
Dopamine is released by some sympathetic fibers
67
The typical PSNS fiber is Chol chol]
| SnS Chol adrenergic
si
68
Where is AcH stored in the syaptic terminal?
In the VAcHT (transporter) on H exits for each Ach entered
69
How is the AcH signal terminated mainly?
It is broken down by acetyltcholinesterase in the synaptic cleft. Many nerve terminals also have an M2 receptor whose role is to inhibit the AcH pre syntactically, whihc inhibits partially the release of AcH. Some nerve terminals also have presynaptic a2 receptors for AcH that is being released by neighboring fibers. once activated the a2 receptor inhibits AcH release.
70
What is the role of MAO in adrenergic fibers?
It prevents the excessive production of NE by breaking down NE that escapes the storage vesicle
71
How does the amino acid tyrosine enter the nerve terminal?
System L which is shared by other amino acids as well
72
What is the rate limiting step in the production of NE?
The conversion of Tyrosine to Dopamine
73
Where is NE made?
In the vesicle withing the nerve terminal, dopamine is made outside of the nerve terminal
74
What is the role of COMT?
COMT is an enzyme used for nuero metabolism of NE and is an important pharmacological target
75
How is an adrenergic (NE) signal depleted?
The synaptic terminal is larger and diffusion can occur and the signal can fade from simple diffusion, or specific re-uptake transporter NET NE transporter. NET is a co-transporter with NA. We also can have the a2 and M2 receptors that are seen in Cholinergic receptor to inhibit the signals.
76
What are the two types of cholinergic recpetors?
Muscarinic (G-protein) and nicotinic (Ligand gated ion channel for Na)
77
What are two types of Nicotinic recpetors?
Nm (NMJ muscular) and Nn (nueronal found everywhere else)
78
Where are muscarinic receptors located?
On the plasma membranes of cells in the CNS
In organs innervated by PSNS
Endothelial cells
On tissues innervated by cholinergic postganglionic sympathetic nerves
79
Why is the M3 receptors so important?
There is no Parasympathetic innervation of blood vessels, BUT, there IS M3 receptors that are unninervated. These endothelial cells that line the vasculature contain NO synthase, which catalyze NO from arginine. Activation of these receptors by a muscarinic Agonist causes a rise in intracellular Calcium, which activates NO synthase and causes the production of NO which then diffuses from the endothelium to the smooth muscle of the blood vessel wall.
80
WHat is the effect of NO on smooth muscle cells?
In the cytosol NO activates guanyly cyclase which catalyses the formation of cGMP from GTP. cGMP activates cGMP dependent kinases which phosphorylates proteins leading to relaxation of the smooth muscle wall and vasodilation.
81
What are the two types of adrenergic receptors?
b and a, all of which are G protein linked.
82
Of adrenergic receptors there are alpha and beta, what are the different types of b receptors?
b1, b2, b3, defined by their affinity to NE and Epi,
b1 and b3 equal affinity NE and Epi
b2 higher affinity Epi
83
What do all b adrenergic receptors stimulate?
Adenylyl cyclase with interaction of Gs
84
What are the two dopaminergic receptors and what is their role?
D1 and D5 both of which increase cAMP and are found in the smooth muscle of the renal vascular bed and cause relaxation. Very important pharmacologicaly in Shock
85
What is the effect of a muscarinic agonist on the eye?
cause contraction of the ciliary muscle of the eyes vie the M3 receptor, this increases the outflow of the aquas humor via the canal of sclemm which decreases the intraocular pressure and helps with glaucoma. Muscarinic ANTAGONIST results in relaxation and long distance accommodation.
86
What is the effect of ADRENERGICs on the eye?
a1 receptors causes contraction of the pupillary dilator muscles resulting in Mydriasis.
b2 receptors facilitate production of aqueous humor-blocking these receptors with a beta blocker can reduce the intra-ocular pressure and help treat glaucoma.
87
Cholinergic Agonists can be direct or indirect what is the effect of both?
Direct bind to and activate either Muscarinic or Nicotinic receptors.
Indirect inhibit AcHesterase thus reducing the breakdown
88
What are the direct effects of AcH?
* Vasodilation (M3 effect).
