Pharm Flashcards
quantal dose-response
all or nothing- you are either protected or you are not
ED50
where 50% of animals are protected
LD50
kills 50% of animals
chemical vs physical form
same drug cannot be in different chemical forms, but can be in different physical forms
Therapeutic Index
LD50/ED50
ideally 10
margin of safety
LD1/ED99
comparing extremes of the dose response curves to indicate any over lap
Protective Index
=ED50 (undesireable)/ED50 (desireable)
chronicity index
=(1-dose of LD50)/(90-doseLD50)
has to do with clearance
1 is best (total clearance) vs 90 (virtually no clearance)
Threshold dose
apparent all or none phenomenon at a specific threshold dose
–may not be a REAL threshold but an apparent threshold
potency
relative dose required to produce a given effect
(should not be equated with therapeutic superiority)
affinity is one component, but not the whole thing
intrinsic activity
often referred to as efficacy in intact patient; magnitude of maximal response (highest dose)
efficacy is one component, but not whole thing
affinity
K1/K2
efficacy
K3
Chemical antagonism
direct interaction of the agonist and antagonist
functional antagonism
two agonists act independently but lead to opposite biological effects, so kinda cancel each other out (or one takes over)
competitive antagonism
the antagonist binds to the receptor, but elicits no response (affinity, but no efficacy)- however, competes with agonist for binding sites
–eq and non-eq
Eq antagonism
competitive
reversible
can be overcome if dose of against is increase enough
non-eq antagonsim
competitive
irreversible-perm block of agonist binding and receptor function
cannot be overcome by increasing dose ofagonist
non-comp antagonist
antagonist acts at a site other than the site of agonist binding but affects the same process
could also bind to another site on same receptor and alter the ability of the receptor to interact with agonist–“allosteric effect”
inverse antagonist
shifts eq towards inactive
synergy
need more than one to make–>additive
potentiation
the effect of one drug makes another work better
rate of absorption
movement of drug from site of administration to the blood
rate of distribution
delivery of drug from blood to tissues and target sites
bioavailability
amount of drug that actually reaches the target site in a pharmacologically active and bioavailable form
only bioavailable drug
drugs that are not bound to albumin
passive diffusion
down a concentration gradient in non-ionized form; dependent on partition coefficient
filtration
down a pressure gradient
bulk flow
across a cap wall (small molecules)
mechanisms of drug transport across membranes
1) active transport
2) facilitated transport
3) ion pair transport-
4) endocytosis
oral is good for drugs with
high partition coefficient and favorable pKa
stomach only absorps
weak acts
small intestine uses
passive diffusion
5 factors affecting GI absoprtion
gastric emptying time intestinal motility food and food consumption formulations of drugs metabolism & digestion
high partition coefficient means it is
lipophilic
what crosses very readily in lung?
high partition coefficient anesthetics
albumin has
positive and negative charged binding sites
lung receives
100% CO
kidney receives
25%CO
what can cross the BBB
high partition, non-ionized, free drugs can cross
inflammation can increase permeability
half-life
t=0.693/Kel
Volume of distribution
Vd=D/Co (L/Kg)
Clearance
Clp=KelxVd (L/hr/kg)
oral fraction
Foral=AUCoral/AUCiv
Loading Dose
D*=Css x Vd (mg)
Maintenance Dose
MD=Css x Vd x Kel (mg/hr or mg/min)
=Css x Clp (x time interval)
rate of eliminaton
x=xe^(-kt)
if route of elimination is saturated,
drug follows0 order onnects
Vd: 3-5 L
no penetration from plasma
Vd: 12-15 L
no penetration into cells from interstitium
Vd: 30-40L
distributed throughout body water
> 50 L
accumulated in body tissues (e.g. lipophilic)
ares of concern in dosing
time to peak concentration (tmax) in blood
Maximum attained concentration (cmax)
area under curve (AUC)
steady state
independent of dose and depends only on rate of elimination (Kel), so to avoid delay use a loading dose
pro-drug
more active than parent compound
mitomycin C, cyclophosphamide, codeine
Pro-toxin
when metabolized drug turns toxic
aflatoxin B1, benzoapyrene
goal of phase 1 metabolism
make lipophilic drugs more hydrophilic
CYP liver enzymes add groups, oxidate, reduce
phase 2 metabolism
conjugation
take phase 1 metabolite and bind to large, polar glucoronic acid so can be readily excreted from body
occurs predominantly from UDP-GT
neonatal hyperbilirubinemia
inability of newborn babies to metabolize bill to bill fluuronide conjugate–>leads to CNS damage
chloramphenicol (antibiotic)
deficinecy in UDP-GT leads to excessive free drug in blood and tissue and drug-associateed toxicities
