Pharmacology MT Flashcards
Pharmacology is the study of ______ that interact with ______ through ________ process
Pharmacology is the study of substances that interact with living systems through chemical process
define medical pharmacology
the study of substances used to prevent, diagnose and treat disease
_______ is the study of undesirable effects of chemicals on living systems & ecosystems
toxicology
medical pharmacology studies _____ where as toxicology studies _____`
efficacy; side effects
Drug –> body is studied via __________
pharmacodynamics
body –> drug is studied via _________
pharmacokinetics
________ is the science of drug preparattion. and medical use of drugs in roman times (after 2500 BC)
materia medica
Francois Magendie & Claude Bernard are known for ..
developing methods of experimental physiology and pharmacology
The relation of an individuals genetic makeup to their response tot specific drugs is called _________
pharmacogenetics
What are 3 advances from the field of pharmacogenetics?
- understanding that certain diseases are inherited
- genomes of humans, animals and plants have been decoded - options for new research and treatment
- genetic techniques - gene therapy, KO mice
A new drug compound requires the discovery of a new ___________ (i.e the pathophysiological process or substrate of a disease condition)
new drug target
What occurs in in vitro studies and how long does it typically take?
Biological products and/or chemical synthesis, optimization (enzymes etc.) combine to form a lead compound.
~ 2 yrs
What is evaluated during animal testing? What occurs directly after?
Animal testing is the best model of disease for evaluating efficacy, selectivity and mechanism
- directly after: submit to a regulatory body = investigational new drug
~ 2 yrs
What does phase 1 of clinical testing evaluate? how many subjects?
Is it safe? Pharmacokinetics
20-100 subjects
What does phase 2 of clinical testing evaluate? how many subjects?
Does it work in patients w/ disease?
100-200 pt.
What does phase 3 of clinical testing evaluate? how many subjects?
does it work, double blind? (need significant effect)
randomized control trial
1000-6000 pt.
the clinical testing phase of drug development takes _- _ years
3-4 years
______ is an activator of biochemical pathway that mimics endogenous signalling
agonist
_________ stabilize receptors in an inactive form by shutting down constituent receptor
inverse agonist
______ inhibits a biological pathway by blocking endogenous signalling.
antagonist
_______ antagonist compound loosely binds to the same site as the natural ligand and inhibits natural action of ligand
competitive
_______ antagonist compound binds to _______ on the receptor and inhibits function
noncompetitive
_______ antagonist causes covalent modification of receptor
irreversible
Agonists and Antagonists require ___________ to induce change
target molecule (receptor)
a partial agonist increases ______ (compared to normal) but decreases ______ (compared to full agonist)
effect; effect size
Most rapid onset is the characteristic of ______ route drugs
IV
- large volumes often feasible
- may be painful
- used for when you cant take meds on daily basis describes which drug route
intramuscular
Smaller volumes than IM - may be painful is the characteristic of ______ route drugs
Subcutaneous (SC)
most convenient route with a significant first past effect is the characteristic of ______ route drugs
Oral (PO)
Less first pass effect than PO is the characteristic of ______ route drugs
Parenteral Rectal (PR)
Often very rapid onset (2nd to IV) is the characteristic of ______ route drugs
inhalation
Slow absorption used for lack of first pass effect and prolonged duration of action is the characteristic of ______ route drugs
Transdermal
The fact that drugs exist in the form of organic and inorganic compounds is important for _______
how the body handles the drug
Drug size is an important factor for ______
administration
rational drug design describes …
design based on known structure of ligand & receptor
Allosteric Activator + Agonist = ______ response
max
Agonist + Competitive inhibitor = _____
Right shift - same max response but don’t increase max effect
Agonist + Allosteric inhibitor = ______
decrease below the use of a competitive inhibitor
What occurs when an agonist binds to a receptor
electrostatic changes = conformational change of receptor
ex. GPCR opening ion channel
4 process that are involved in termination of drug action
- dissociation of drug from receptor = terminate effect (ex. ionotropic receptor)
- action persists after drug has dissociated (ex. GPCR, phosphorylation)
- covalent bond - drug receptor complex must be destroyed and new receptors synthesized
- desensitization mechanisms - receptor mineralization
How do receptors determine the drug dose/ conc. & the effect
dose/conc: receptor affinity for a drug
effect: total # of receptors
____ is the maximal response that can be produced by a drug
Emax
____ is he concentration of drug that produced 50% of maximal effect
EC50