* Decrease in cardiac rate (M2 effect).
* Decrease in rate of conduction in the SA and AV nodes (M2 effect).
* Decrease in force of contraction (M2 effect)
* Some of these direct effects can be obscured by baroreceptor reflexes
89
Atropine
A muscarinic antagonist, muscarinic effects are blocked by atropine, large doses of acetylcholine produce nicotinic
effects:
•Increase in blood pressure and vasoconstriction
due to stimulation of sympathetic ganglia and
release of epinephrine from the adrenal medulla
90
What are the two types of Direct acting cholinergic Agonists?
Esters of Choline (cousins of AcH) and Alkaloids (structurally completely different)
91
What are Choline esters?
* Choline esters are quaternary ammoniums.
* Poorly absorbed and poorly distributed into the CNS.
* They differ in their susceptibility to hydrolysis by cholinesterase.
* Acetylcholine is very rapidly hydrolyzed.
* Methacholine is more resistant to hydrolysis.
* Carbachol and bethanechol are still more resistant to hydrolysis by cholinesterase.
92
Acetylcholine
Cholinergic agonist, no therapeutic effect because so wide reaching,
•Used to obtain rapid miosis after delivery of the
lens in cataract surgery and other anterior
procedures where rapid miosis is required.
93
Bethanacol
Cholinergic Agonist (choline ester),
•Treatment of acute postoperative and postpartum urinary retention.
•Neurogenic atony of the urinary bladder with retention.
•Not hydrolyzed by acetylcholinesterase
•Inactivated by other esterases.
•Little or no nicotinic actions.
•Strong muscarinic activity.
94
All muscarinic agonists have what adverse effects?
* Sweating
* Salivation
* Flushing
* Low blood pressure
* Nausea
* Abdominal pain
* Diarrhoea
* Bronchospasm
95
Carbochol
•Cholinergic agonist-Both muscarinic and nicotinic agonist.
•Poor substrate for acetylcholinesterase.
•Biotransformed by other esterases at much slower rate.
Uses:
25
CARBACHOL: USES
•Miosis during surgery.
•Reduces intraocular pressure after cataract
surgery.
96
Methacholine
Primarily Muscarinic agonist
•Diagnosis of bronchial airway hyperreactivity in
subjects who do not have clinically apparent
asthma.
97
Pilocarbine
Natural alkaloid, mainly muscarinic agonist. Sialologue (increases saliva) and miotic
•Tertiary amine
•Stable to hydrolysis by acetylcholinesterase.
•Partial muscarinic agonist.
•Second line agent for open angle glaucoma.
•Management of acute angle-closure glaucoma.
98
Nicotine
Nicotinic agonist, effects the NMJ.
•Low doses: ganglionic stimulation by depolarization.
•The response resembles simultaneous discharge of both parasympathetic and sympathetic nervous systems.
•CV system: Mainly sympathomimetic effects. Increase in HR and BP due to catecholamine release from adrenergic nerve terminals and from adrenal medulla.
•GI & urinary tracts: Mainly parasympathomimetic effects: nausea, vomiting, diarrhea, voiding of urine.
•Secretions: Stimulation of salivary and bronchial secretions.
•High doses: ganglionic blockade and neuromuscular blockade.
•Symptoms of acute, severe nicotine poisoning: nausea, salivation, abdominal pain, vomiting, diarrhea, cold sweat, mental confusion and weakness.
•The blood pressure falls, the pulse is weak. Death may occur from paralysis of respiratory muscles and/or central respiratory failure.
99
there are three indirect cholinergic agonist groups (anti cholinesterases): Edrophonium, Carbamates and organophosphates, how does each group work?
* Edrophonium binds reversibly to the active site of the enzyme. The enzyme-inhibitor complex doesn’t involve a covalent bond and is short-lived.
* Carbamates form a covalent bond with the enzyme.
* Organophosphates phosphorylate the enzyme. The covalent bond formed is extremely stable and hydrolyzes very slowly. A processes called aging makes this bond even stronger.
100
How does an indirect cholinergic agonist differ from direct in regards to its effect on blood pressure?
* Cholinesterase inhibitors have less marked effects on blood pressure than direct-acting muscarinic agonists.
