Transcript No Slide Title

Pharmacology
Jeopardy
Block 2 Part II
Peter O. Beaumont, M.Sc. (Pharm)
St. Vinnie’s Fall 2000
Local and General
Anaesthesia
The Five Goals of
General
Anaesthesia
What are…
Analgesia, amnesia,
muscle relaxation, LOC
and Loss of somatic &
visceral reflexes
– The first three are universal, the last
two are somewhat secondary
The Surgical Stage
of Anaesthesia,and
the easiest test to
determine it
What are…
Stage III, and the
eyelash reflex test
The greatest medical
concern in
Guedel’s stage II of
anaesthesia
What is…
Aspiration of vomit
– During this stage, delirium and
excitement are often accompanied by
retching,vomiting and incontinence.
– Intubation must unfortunately wait
until the patient loses gag reflexes
The earliest feature
of Guedel’s stage I
What is…
analgesia
– this is soon accompanied by
amnesia, but consciousness is not
lost.
– Remember, not all anaesthetics
show all stages, and further, not all
agents are good analgesics e.g.
halothane
The only true
anaesthetic ‘gas’
What is…
Nitrous Oxide
– The others are all volatile liquids
The rate of onset of
an excellently
soluble anaesthetic
What is…
Very slowly
– The sooner the point of saturation
is reached, the sooner the blood is
willing to give up the agent to the
brain tissues
The rate of onset of
anaesthesia in a
patient with heart
failure
What is…
Faster than normal
– This is is a tough concept
– slowly flowing blood will reach its
saturation sooner than fast flowing
blood
– A greater fraction of the CO goes
to the brain in failure
Once you stop the
flow of Nitrous and
oxygen, this may
happen to the
patient post-op
What is…
Diffusion Hypoxia
– A high partial pressure of gas coming
out of solution dilutes oxygen in the
lungs in the post-op patient
– Only happens with nitrous oxide, others
are used a too low partial pressure
When 1/2 your
patients do not
jump off the table
following induction,
this point is
reached
What is…
MAC
– By definition… when 50% of
patients do not respond to a
painful stimulus
– highly dependent on degree of
stimulation
– Elderly and children have lower
MAC
This prototypic GA
has good effect, but
high metabolism
makes it
undesirable these
days
What is…
Halothane
– Release of halogens can cause
hepatotoxicity (methoxyflurane
does this as well, so it is rarely
used)
If you use halothane
for a D&C, you
must also use
these two adjuncts
What are…
Opiods and oxytocin
– Halothane has virtually no
analgesic effect
– oxytocin causes uterine
contraction to counteract the
relaxant effect of halothane
Were it not for
concurrent muscle
paralysis, patients
induced with this
agent might hurt
themselves
What is…
Enflurane
– Seizure complexes on EEG
– EEG goes with Enflurane
This GA is great for
maintenance, but
rarely used for
induction
What is…
Desflurane
– Extreme sympathetic stimulation
during induction. Also has a sharp
irritating odour
– Rapid post-op recovery
Some consider this
GA to be the
‘Cadillac’ inhalation
agent for short
procedures
What is…
Sevoflurane
– rapid onset and recovery
– little airway irritation
– 2-5% hepatic metabolism makes it
less desirable for long procedures
– Sevo is the “Seville”
Were it not for a
high MAC, this
agent would be a
nearly ideal GA
What is…
Nitrous Oxide
– No CV depression, excellent
analgesia
– Must be used with a second GA
and paralytic agent
This class of IV GA’s
are the prototypical
induction agents
What are…
Barbiturates
– Thiopental was the first - Still used
widely today
– Onset in 1 minute
While inhalation
agents terminate
their effect by
exhalation, this is
the mechanism for
barbiturates
What is…
Redistribution
– Also known as gamma phase
redistribution
– 99% hepatic metabolism to inactive
compound AFTER termination of
sedation effect
Incapable or
reaching stage III
themselves, these
agents provide
sedation and
amnesia
What are…
benzodiazepines
– Diazepam, lorazepam and
midazolam are short acting agents
– Slower onset than barbiturates
– used as part of “balanced
anaesthesia”
Occasionally used
alone in Cardiac Sx,
these agents
typically support
GA agents with
analgesia
What is…
Opiods
– patient may be ‘aware’ of or recall
the Sx
– Chest tightness impairing
ventilation may occur
Opiod + neuroleptic
+ Nitrous Oxide =
What is…
Neuroleptanesthesia
– Important for painful, invasive
procedures requiring patient
cooperation
Dr’s and patients
agree, this drug is
the ‘real Pro’ of the
induction agents
What is…
Propafol
– Similar induction to barbiturates,
but faster recovery
– Patients feel much better post-op