What is the eqn for the effect observed at conc. C
Constitutive activity describes… and is inhibited by ______
…the fact that some receptors are active w/o being bound to endogenous ligands.. inhibited by inverse agonist
____ can be used to measure he potency between different drugs in a log scale
EC50 - the drug conc.(on x axis) which induces a 1/2 max effect (Emax) response
responses to low doses usually _____ in _____ proportion to dose. Response increment _______ as dose increases
increase ; direct ; diminish
How do we chose among drugs and determine appropriate dosing? (2)
• pharmacologic potency (position dose axis)
• maximal efficacy (end point on response axis)
the maximum effect is driven by …. and reduced by increasing the concentration of _____
..the total # of receptors activated ; antagonist
Low doses of antagonists affect the agonist concentration effect curve by _______ whereas high dose antagonists cause it to _______
shift to the right ; reduce max response and R shift
EC50 is the dose required for ______ to experience 50% ____ effect and is seen in ______
ED50 is the dose required for 50% __________ to obtain the ____ effect and is seen in ______
individual; max; lab tests
of the population; therapeutic; clinical effects
IC50 is the measure of the _______of a substance in inhibiting a ____________ by 50%
potency; specific biological or biochemical function
You want IC50 to be high when you want to see ____ activity whereas you want EC50 to be high when you want to see _____ activity
decreased; increased
if Kd is ___ binding affinity is ____
low; high
___ is the concentration (molar) of free drug at which 1/2 amt of possible receptors are bound bound
Kd
Kd is _______ (directly or inversely) related to binding affinity
inversely
EC50 is generally ____ (lower, higher) than Kd
lower - b/c some spare receptors
____ is the maximum number of receptors that can be bound
Bmax
spare receptors occur when (2)
- drug dosent bind long but effect lasts (drug bouncing around to diff receptors)
- # of available receptors > # of effector molecules `
____ is the median effective dose - at which 50% of individuals exhibit the specific effect
ED50
____ is the median lethal dose - at which 50% of individuals exhibit a toxic effect
TD50
________ relates dose of a drug required to produce a desired effect to that which produced an undesired effect
Theraputic index
Theraputic index equation
TI = TD50/ED50
A safe drug has a ____ theraputic index b/c need a _____ dose for toxic effects and a ____ dose to be effective (high, low)
high; high; low
What are the 4 kinds of transmembrane receptors and how do they work
- transmembrane receptor protein - acts as an enzyme intracellular when ligand binds outside
- Transmembrane receptor bound to enzymatic protein (tyrosine kinase)
- ligand gated ion channel - open or closed w/ ligand binding
- Transmembrane receptor protein coupled with G protein - modulates second messenger production inside cell
How do lipid soluble ligands work?
cross membrane and act on intracellular receptor = stimulates gene transcription via binding to DNA sequences
ex. steroid hormones
steroid hormone (lipid soluble ligand) effects occur (when) ______ and last for ________
lag period (hours-days) ; hours-days
cytokine receptors are an example of ________
transmembrane protein receptors with intracellular enzymatic activity or stimulate protein tyrosine kinase
acetylcholine nicotonic receptor is an example of a ____________. Its effects take ________
ligand-gated transmembrane ion channel; milliseconds (instant)
the activated alpha unit in the GPCR ________ resulting in ________
exhanges bound GDP with GTP; dissociation of alpha subunit from beta-gamma dimer
The 2 signalling cascades of G protein coupled receptors are _____ & _____ and depends on ______
cAMP and phosphatidylinositol ; alpha subunit type
cAMP mediates
_____ in liver
_____ in kidney
____ homeostasis
______ in heart tissue
_______ of smooth muscles
regulation of __________
carb breakdown
water conservation
Ca2+
increased rate of contraction
relaxation
Adrenal and sex steroids
Describe the cAMP mechanism (5 steps)
- GTP activates adenyl cyclase
- adenyl cyclase converts ATP –> cAMP
- cAMP stimulates cAMP-dependent protein kinases
- protein kinases activate/ deactivate further proteins
- cascade effect
Phosphoinositides (PPIs) are membrane bound _____. They regulate (4 processes in cell)
lipids
1. migration
2. proliferation
3. survival
4. diffrentiation
phosphatidylinositol is a _____ and mediates the generation of _____ by it’s phosphorylation and dephosphorylation
membrane lipid precursor ; PPIs
Provide 2 examples of interplay among signalling systems (one opposite, one working together)
- vasopressor agents contact smooth muscle by phospholipid mediated mobilization of Ca2+ & agents that relax smooth muscle act by elevation of cAMP
- in the liver cAMP and phosphoinositide work together to stimulate glucose release
almost all 2nd messenger signalling involves ______ phosphorylation.