* Few vascular beds receive cholinergic innervation.
* Therefore the effects of cholinesterase inhibitors on vascular smooth muscle are minimal.
101
Edrophonium
•Quaternary ammonium.
USES
•Used in diagnosis of myasthenia gravis (AB against NM receptors). Edrophonium IV leads to rapid increase in muscle strength by decreasing AcH breakdown=increase available AcH in cleft.
•Also used to reverse the neuromuscular block produced by non-depolarizing muscular blockers.
102
Physostigmine
•Tertiary amine.
•Can enter and stimulate CNS.
USES
•Treatment of overdoses of anticholinergic drugs.
NOTE:
•Physostigmine should not be given to a patient with suspected TCA overdose because it can aggravate depression of cardiac conduction.
103
Neostigmine
Indirect Cholinergic Agonist, anti Acetylcholinesterase
•Quaternary ammonium.
•Doesn’t enter CNS.
USES
•To stimulate bladder and GI tract.
•Antidote for competitive blockers of the NMJ.
•Symptomatic treatment of myasthenia gravis
104
Somebody overdoses on an anticholinergic drug should we give them physostigmine or neostigmine?
Neostigmine is NOT the good choice because as a quaternary ammonium it cannot pass the CNS so all the poisonous effects would not be counteracted. Physostigmine as a tertiary amine can act both peripherally and centrally
105
Pyridostigmine
```
Anticholinesterase
•Quaternary ammonium.
USES
•Treatment of myasthenia gravis.
•Most commonly used anticholinesterase for this indication.
```
106
ECHOTHIOPHATE
Organophasphate, anticholinesterase
| •Used for glaucoma.
107
Some oral anticholinesterase are used to treat the Sx of Alzheimers, which are they?
* Tacrine
* Donepezil
* Rivastigmine
* Galantamine
108
What are the three nerve agents we learned about?
Sarin Tabun Soman
109
There are two thiosulphate insectisides, what are they and how do they illicit their effect?
MALATHION
PARATHION
•They must be activated in the body by conversion to oxygen analogs.
110
Pralidoxime
Reactivator of AcHesterase
•If given before ageing has occurred, drugs like pralidoxime
split the phosphorous-enzyme bond.
•Pralidoxime can be used as cholinesterase regenerator
for organophosphate insecticide poisoning.
111
Atropine
Non-selective Muscarinic receptor antagonist, A bella donna alkaloid along with scopalamine.
•Binds competitively to muscarinic receptors, preventing acetylcholine from binding.
•Tertiary amine: both central and peripheral muscarinic blocker
USES
•GI: Reduces gastric motility.
•Urinary system: Decreas hypermotility of urinary bladder.
•Low doses: bradycardia. Due to blockade of presynaptic M2 receptors that normally inhibit ACh release.
•Moderate to high therapeutic doses: Blockade of atrial M2 receptors: tachycardia.
•High doses of antimuscarinic agents may cause cutaneous vasodilation. This is called ‘atropine flush
•Salivary, sweat and lachrymal glands are blocked.
•Inhibition of sweat glands may cause high body temp.
•Mydriasis and cycloplegia.
•Antispasmodic: to relax GI tract and bladder.
•Antidote for cholinergic agonists.
•Antidote for mushroom poisoning due to muscarine, found
•block respiratory tract secretions prior to surgery.
Side effects are the opposite of the PSNS effects:
•Dry mouth, blurred vision, sandy eyes, tachy, constipation.
•Effects on CNS (since tertiary amine): restlessness, confusion, hallucinations, delirium, which may progress to depression, collapse of the circulatory and respiratory systems and death.
112
When you see a questions with a pt with confusion and blurred vision, hallucination etc think anti muscarinic
Like atropine
113
Hot as a hair, blind as a bat, dry as a bone, red as a beet and mad as a hatter. These refers to the S/S of which drug?
All the effects of Atropine
114
Scopalamine
Sea sickness and blocking of short term memory. Bella donna alkaloid, muscarinic antagonist
115
There are two quaternary ammonium muscarinic antagonist, what are their names and what are they used for?
IPRATROPIUM AND TIOTROPIUM
•Used as inhalational drugs in the treatment of chronic obstructive pulmonary disease (COPD).