– May even have anti-emetic
properties
– much much more expensive than
thiopental
Catatonia, amnesia
and analgesia
without LOC
What is…
dissociative
anesthesia
– Produced by ketamine alone
– Similar to PCP
– only CVS stimulant
– good for Sx on patients in shock
This untoward effect
of ketamine is
obviated by premedication with
diazepam or
fentanyl
What is…
Emergence
Phenomenon
– hallucinations and perceptual
illusions
This iv induction
agents shares one
shortcoming with
halothane and one
with nitrous oxide
What is…
Etomidate
– No analgesia (halothane), no
muscle relaxant effect (nitrous)
This effect makes
Etomidate
unsuitable for long
Sx and ICU
sedation
What is…
inhibition of adrenal
steroid synthesis
– produces hypotension, electrolyte
imbalance and oliguria
The two chemical
groups required for
effect as a local
anaesthetic
What is…
lipophilic group and
ionizable group
– Must be able to readily pass
through lipid bilayer, yet interact
with ion channel
Relative
effectiveness of
locals on infected
tissue
What is…
Decreased
– lower pH of tissue causes more
ionized agent, which is unable to
enter the cell
Major benefit of
cocaine as a Local
anaesthetic
What is…
vasoconstriction
– All other agents are vasodilators
– functions through blocked NE
reuptake
– prolongs anaesthetic effect
– used in URT and ear
Cocaine
Tetracaine
Benzocaine
What are…
The ‘ester’ locals
– Typically shorter T1/2 due to
hydrolysis by plasma
cholinesterase
Mechanism of action
of the local
anaesthetics
What is…
blockade of voltagedependent Na
channels
– Use-dependent
– blocks from inside
Characteristics of
the earliest blocked
nerve fibres
What are…
small, myelinated, rapidly
firing, peripherally
located on the bundle
– why myelinated first - I don’t know!
– Use-dependent means rapidly
firing sensory fibres blocked
before motor fibres
CNS sedation,
restlessness,
nystagmus,
seizures
What is…
Toxic effects of local
anaesthetics
– Premedication with benzos, and
hyperoxemia are prophylactic for
these symptoms
Local that does not
permeate the skin
when applied
topically
What is…
benzocaine
Three LA agents that
cross mucous
membranes in
therapeutic
amounts
What is…
tetracaine, lidocaine
and cocaine
– tetracaine suitable for ophthalmic
use - no irritation (cocaine too?)
– epinephrine cannot be used in
topical preps.
Rationale for use of
nerve blocks
What is…
Covers larger area,
with smaller
amount of drug
– prevents systemic toxicity
– (also, prevents distortion of wound
when suturing!)
Three techniques to
prevent cephalad
diffusion of spinal
anaesthesia
What are…
Tilt the patients, use
small amount, use
‘heavy’ diluent
– Specific gravity determines
whether agent will rise, sink or
remain static
Small muscles,
trunk muscles,
diaphragm
What is…
Order of effect of
NMJ blockers
Effect of presynaptic NMJ
blockade of
nicotinic receptors
What is…
‘Fade’
– These receptors normally cause
increased release of ACh required
to maintain repetitive firing
AChE inhibitors
have this effect on
non-depolarising
NMJ blockers
What is…
antagonism
– non-depol agents are essentially
pharmacological antagonists. AChE
inhibitors increase the amount of
ACh
– On the other hand, they would
enhance depolarising blockade
Primary use of
depolarising NMJ
blockers
What is…
temporary paralysis to
allow intubation
– Succinylcholine is the only agent in
use
– onset < 1 min, duration 5-10 min rapid metab by plasma cholinesterase
These two classes
of agents are
known to cause
malignant
hyperthermia
What are…
volatile anaesthetics
and
succinylcholine
– Causes over-release of Ca from SR
- Tx with Dantrolene
– Genetic susceptibility
Basis for emesis
due to
succinylcholine
What is…
Increased intragastric
psi due to abdominal
muscle contraction
– Not triggered by CTZ
inhalation, local and
IV anaesthetics,
and
aminoglycosides
What are…
agents that
potentiate NMJ
blockade
Goal of Tx with
spasmolytics
What is…
reduction in tone,
without reduction
in strength
– Useful in CP, MS and stroke
Facilitates GABAmediated pre-syn
inhibition
What are…
benzodiazepines
(diazepem)
– muscle spasms of any origin
– marked sedation
GABA-mimetic at
GABAB receptors
What is…
baclofen
– hyper-polarises pre-syn afferent of
reflex arch
– decreases transmitter release
– works in brainstem
– equally effective as diazepam - less
sedation
spasmolytic with 3
month duration of
action
What is…
botulinum toxin
– effective in blepharospasm,
dystonia and achalasia
– admin by local injection
Tuberculosis
and Leprosy
Guess the first-line
drugs for Tx of TB
and win the
P.R.I.S.E.