reversible
In terms of a signal - phosphorylated = _______ (via _____) dephosphorylation = _________
activation (via kinases); terminates effect
_____ is the transfer of drug from its site of administration to the blood stream
absorption
- IV has none b/c direct into blood stream
most drugs are absorped by the manner of ______ transport
passive
__________ and __________ are important PK parameters
fraction of administered dose ; rate of absorption
List 5 factors that affect absorption
- conc. gradient - drugs move from [high] –> [low]
- blood flow to absorption site
- total surface area available for absorption - bigger = more
- contact time with absorption - more time = more
- drug properties - lipid solubility, molecular weight, polarity
a ______ (charged or uncharged) is hydrophobic and can _______ diffuse across lipid bilayer membranes.
a _____ (charged or uncharged) drug is hydrophilic and cannot diffuse
uncharged; passively
charged
most drugs are the salts of _____ acids or bases
weak
relative amounts of protonated and unprotonated forms depends on the drug’s ______ and the environment’s ____
pka; pH
The two mechanism that drugs can cross a cell membrane include _______ and _________
passive diffusion; protein-mediated transport (facilitated or active transport) `
________ is the fraction of unchanged drug reaching the systemic circulation following any administration
bioavailability
______ bioavailability is the amount of drug from a formulation that. reaches the systemic circulation relative to an IV dose
absolute
______ bioavailability is the amount of drug from a formulation that reaches systemic circulation relative to a different formulation (non-IV)
relative
- can compare drugs via ratio at relative
___________ for the test and reference formulation/route is used to calculate bioavailability
ratio of area under the curve (AUC)
For AUC curves _______ is the time in the therapeutic range
duration of action
For AUC curves __________ is the conc. for therapeutic benefits
theraputic range
For AUC curves _______ is the time to get in the therapeutic range
onset time
____ is the max conc of drug found in the body and _____ is the time of Cmax
Cmax; Tmax
there are different _____ and ______ of AUC for different routes of administration
shape and size
________ is a phenomenon in which a drug gets metabolized at a specific location in the body -results in reduced conc. of active drug when reaching its site of action or systemic circulation
the first pass effect
the first pass effect is most toften associated with the _____ but can also occur in ____, ______, _____
liver; lungs, vasculature, GI tract (metabolic enzymes)
______ is a # you. can use to calculate how much drug you have in your body if you know the conc. of drug in your body
Volume of distribution (Vd)
the _____ the Vd the more likely the drug is found in the tissues of the body.
the ______ the Vd the more likely the drug is confined to the circulatory system
larger; smaller
Drugs with Vd:
< /= 4L are ______
4L –> 7L are _____
> 42 are ______
< /= 4L are - confined to plasma
4L –> 7L are - distributed throughout blood
> 42 are - distributed to all tissues in body (esp. fatty)
_______ is the time required to change the amount of drug in the body by 1/2 during elimination.
half life
half life is relative to ______ and over time _____
Cmax; stays constant ( not dependent on amt of time).
_____ is the rate of drug elimination divided by plasma concentration of the drug
clearance (CL)
note: elimination means removal of active drug not excreted.
The formula for half life is
half-life = (0.693 • Vd)/ CL rate
- Vd and CL provided
______ is the process by which drug reversibly leaves the blood stream (moving b/w body compartments or reaching target receptors)
distribution
list 4 factors affecting distribution
1.Organ blood flow
- faster if highly perfused = rapid onsett
2. molecular size
- for extremely large - cant get out of blood
3. lipid solubility
- important for the brain and transport mechanisms
4. plasma protein binding
- bound = inactive - depends on affinity
_____ is the conversion of a parent (original) drug to metabolite(s)
metabolism
the goal of metabolism is to make the drug ____ polar to ______ renal excretion
more; increase
metabolism occurs primarily in the _____ as well as some in the ____, ____, _____, _____
liver; gut, lungs, plasma, brain
Phase 1 of metabolism involves _____, ______ and _____ reactions with the. majority being _______
oxidative, reductive, hydrolytic; oxidative
phase 1 of metabolism is catalyzed by _________ isoforms. aka hepatic oxidative isoenzymes
cytochrome P450 (CYP)
_____ increase enzyme activity = metabolism ______. Cause of many drug-drug interactions that____ potential clinical effects (___ drug)
inducers; speed up ; lower; less
____ decrease enzyme activity = metabolism _____. See toxic effects b/c you stay in therapeutic range____ and _____ Cmax
inhibitors; slows down; longer; increase
in phase II of meabolism _______ enzymes which are _____ liver enzymes covalently add ____, _____, _____ molecules to parent drug or phase I metabolite to prep for excretion
conjugation; non P50; large, polar, endogenous`
List 2 alternative sequences of metabolism
- some drugs enter phase II directly
- some drugs skip metabolism all together
______ are administered as an inactive drug that relies on metabolism to produce pharmacologically active produce
Produrgs
ex. codeine –> morphine (via CYP2D6)
3 pathways of drug excretion in kidney
____ glomular filtration
______ tubular secretion
_______tubular reabsorption
- Passive glomular filtration - small drugs
- Active Tubular secrettioon - large drugs + transport proteins
- Passive tubular reabsorption - reabsorbed back into blood –> urine (pH is key)
A carrier mediated process. that is not limited by passive diffusion rules excretes larger drugs by secreting them from the _____ to ______ via ________
liver; intestine; common bile duct.