•Also used as inhalational drugs in asthma.
116
HOMATROPINE
CYCLOPENTOLATE
TROPICAMIDE
Tertiary Amine muscarinic antagonists
•For use in ophthalmology.
•Produce mydriasis with cycloplegia.
•Preferred to atropine because of shorter durat of action.
117
BENZTROPINE
| TRIHEXYPHENIDYL
Tertiary Amine muscarinic antagonists
| •Used to treat parkinsonism and the extrapyramidal effects of antipsychotic drugs.
118
Glycopyllorate
Anti muscarinic
•Used orally to inhibit GI motility.
•Used parenterally to prevent bradycardia during
surgical procedures.
119
Tolterodine
Antimuscarinic
| Used for an overactive bladder
120
What are the contraindications of Antimuscarinic drugs?
* Contraindicated in patients with angle-closure glaucoma. By closing the angle we increased intraocular pressure and can cause damage
* Should be used with caution in patients with prostatic hypertrophy and in the elderly
121
Among the antinicotinic agents there are ganglion blockers which work in two ways, what are they and what are some examples of each?
Ganglion blockade may occur by the following
mechanisms:
•By prolonged depolarization. Example: Nicotine(first agonist then desensitization).
•By antagonism of nicotinic receptors.
Examples: Hexamethonium, mecamylamine, trimethaphan.
122
What are ganglion blockers used for?
•Ganglion blockers such as hexamethonium,
mecamylamine and trimethaphan were used for
hypertension in the past.
•Due to their adverse effects they have been
replaced by superior antihypertensive agents.
123
One type of antinicotinic agent is the neuromuscular blocker of which there is two classes, what are they?
TWO CLASSES:
•COMPETITIVE ANTAGONISTS (NONDEPOLARIZING BLOCKERS)-Tubocurarine
•AGONISTS (DEPOLARIZING BLOCKERS)
124
Tubocurarine
Tubocurarine is the prototype competative antagonist (non-depolarizing blocker)
MECHANISM OF ACTION
•Competitive antagonists.
USES
•As adjuvant drugs in anesthesia during surgery to relax skeletal muscle.
125
What are non-depolarizing blockers?
Real competitive, reversible antagonists
126
Succinylcholine
Depolarizing blocker,
•Binds to the nicotinic receptor and depolarizes the junction. Not broken down by acetylcholinesteras so Persists in the synaptic cleft, stimulating the receptor: receptor desensitizes.
•This leads to flaccid paralysis.
USES
•Useful when rapid endotracheal intubation is needed.
•During ECT.
Rapid, short acting
Negative effects: •
Malignant hyperthermia: Due to excessive release of Ca2+
from the SR.
•Most incidents due to combination of
succinylcholine and an halogenated anesthetic.
•Treatment: dantrolene.Blocks release of Ca2+ from SR.
127
What are the three classes of drugs that act presynaptically?
Inhibitors of AcH synthesis, storage and release
128
Hemicholinium-3
Presynaptic drug that inhibits AcH synthesis,
•Blocks the CHT.
•Prevents uptake of choline into neuron required for ACh synthesis.
•Research tool.
129
Vesamichol
Presynaptic drug that block entry of AcH into presynaptic vesicle for storage. blocks the ACh-H+ antiporter that is
used to transport ACh into vesicles, thereby preventing the storage of ACh.
•Research tool.
130
BOTULINUM TOXIN
Presynaptic drug
•Inhibits acetylcholine release
•Injected locally into muscles for treatment of several diseases involving muscle spasms.
•Also approved for cosmetic treatment of facial wrinkles.
Uses: Blephoraspasm
131
What are the endogenouse direct acting catacholamines?
Epinephrine, Norepinephrine, Dopamine
132
What is the cardiovascular effect of epinephrine?
When a large dose is given IV
•There is increase in blood pressure. Due to:
1.Increased ventricular contraction (β1 effect).
2.Increased heart rate (β1 effect) This may be opposed by
the baroreceptor reflex.
3.Vasoconstriction(α1 effect).
When a low dose is given IV
•Peripheral resistance decreases, because β2 receptors are more sensitive to epinephrine than α1 receptors. D
iastolic pressure falls.
