Final pharma Flashcards
(213 cards)
1
Q
what are 3 components of GPCR signal transduction pathways?
A
GPCR
Heterotrimeric G-protein
Signaling effector
2
Q
what are the types of the Family A GPCR
A
- Rhodopsin/ Beta 2 adrenergic receptor like
3
Q
what are the key distinguishing features of family A GPCR
A
- DRY ( in the second cytoplasmic group)
- Palmitoylated cysteine (highly conserved)
4
Q
what is the function of a direct binding assay?
A
- measures direct interaction of radioactively-tagged ligand with a receptor
- determines kinetic and equilibrium properties
- provides estimates of receptor density
- estimates range of ligand concentration
5
Q
what do “cold” non radioactive ligand do?
A
it binds to the receptor and prevents the hot ligand from binding to specific sites
6
Q
what is the scatchard plot used for?
A
useful to determine if a single receptor has different affinity states for the same ligand.
7
Q
what does the indirect binding assay do
A
Measures the binding affinity of a novel receptor ligand by determining its ability to competitively prevent the binding of a known radioactively-labeled ligand to the receptor
8
Q
what are the steps of GPCR activation and conformational changes?
A
Ligand binding alters GPCR conformation
-Altered receptor conformation alters conformation of G-proteins, activating them via GDP-GTP swap
- Activated G-proteins interacts with & activates Effectors by altering their conformation
9
Q
what is the ligand retinal bound to ?
A
It is covalently linked to the GPCR
- there is a cis retinal, gets incontact with light, then turns into trans-retinal
- there is a conformation change in rhodopsin
- causing G- protein activation
- vision
10
Q
what is the ligand retinal bound to ?
A
It is covalently linked to the GPCR
- there is a cis retinal, gets incontact with light, then turns into trans-retinal
- there is a conformational change in rhodopsin
- causing G- protein activation
- vision
11
Q
G protein heterotrimers are made of what
A
3 polypeptides
G alpha, G beta, G gamma
GTP/GDP binds to G alpha
G alpha and G beta are attached to the plasma membrane via lipid anchors
12
Q
G beta and G gamma what do they do ?
A
- forms a stable dimer with coiled-coil N- terminal interactions
13
Q
What does G gamme interact with?
A
- interacts with G beta, but no G alpha
14
Q
explain the signaling by GTP- binding? Step by Step
A
-GDP is off, a signal comes in
- GDP is off, GTP binds
- Then signalling happens, the signal goes out
- GTP hydrolysis happens and GTP is off, losses phosphate and GDP is back on
15
Q
Explain how G-proteins function as molecular timers?
A
- it is the duration of time GTP remains unhydrolyzed, and its characteristic for different G alpha subunits
- certtain classes of proteins accelerate G alpha intrinsic rate of GTP hydrolysis
16
Q
what is the function of RGS proteins?
A
- modulate the duration of G-protein activation
- control the duration of signaling event
- they can speed up and slow down hydrolysis
- the GTPaase activity and the association and dissociation of GTP/GDP from the G proteins are regualted by a RGSS
17
Q
what are 4 types of G alpha proteins
A
- Gs- stimulates adenylyl cyclase
- Gi/o- inhibits adenylyl cyclase and regulates ion channels
Gq/11 activates phospholipase CBeta
G12/13 activated sodium hydrogen pathway
18
Q
Gs alpha are sensitive to
A
chloera toxin
19
Q
Gi/o alpha proteins are sensitive to
A
pertussis toxin
20
Q
Cholera toxin function
A
it has a covalent modification of G alpha prevents GTP hydrolysis
This causes the timer to be on
- G beta gamma and G alpha complex cannot activate adenylyl cyclase
- Cholera toxin ADP ribosylation an arginine residue on GsAlpha g-protein subunit
21
Q
how does the pertussis toxin function?
A
- stops the cycle at a different point, thereby preventing signaling
it phosphorylates the inactive state of GDP
there is covalent modification of G alpha, and prevents GDP dissociation
it makes sure effectors cannot be activated
Pertussis toxin (PTX) ADP-ribosylation a cysteine residue (position –4 from carboxyl terminus end) on Gi/o alpha G-protein subunits.
22
Q
Non-hydrolyzable GTP analogs
A
Gamma S, is gamma with Sulfur
it prevents the gamma to be removed to make GDP to GTP
23
Q
what is activated by cAMP
A
- PKA
C portion of the PKA phosphorylates the substrate
24
Q
PKA phosphorylates …?