_____ nerves are craniosacral meaning they originate from the ________ regions of the spinal cord
PNS; top and bottom
_____ nerves are thoracolumbar meaning they orginate from the ___________ regions fo the spinal cord
SNS; thoracic and lumbar
SNS ganglia have ____ chains to the ganglia from the spinal cord vs PNS
shorter
most drugs work at the _________ receptors on ________
postganglionic ; target organs
Acetylcholine (ACh) is released onto _______receptors at _________ and __________in both PNS and SNS. but only onto _____. receptors in PNS
nicotinic; ganglia; target organs; muscarinic
ACh is synthesized from ______ and _______ and stored in synaptic vesicles
Acetyl CoA and Choline
Catecholamines NT such as dopamine, NE and Epi are synthesized from ______
tyrosine
Nm receptors are found in ______
Nn receptors are found in _____, _____, _____, _____
muscle
ganglia, adrenal, CNS, immune
PNS receptors are _______ and have __ subtypes . ____ (more or less) drugs target these receptors and they are important for _________
muscarinic; 5; fewer; drug side effects
_________(number of M receptors) cause _____ bladder muscle contraction via increased ____–>____and are ___ (q or i) G protein coupled
M1,M3,M5 ; smooth; PLC –> IP3; Gq
_________(number of M receptors) cause _____ heart rate via decreased ___ –> ____ and are ___ (q or i) G protein coupled
M2, M4; decreased; AC –> cAMP; Gi
The effects of a _____ (PNS) agonist oppose those of an _____ (SNS) agonist
muscarinic; adrenergic
Effects of a muscarinic agonist in
heart -
lungs-
sphincers (GI and bladder)-
Walls (GI and bladder) -
heart
- decreased rate and contraction
lungs
- bronchoconstriction
sphincers (GI and bladder)
- relax (M3)
Walls (GI and bladder)
- contract (M3)
In the _____ (PNS or SNS) How does coordinated action lead to urination.
PNS
- M3 (bladder wall) = contract
- M3 (sphicter) = relax
____ (PNS or SNS) muscarinic receptors _____ secretion (salivary, respiratory, tears)
PNS; increase
to directly stimulate M receptors you use _______
to indirectly stimulate M receptors you use _______ both which ______ Ach
an agonist; acetylcholinesterase (AChE) inhibitors; increase
______ (rapid recovery) and _______ (slower recovery) are reversible reaction when cholinesterase is bound (more ACh). Whereas ______ is irreversible
Acetylation (rapid- physiological); Cabamylation (slower - drugs); phosphorylation
parasympatholytics (aka anticholinergics) block _______ (PNS or SNS) response/ _____receptors. ex. Atropine
PNS; muscarinic
side effects of anticholinergic drugs (ex. atropine)
mouth -
heart -
gut -
bladder -
mouth - dry
heart - tachycardia
gut - constipation
bladder - difficulty urinating
_____ receptors in the SNS constrict smooth muscles
alpha - 1. (a-1)
a-1 receptors constrict ______ in _____ and most critically on _____ for ______
sphincters; bladder and GI tract; blood vessels; vasoconstriction
a-1 receptors are ________ (receptor type) that produce ___ which results in ______ Ca2+. leading to smooth muscle contraction
G-protein coupled; IP3; increased
______ receptors in the SNS inhibit presynaptic NE release
alpha - 2 (a-2)