What is…
Pyrazinamide,
Rifampin, Isoniazid,
Streptomycin &
Ethambutol
Slow growth,
intracellular,
resistance
What are…
Three reasons for
difficulty in Tx TB
– Combination Tx is often used to
ovecome these problems
Mechanism of action
of the most import
drug in the Tx of TB
What is…
inhibition of mycolic
acid synthesis by
INH
– Pyridoxine congener
The dose-limiting
toxicity of INH
What is…
hepatotoxicity
– “INH: Injures Neurons and Hepatocytes
– peripheral neuritis is easily Tx with B6
- so, technically, not ‘dose-limiting’
– significant (1%) incidence of severe
hepatitis; even greater in alcoholics
This TB agent is an
inhibitor of DNAdep-RNA polymerase
What is…
Rifampin
– Effective in all mycobacteria and
many other agents
– good CSF penetration exposure/carrier prophylaxis in
meningococci and H.flu
Rifampin and
phenazopyridine
have this in
common
(think back to UTI)
What is…
colours body fluids
RED
– 4 R’s
– RNA-poly, Reves P450, Red fluid,
Rapid Resistance used alone
If you took this TB
drug, you may not
know that your
urine was red from
rifampin
What is…
Ethambutol
– Causes loss of red-green
discrimination
– relative contraindication in
children
– 2nd TB agent that causes hepatitis
This TB agent may
precipitate gout in
susceptible
individuals
What is…
pyrazinamide
– Hyperuricemia occurs in all
patients, but only some are
symptomatic
INH, rifampin,
pyrazinamide, but
not ethambutol or
streptomycin
What is…
First-line TB agents
that cause
hepatotoxicity
– Ethambutol does, not… as may
have been stated in class
This quasi-first line
agent is still used
for life-threatening
TB
What is…
Streptomycin
– Especially useful in meningitis and
milliary TB
– some do not consider it 1st-line for
TB anymore
Mech of act of this
primary Tx for
Leprosy
What is…
Inhibition of
dihydropteroate
synthase by Dapsone
– Just like all of the other PABA
analogues
This dapsone ADR
is similar to that
seen in the Tx of
spirochete infection
What is…
the Lepra Reaction
– somewhat like Jarisch-Herxheimer
reaction (erythema nodosum
leprosum)
– Tx with thalidomide, chloroquine
and clofazime (not in G&G)
Perhaps the most
effective drug in
leprosy, it can
never be used
alone
What is…
Rifampin
– Resistance is a major concern
The main ADR of the
main Dapsone
alternative in
resistant Leprosy
What is…
Skin discolouration
– Clofazime is an ‘azo’ dye that
discolours the skin
Malarial parasites
with more than one
exoerythrocytic
cycle
What are…
Vivax and Ovale
– Falciparum and Malariae have only
one cycle before proceeding to
RBCs
– Basis for dormant infection in V &
O
Stages of the
lifecycle taken up
by the mosquito,
and later injected,
respectively
What are…
Gametocytes and
sporozoites
DOC for Tx and
prophylaxis of P.
falciparum (area
without resistance)
What is…
Chloroquine
– often used in combo with
pyrimethamine
DOC for prophylaxis
of P. falciparum, in
resistant areas
What is…
Melfoquine or
Chloroquine + pyrimethamine
(Depending on your source)
– 2nd choice doxycycline, 3rd chloroquine +
proguanil (Katzung and G&G agreee)
– Can also be used for the other plasmodia
too
DOC for Tx of
chloroquine-resistant
P. falciparum
What is…
Quinine
– given with a tetracycline or
antifolate
– Mefloquine is used in some
geographic areas
Drug that would
have made Dr.