•Systolic pressure increases due to increased cardiac contractile force (β1 effect)
•Heart rate increases (β1 effect)
•There is no increase in mean blood pressure,
so the baroreceptor reflex does not kick in.
133
What are the metabolic and respiratory effects of epinephrine?
Respitory effects are bronchodilations via b2
•↑glycogenolysis in liver (β2 effect)
•↑Lipolysis (β3 effect)
134
Epninephrine uses?
* Anaphylactic Shock: drug of choice.
* Used to treat acute asthmatic attacks.
* Cardiac arrest: can restore cardiac rhythm in patients with cardiac arrest.
* In Local Anesthetics: Epinephrine increases duration of local anesthesia by producing vasoconstriction at the site of injection.
135
What are nor-epinephrine main receptors?
* Potent agonist at α1, α2, and β1 receptors
| * Little action on β2 receptors
136
NE
•Vasoconstriction: α1 effect.
•Both systolic and diastolic blood pressures increase.
•Cardiac output is unchanged or decreased
Baroreceptor reflex:
•The increase in blood pressure induces reflex rise in vagal activity by stimulation of baroreceptors: bradycardia.
137
What is the effect of Effect of atropine pre-treatment to norepinephrine?
if atropine is
given before norepinephrine, norepinephrine
causes tachycardia.
138
Uses of norepinephrine?
•To treat shock because it vascular resistance
and therefore blood pressure.
•Dopamine is better because it doesn’t blood flow to the kidney as does norepinephrine.
139
WHat are the uses and effects of dopamine?
* Activates dopamine receptors and α and β receptors.
* Substrate for both MAO and COMT→ineffective when given orally.
* Drug of choice for shock.
* blood pressure by stimulating heart (β1 effect).
* perfusion to the kidney (D1 effect).
* Superior to norepinephrine that may cause kidney shutdown.
140
ISOPROTERENOL
•Stimulates β1 andβ2 adrenergic receptors.
•Action on α receptors is insignificant.
•Increases heart rate and force of contraction (β1 effect).
•Dilates arterioles of skeletal muscle (β2 effect): decreases peripheral resistance.
Lungs: Broncholdilation b2
Stimulates hrt in emergency
141
Dobutamine
Selective b1 adrenergic agonist
•Acute management of CHF: Increases cardiac output.
•Increases cardiac output with little change in heart rate.
•Doesn’t significantly elevate O2 demands of the myocardium: major advantage over other sympathetic drugs.
142
What are the two short acting b2 adrenergic agonists and what are they used for?
Used in asthma.
•SHORT-ACTING-used for emergency
•Terbutaline
•Albuterol
143
What are the two long acting b2 adrenergic agonists and what are they used for?
* LONG-ACTING-very lipophlic
* Salmeterol & formoterol
* Prolonged duration of action: 12 hours.
* Slow onset of action: not suitable for prompt relief of breakthrough attacks of bronchospasm.
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What are the β2-ADRENERGIC AGONISTS: ADVERSE EFFECTS
* Tremor, restlessness, apprehension, anxiety, tachycardia.
| * Adverse effects are less likely with inhalation therapy than with parenteral or oral therapy.
145
What is phenylephrine and what are its effects?
* α1 selective adrenergic agonist
* Vasoconstrictor.
* Nasal decongestant . Given orally or topically.
* Mydriatic.
* Used to increasing blood pressure in hypotension resulting from vasodilation in septic shock or anesthesia.
* Used to increase blood pressure and terminate episodes of supraventricular tachycardia.
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What are the α2-SELECTIVE ADRENERGIC AGONISTS
* CLONIDINE
* METHYLDOPA
* BRIMONIDINE
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Clonidine
* Partial α2 agonist.
* Activates central α2-adrenoceptors.
* Reduces sympathetic outflow. This reduces blood pressure.
* Adverse effects: lethargy, sedation, xerostomia
148
METHYLDOPA
α2-SELECTIVE ADRENERGIC AGONISTS
•Taken up by noradrenergic neurons.
•Converted to α-methylnorepinephrine which activates central α2-adrenoceptors.
•This decreases blood pressure.