a-2 ________(agonist or antagonist) would lead to no NE released into synapse
agonist
_____ receptors in the SNS stimulate the heart rate, AV conduction and contraction.
Beta - 1 (B-1)
B-1 receptors are ________ (receptor type) that produce ___ which results in ______ Ca2+. leading to increased HR contractility
G-protein coupled; AC/cAMP; more channels
B-1 receptors in the ____,____, ____. are only innervated by the ____(SNS or PNS)
liver, kidney, uterus; SNS
B-1 receptors in the kidney _____ renin release which causes a _____ in blood pressure
stimulate ; increase
_____ receptors in the SNS cause relaxation of smooth muscles
Beta-2 (B-2)
B-2 receptors cause _____ (dilation or contraction) in the ____, _____, and (contraction or relaxation) in the walls of ____, ____, ____
dilation; lungs, blood vessels (skeletal muscle)
relaxation; bladder, uterus, GI tract
there is a coordinated effect between _____ and B-2 receptors
a-1
B-2 receptors are ________ (receptor type) that produce ___ which results in _____
G-protein coupled; AC/cAMP; dilation
How does coordinated action of SNS receptors lead to peeing
bladder wall (B-2) contracts
sphincter (a-1) relaxes
B-2 receptors in the ____ mediate glucose release by ______ and ________ which _____ blood glucose conc.
liver; gluconeogenesis and glycogenolysis; increases
_________ are drugs that mimic sttimulation of the SNS
sympathomimetics
sympathomimetics work by 2 mechanisms …
- directly activating adrenergic receptors (NE and Epi)
- increasing amt of NE and Epi in synapse
what are the three ways sympathomimetics work to. increase the amt of n.t in the synapse?
- increase n.t release
- inhibit reuptake of n.t - inhibit reuptake pumps
- inhibit metabolism of n.t - enzymes for catecholamine breakdown
__________ are drugs that block or reduce sympathetic activity
sympatholytics
sympatholytics work by 2 mechanisms..
- blocking adrenergic recepors (ex. propranolol)
- decrease amt of epi and NE released into synapse (ex. clonidine)
propranolol is a __________ drug that works by …. and acts on ____ receptors
sympatholytic; directly blocking adrenergic receptors; B-1
clonidine is a _________. drug that works by … and acts as an. _____ receptor agonist
sympatholytic; decreasing the amt of SNS n.t released into the synapse; a-2 agonist
What are the 2 different iris muscles and how do they affect the pupil when contracted
Circular (sphincter) - contract = constrict pupil
Radial (longitudinal)- contract = dilate pupil
Circular (sphincer) contracting resuls from ______(PNS or SNS) stimulation of ____ receptor(s). = ________(constrict or dilate) pupil
PNS; M2, M3; constrict
Radial (longitudinal) contracting results from______(PNS or SNS) stimulation of ____ receptor(s). = ________(constrict or dilate) pupil
SNS; a-1; dilate
The most common ways to. treat glaucoma are to increase _____ of AH and decrease______ of AH
drainage; production
In the PNS ______ receptor(s) stimulation results in ______ ciliary muscle, _____ meshwork and canal = (increased or decreased)_____ drainage
M2, M3; contract; open; increased
In the SNS, ____ receptors (increase or decrease) ______AH secretion so ______ drugs are used to (increase or decrease) ______ secretion
B-2; increase; B-2 antagonists; decrease
In SNS, _____ receptors (increase or decrease) ____drainage and ______ production of AH so _____ drugs are used
a-2; increase; decrease; a-2 agonists
In the PNS side effects of ____ receptor stimulation causes ____ of ciliary muscles = the lens to bulge which improves ____ vision and blurs ___ vision (near or far)
M; contraction; near; far
List the PNS and SNS receptors found in the GI tract
M3 - contract walls, relax sphincters
a-1 - contraction of sphincters
B-2 - relaxation of wall
List the PNS and SNS receptors found in the heart
M2 - decrease HR and contraction
B-1 - increase HR , AV conduction and contraction
List the PNS and SNS receptors found in the blood vessels
a-1 - vasoconstriction
B-2 (in skeletal muscle) - vasodilation
List the PNS and SNS receptors found in the bladder
M3- contraction of walls & relax sphincters
a-1 - contract sphincter
List the PNS and SNS receptors found in the bladder
M3- contraction of walls & relax sphincters
B-2: relax walls
List the PNS and SNS receptors found in the eye
M2, M3 - contraction of circular muscles = constrict pupil
a-1 - contraction of radial muscles = dilate pupil
List the PNS and SNS receptors found in the kidney
B-1 - stimulate renin release = increase BP
List the PNS and SNS receptors found in the lungs
M: bronchoconstriction
B-2: bronchodilation
List the PNS and SNS receptors found in the liver
B-2 - increase glucose release via glycogenolysis and. gluconeogenesis