McPhearson a
millionare, and
which was not
covered in class!
What is…
Artemisinin
– Effective blood schizontacide in all
types of malaria, including
resistant P.f.
– Not good for prophylaxis
– Not available in US… yet.
Only drug for
eradication of
tissue schizonts
What is…
Primaquine
– One of the few indications that is
absolute
– only required in Ovale and Vivax
Enzyme deficiency
associated with
ADRs in
primaquine and
quinine
What is…
Glucose-6phosphate DeHase
– Produces hemolysis and
methmoglobin - toxic to kidneys
Antiviral
Pharmacology
Amantadine is used
in the Tx of:
Influenza A, and...
What is…
Parkinson’s Disease
– I hope you didn’t guess Influenza B
or C!
This drug….
Is an excellent
prophylactic for the
Flu, but won’t make
you feel any better
once you get it
What is…
amantadine or
rimantadine
– these agents block uncoating of
the viral particle in the cytosol, but
by the time you feel sick, you
already have lots of viral particle in
your system
These agents limit
the abilitiy of
viruses to enter
cells
What are…
Gamma-globulins
– Temporary, passive immunity
– duration about 3 wks
Mech of Act of
amantadine
(for viruses)
What is…
blocks uncoating of
the virus
– Raises pH of endosome to alkaline
levels
– SE are all neuro related (increased
release of DA)
Agents that require
HSV viral thymidine
kinase to be
effective
What are…
All of the
“__ciclovirs”
– Applies to Tx of HSV 1, 2, and 3
(VCV)
– acyclovir, famciclovir, ganciclovir,
valaciclovir, etc.
Key difference in
phosphorylation of
Ganciclovir
What is…
phosphorylated by
CMV-specific
kinase
– uses regular thymidine kinase for
HSV, but a different one in CMV
Mech of Act of
acyclovir
What is…
comp inhibit viral
DNA polymerase &
causes chain
termination
– May cause some renaldysfxn, but
generally well tolerated
Key indication for
use of Ganciclovir
What are…
CMV retinitis,
pneumonitis,
esophagitis, and colitis
– SE: reversible neutropenia and
renal dysfxn
Spectrum of action
of inhaled Ribavirin
What is…
RSV, Influenza A & B
Spectrum of action
of oral/IV Ribavirin
What is…
Lassa fever
– HCV effects are debatable
– many more SE when given
systemically - cytopenias and
suppressoin
Mech of Act of
Ribavirin
What is…
Inibits RNA-depRNA polymerase
– May interfere with GTP synthesis
and the cap on mRNA as well
– effective in BOTH DNA and RNA
viruses
Phosphorylated by
Host cell kinases
What are…
Idoxuridine, cytarabine,
Vidarabine, Trifluridine
– Inhibit viral DNA poly
– too toxic for systemic use, except
Vidara for neonatal herpes in
immunocompromised
HSV /VCV drug
requiring no host or
viral kinase activity
What is…
Foscarnet
– Inhibits viral DNA & RNA poly AND
HIV reverse transcriptase
Key uses of
Foscarnet
What are…
• AIDS-related CMV
• Acyclovir resistant /
thymidine kinase def HSV
• Gancicovir-resistant CMV
– Limited resistance has been
observed
3 mechanisms of
action of
interferons
What are…
• synth of protein kinases to
inhibit further protein synth
• oligoadenylate synthase
activates RNAase
• PDE degrades tRNA
Major indications for
interferon Tx
What are…
• Pv disseminated HSC,
relapse CMV, and
trigeminal HSV
• Hep B & C
• Kaposi’s and warts
...to name a few
Major SE of
interferon Tx
What is…
Constitutional
symptoms
– Fever, malaise, chills, etc.