gray baby syndrome
crigler-naijar syndrome
almost total genetic deficiency in hepatic UDP-GT
babies highly jaundiced–>death occurs in early childhood
B-glucuronidsae
releases drug
present in mucosa of small intestine
entero-hepatic circulation for drug (re-abs by GI)
n-acyetyl conjugation
catalyzed by n-acetyltransferases in population
fast and slow acetylators in population
important for isonizaid, sulfamethazine, paninosaliyclic acid, hydralazine
overdosing on acetaminophen
generates reactive metabolites that attack tissues and lead to liver toxicity and failure
acute alocohol
inhibits drug metabolism, prolonging and intensifying effects of drugs (esp CNS depressant), though competitive inhibition of metabolism
chronic alcohol
increases drug metabolism and clearance through induction of P450 and other enzymes
induce drug metabolism because induce P450
green things, brussel sprouts cabbage, cauliflower
grape fruit juice
contains furanocoumarins that inhibit CYP3A4 metabolism
also inhibit Pgp- mediated durg efflus in intestine and liver
–>both mechanisms increase bioavailability and toxicity of a large group of CYP3A4 substrate drugs
charcoal broiled beef diet
xenobioti metabolizing enzymes induced higher in beef eaters so they have lower phenacetin plasma levels
ABC transport proteins
Pglycoprotein: transport large and functionally unrelated molecules
MRP: phase II conjugates of drugs and metabolites
large and diverse group of molecules out of cells
Sympathetic Neruons
T1-L3 short–>ACH to ganglia -long–>target organs (NE)
Parasympathetic Neruons
cervical and sacral areas-long—>ACH at ganglia near target organ-short—>target organ (ach)
pressor center is in
medulla
how to cholinergic neurons make Ach
acetyl coa + choline–< acetylcoline–>put in vesicles–>exocytosed
M1 Ach R
nerve endings
Gqcoupled–>increase IP3 & DAG
myenteric plexus
M2 Ach R
heart, some nerve endings
Gi–>decrease cAMP, activate K+ channels
slow SA node
M3 Ach R
smooth muscle glands
Gq coupled–>inc IP3, DAG
contract detruser muscle, increase salivation
Nn ACh Receptor
ANS ganglia
Na-K ion channel–>Na
depolarizes postgang fiber–>evokes AP
Nm Ach Receptor
neuromuscular end plate
Na-K ion channel–>Na+
depolarizes muscle cell, evokes AP and contraction
how to make NE
tyrosine–>DOPA–>Dopamine–>into vesicle–>adds B-hydroxyl–>NE
5 Ach Receptors
M1, M2, M3, Nn, Nm
6 NE receptors
A1, A3, B2, B3, B4, DA1
A1 NE receptor
smooth muscle, glands,
Gq
increase Ca2+–>contraction (vascular SM- vasoconstriction), secretion
also inhivits SA node
*STIMULATE BP**
A2 NE receptor
nerve endings (some smooth muscle)
Gi
decrease transmitter release (nerve)- contract, SM
Beta 1
Cardiac muscle, JGA
Gs–>increase camp
increase HR and contractility, renin release
also stimualtes SA node
Beta 2
smooth muscle, liver, heart
Gs–>inc camp
relax bronchiolar SM, increase glycogenolysis, increase HR and contractility
Beta 3
adipose tissue
Gs
increase lipolysis
Da1
smoth muscle
Gs
relax vascular SM in renal arterioles
sarin nerve gas
increases amount of Ach in body (inhibits AchE)
5 ways SNS helps BP go up
arterioles (SVR) SA node (HR) LV (contractility) veins (tone) kidneys (renin) adrenal medulla (releases E and NE)
PANS CNS origin
rostral ventrolateral medulla
PANS origin
Nucleus ambiguus
direct acting sympoatomimetic drugs
act on post-syn receptors
NE, EPI
indirect acting drugs
keep NE in synapse longer
- enhance release of NE at synapse
- block reputake of NE after release at synapse
- blocks degradation of NE
enhances release of NE at synapse
amphetamine, meth MDMA
blocks reuptake NE
cocaine, amitriptyline
blocks degradation of NE
MAO-inhibitors
2 alpha agonists
Phenyleprine (a1)
Clonidine (a2)
mixed alpha, beta agonists (3)
Epinephrine
NE
Dopamine
4 Beta agonists
Isoproterenol
Dobutamine
Albuterol
Mirabegron
alpha antagonists
prazosin/minipress
tamsulosin/flomax
phentolamine/regitine
beta antagonists
atenolol
propanolol
Mixed a,b
labetolol
nonspecific Ach agonists (2)
Ach
Carbachol
3 Muscarinic Agonists
Methacholine
Bethanechol
Pilocarpine
2 Nicotinic Agonists
Nicotine
Varenicline (Chantix)
Short Acting cholinesterase inhibitors
edrophonium
Int acting cholinesterate inhibitors
neostigmine
physostigmine
long acting cholinesterase inhibitors
echothiphate parathion malathion sarin soman
presynaptic indirect cholinomimetics
metoclopramide
3 places M receptors are located at
effector tissues innervated by PS fibers
very select postganglionic sympathetic targets (sweat glands)
endothelium (non-innervated tissue)
Cholinomimetic overdose-cholinergic syndrome
muscarine poisioning
DUMBBELSS
SLUDGE syndrome
major muscarinic/nicotinic effects salivation lacrimation urination defetation GI upset Emesis
Why do muscarinic receptors cause hypotension?