•Drug of choice for treatment of hypertension during pregnancy.
•Adverse effects: sedation, impaired mental concentration, xerostomia.
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BRIMONIDINE
* Highly selective α2 agonist.
* Given ocularly to lower intraocular pressure in glaucoma.
* Reduces aqueous humor production and increases outflow.
150
There are two types of INDIRECT-ACTING ADRENERGIC AGONISTS, what are the two classes?
* RELEASING AGENTS
| * UPTAKE INHIBITORS
151
What are the effects of the releasing agents, a class of indirect acting adrenergic agonists and what are three examples?
AMPHETAMINE
METHYLPHENYDATE
TYRAMINE
•Cause norepinephrine release from presynaptic
terminals.
•Potentiate effects of norepinephrine produced endogenously.
152
Amphetamine
Adrenergic agonist, releasing agent
•Has central stimulatory action.
•Can increase blood pressure by α-agonist action on vasculature as well as β-stimulatory effects on heart.
153
Methylphenydate
Adrenergic agonist, releasing agent
•Structural analogue of amphetamine.
•Widely used to treat ADHD in children.
154
Tryramine
•Found in fermented foods such as ripe cheese and Chianti wine.
•Normally oxidized by MAO.
•If the patient is taking MAO inhibitors, it can precipitate
serious vasopressor episodes.
155
Cocaine
INDIRECT-ACTING ADRENERGIC AGONISTS
•Blocks monoamine reuptake.
•Monoamines accumulate in synaptic space.
•This results in potentiation and prolongation of their central and peripheral actions.
156
ATOMOXETINE
INDIRECT-ACTING ADRENERGIC AGONISTS
•Selective inhibitor of the norepinephrine reuptake transporter.
•Indicated for the treatment of ADHD
157
What are the MIXED-ACTING ADRENERGIC AGONISTS and whats their method of action?
EPHEDRINE
PSEUDOEPHEDRINE
•Induce release of norepinephrine
•Activate adrenergic receptors.
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EPHEDRINE
MIXED-ACTING ADRENERGIC AGONISTS
•Stimulates α and β receptors and releases norepinephrine from nerve endings.
•Not a catecholamine poor substrate for COMT and MAO long duration.
•Excellent absorption orally and penetrates the CNS.
•Increases systolic and diastolic blood pressures.
•Causes bronchodilation.
•Mild stimulation of CNS: Inc. alertness, Inc. fatigue and prevents sleep.
•Improves athletic performance.
•Ephedrine-containing herbal supplements were banned by the FDA because of life-threatening CV reactions.
•Used as a pressor agent, particularly during
spinal anesthesia when hypotension frequently
occurs.
•Used in myasthenia gravis.
•Used in allergic disorders, such as bronchial
asthma. Now used infrequently to treat asthma.
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PSEUDOEPHEDRINE
MIXED-ACTING ADRENERGIC AGONISTS
•One of four ephedrine enantiomers.
•Available over the counter as a component of many decongestant mixtures.
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Classic vignette on Warfarin and Cimetidine
Pt on Warfarin for long time, goes home, gets heartburn, takes Cimetidine, all of a sudden INR goes crazy and Pt enters a bleeding crisis: Cimetidine inhibits the action of CYP450 thus exacerbating the effects of Warfarin.
161
What is one of the adverse effects of Spirnolactone?
Since Spirnolactone has antiandrogen effects (gynecomastia) it can have an adverse effect on androgens. As well as gastric ulcers, Hyperkalemia, Nausua, vomiting and confusion
162
ACE inhibitors
Know the difference between effectiveness for Whites and blacks, young and old, Black and elderly have lower levels of circulating Renin so ACE is slightly less effective for these populations.
163
What must patienets on ACE inhibitors be monitored for?
Risk of Hyperkalemia, we expect GFR to fall resulting in an increase of creatinine, as long as this remains below 30% its fine. Dry cough due to increase of bradykinin, if this occurs we can switch to an ARB
164
WHat are two testable contraindications to ACE inhibitors or ARB's? (Same contraindications)
Bilateral renal artery stenosis
Pregnancy: 1st trimester-congenital malformation
2nd, 3rd- Hypotension, anuria and renal failure