Type of kinases
used on 5 out of 6
HIV reverse
transcriptase
inhibitors
What are…
Host cell kinases
– All 3 phosphorylation steps, c.f.
just the last two step for antiherpes
drugs
Primary means of
resistance to AZT,
et al
What is…
mutation of RT gene
– Much more common in mono Tx
and in advanced disease
Basis for selective
toxicity of the RT
inhibitors
What is…
our cells do not
have RT!
– Simple point, but commonly
overlooked
Indications for AZT
What are…
• CD4 count < 200 (500 w
symptoms)
• 3rd trimester (with 3TC)
• Prophylaxis for needle
stick
Major toxicity of AZT
What is…
Bone marrow
suppression
– increased by Rx that undergo
glucuronidation, and decerased by
rifampin
Two RTI’s that cause
pancreatitis
What are…
ddI and ddC
– More common in alcoholics
– also cause peripheral neuropathy
Claim to fame of
Nevirpapine
What is…
NON-nucleoside RTI
– potentiallife threatening rash
The function of HIV
aspartate protease
What is…
Final protein
cleavage into
mature, infectious
particles
– SE: kidney stones and
unconjugated hypernilirubinemia
General formulae for
HIV Tx
What is…
AZT + 2nd RTI +
Protease inhibitor
Hypertension
Long term Mech of
Act of diuretics
What is…
Reduction in Na
altering vascular
tone
– Volume reduction occurs early, but
is abated over 6-8 weks in mild
essential HTN
Location and
Mechanism of
Action of Clonidine
What is…
Central and
peripheral alpha-2
sympathomimetic
– blocks NE release
– SE: sedation and dry mouth
Major caution in
clonidine use
What is…
withdrawal syndrome
– Rebound HTN, tachcardia,
sweating
– As little as one or two missed
doses
– Tx with alpha and beta blockers
Direct vasodilators
must be used with
these drugs
What are…
Beta blockers
– No sympathoplegia, so reflex
response to a decreased BP is still
present
Orally active direct
vasodilators
What are…
Hydralazine and
minoxidil
– work through opening K channels
and hyperpolarises arteriolar SMCs
Fast acting, IV
arteriolar and
venous dilator
What is…
Na Nitroprusside
– high dose > 1 hr assoc w cyanide
toxicity
– onset in 1-10 minutes
– activate guanylyl cyclase - not a K
channel agent
The other IV only
direct vasodilator
What is…
Diazoxide
– much longer acting means less
precise control
– inhibits insulin release
1st-line Tx in an
elderly, black
patient with CHF
and CRF
What is…
A loop diuretic
– Without the RF (GFR < 30 ml/min) a
thiazide would be first choice
– beta blockers have little efficacy in
black patients
Anti-HTN agent
contraindicated in
pregnancy
What is…
ACE-I and AgII
receptor blockers
– fetal hypotension and risk of
malformation
Rationale not to use
direct dilators or
alpha blockers in
coronary artery
disease
What is…
Coronary steal
– provokation of angine
Patients in who you
should not use
amiloride or ACE-I
for HTN
Whe are…
Patients in renal
failure
– both tend to exacerbate
hyperkalemia
Drugs not to be
used for HTN in
diabetes
What are…
thiazides and nonselective beta
blockers
Tx of HTN assoc
with kidney stones
What is…
Analgesia and
hydration
– Different stories in different small
groups
– Texts indicate no benefit of
diuretics or anti-spasmodics
Management of HTN
crisis
What is…
decrease psi by <
25%, and diastolic
not less than 100110
– according to Katzung
BP at which to
initiate Drug Tx
What is…
140/90
(open for discussion)
– For stage I patients, after 6-12
months of lifestyle change
Why
hydrochlorothiazide
and alphamethyldopa are used
in preg assoc HTN
What is…
“fetal friendly”
– May not be the best agents, but
there are proven safe.
– Hard to test new Rx on mothers.
Basis for pulmonary
edema in our case
study
What is…
Albuterol activates RAS via
beta-2 receptors & the
‘infusion’ may have
volume overloaded the
patient
– Discussion….
– MgSO4 may have been better, but
fetus old enough to deliver
Two causes for red
urine in our case
study
What are…
Hemorrhagic cystitis
& doxorubcin die
effect
Two causes of the
erythematous
response at the
injection site
What are…
extravasation of
vesicant
antineoplastics & the
“Adriamycin-flare”
Best of Luck
to you All!

Slides available at
sguweb.tripod.com