active eNOS–>makes NO–>stimulates guanlyl cyclase to turn GTP–>cGMP–>binds myosin lightt chain to vasodilate
Why does muscarinic activation cause bradycardia?
activation of M receptors on SA node (vagus)
other M clinical signs
DUMBBELSS Diarrhea urination Miosis Bronchorrhea/brnchoconstriction Bradycardia Emesis Lacrimation Salvation Sweating
therapeutically useful Ach agents
must be resistant to AchE
modified forms of Ach
methacholine
bethanechol
pilocarpine (glaucoma)
Nicotine Toxicity
Depolarizing-Desensitization Blockade
initial activation–>deactivation due to phosphotylation–> paradoxical flaccid paralysis due to blockade, have to wait until agonist is cleared
*Nm receptors
Major signs of Nicotine Toxicity
Symp and PS stim- tachycardia, hypertension, cold sweat, nausea, vomitting, diarrhea, salivation, urinary incontinence
Nn and Nm blockade- syncopy, collapse, unconsciousness, flaccid paralysis
All ChE inhibitors block
true Ache, plasma Che, and RBC Ache
plasma ChE is inhibited first
what is the major concern of using cholinesterase inhibitors?
respiratory inundation
–paralysis of intercostal muscles and diaphragm via nicotinic desensitization blockade
–increased bronchial secretions and bronchoconstriction (mud)
central resp arrest
AchE mechanism
anionic site binds quat ammoium cation
esteric site-catalytic hydrolyzes Ach ester bond
short acting are
competitive inhibitors and do not form ester bond to AChE
what is used to diagnose MG?
Edrophonium
rapid increase in muscle strength because inhibits ChE transiently and makes Ach more available
2 Muscarinic Antagonists
atropine
scopolamine
Depolarizing Nm cholinolytuc agonists
succinylcholine
Nondepolarizing Nm antagonists
Benzylisoquinolines: d-tubocurarin, Cisatracurium
Aminosterioid: pancuronium, vercuronium, Rocuronium
Nn specific
trimethaphan
Muscarinic Atagonists act
block PS transmission to end organs
inverse agonists
atropine toxicity
mad as a hatter Blind as a bat dry as a bone hot as a hare red as a beet performing the pee pee dance
atropine basically does
unopposed symp acts (no ps)
what is most dangerous effect of atropine in adults vs kid
delirum- self destructive acts
kids- temperature- doesn’t respond to antipyretics; need ice bat
Scopolamine
motion sickness
anesthetic adjuvant
Dicyclomine
irritable bowel and minor diarrhea
M3 selective antag
Tropicamide
mydriatic eye drops for retinal exam
Benzotripine
CNS Parkinsons DIsease
Ipratropium**
Inhibits bronchoconstriction
succinylcholine
Nm blocker
post-surgical procures and intubations
adverse effects- muscle fasciculations, hyperemia, histamine release, hyperthermia
no succinylcholine if
family Hx of malignant hyperthermia
hyperkalemia
burns, trauma, tissue injury
heart failure
d-tubocurarine
paralysis in fully conscious patient; only for anesthetized pt
nondepol paralysis reversal
neostygmine
depolarizing nicotinic blockers
TIME- neostygmine will cause muscurinic syndrome
Trimethaphan
nondepol ganglionic Nn blocker
potent effects on BP
only use in hypertensive crises, dissecting aortic aneurysm
Botox
indirect anticholinergic
light chain escapes from vesicles and cleaves SNARES so no docking
botox applications
coesmetic
prevent arm pit sweating
strabismus
uncontrolled eye twitching