A
target proteins like CREB
25
what are 2 types of GPCR-adenylate cyclase signaling pathways?
stimulatory pathway is G alpha S
inhibitory pathwya G alpha i/o
26
what are pathways that regulate calcium levels
- Organelle that can take up calcium from the cytoplasm and sequester it
- ER/ Mitochondira
PMCA can put calcium on the otueside of the cell
27
what is a way for us to measure calcium through assays ?
using Fluo-3Am and Fluo-3
3AM= cell permeable, cleaved by esterase to Fluo-3, it is a calcium sensor, when calcium comes in via ion channel or receptor
Fluo-3 is what shows increases fluorescence when bound to calcium
28
what is the phospholipase A2 signaling pathway?
phospholipase A2 is activated when G protein is activated, it cleaves phospholipase 1 so it makes arachadonic acid which can make cyclooxygenase
29
G protein receptor kinase and Beta arrestin relationship?
receptor gets activated
GRK gets activated and phosphorylated GPCR
Then Beta arrestin bounds GPCR is internalized
30
Agonists, Antagonists, Partial Agonists and Biased Agonists
Explain their receptor occupancy and biological response
Agonist has receptor binding affinity plus intrinsic activity
Antagonist has receptor binding affinity but no intrinsic activity
Partial agonist has receptor binding affinity and less intrinsic activity
Biased agonist has receptor binding affinity and “selective” intrinsic activity
31
What is an inverse agonist?
An agent which binds to the same receptor binding-site as an agonist for that receptor but exerts the opposite pharmacological effect”. For receptors that have constitutive or basal activity in the absence of a ligand
inverse agonist have negative efficacy
32
what are 2 types of receptor antagonists?
- Competitive
Non competative
33
Describe competitive antagnoist
Bind to the same site as the endogenous ligand or agonist.
Can be over come!
Their presence produces a right- ward shift in both the binding and dose-response curves.
No change in Emax or Bmax.
Similar dose-response curve shapes indicates the presence of a competitive agonist (competing for the same binding sites
34
Describe non competitive antagnost
Does not prevent formation of the DR complex, but impairs the conformation change which triggers a response.
Pseudo-irreversible
Emax and Bmax are reduced but EC50 remains the same for the unaffected receptors.
35
Describe irreversible antagonists
Binds in an irreversible manner, usually by covalent modification of the receptor.
Effectively and practically lowers the number of receptors capable of binding an agonist.
Adding more agonist does not rescue response.
New receptor synthesis is required to restore response.
EEDQ (non-selective modification of carboxyl groups)
N-ethylmalemide (NEM) or other sulfhydryl or alkylating agents (non-selective).
Antibodies
Molecular modifications (mutation)
36
Advantages and disadvantage of irreversible antagonist
Disadvantage
It is irreversible and effects cannot be reversed by an agonist.
advtange
- once the receptor is occupied by antatagonist, the inhibitor is no longer needed to be present in unbound form to inhibit the effects of an agonist
- it binds to the receptor and taken out of action
- independant of rate of eleimination, more depedant on turnover of receptor molecule
37
partial agonists describe them
- never elicit maximal resposne, similar potency, just lower efficacy
Partial Agonist-
Have high receptor binding affinity for the receptor.
Have partial functional activity.
Acts as both agonist and antagonist.
In the absence of full agonist, a partial agonist will bind the receptor and elicit a partial functional response.
In the presence of a full agonist, a partial agonist will compete for binding to receptor and elicit smaller response from the full agonist.
example Abilify- schizo treatmetn
38
Describe Dopaminergic tracts
- increased dopaminergic transmisison in mesolimbic pathway= positive symptoms
- decreased dopaminergic activty in mesocortical pathway- negative symptoms.
39
where are the largest diversity of ion channels found in the body?
Neurons
40
what is electron signaling on cells based on?
ion flow across cell membranes
Basis of all electrical signals in living cells is the uneven distribution of small inorganic ions between extracellular and intracellular compartments
The uneven distribution is created through active transport.
Ions are pumped into or out of the cell using the energy of ATP hydrolysis or transported by carrier mechanisms coupled to the electrochemical gradients.
41
what is the main protein that causes a cation concentration gradient?
Na/K pump (Na/K ATPase)
42
describe secondary active transport
chloride transport coupled to the potassium gradient generated by the sodium potassium pump
43
What is nature's battery
To drive energetically unfavorable reactions
As the source of energy for transport of most nutrients into cells
For fast electrical signaling
44
Ion flow is ?
Channels is passive, it depends on the ion gradient created by pump and transporters
45
what is selectivity filter?
M2 at alpha helix point into the core making a gate, that blocks the flow of ions
-the repel anions, at attract cations
46
ion channels are highly selective for 1 or 2 ions so.....
channels that open makes the inside of the cell more positive (+) generate excitatory electrical signals
more (negative) generate inhibitory electrical signals
47
what are the two most important types of ion channels?
voltage- gated and ligand gated
Voltage-gated channels are opened by a change in cell membrane potential – most often by depolarization or excitatory signals
Ligand-gated channels are opened by a small molecule – most often a neurotransmitter
48
In the voltage refractory period what happens
Na+ channels cannot be activated
49
what are voltage gated channels used for ?
Voltage-gated ion channels are responsible for electrical signal. (action potentials)
action potentials are used for long distance conduction in neurons, nueronal compurtiaon, and cardiac muscles, skeletal muscles
50
how do ligand gated ion channels open?
- open in response to binding of NT.
51
What are parts of neuron important for signaling
Dendrites – receive neurotransmitter inputs
Axon – conducts action potentials
Nerve terminal – releases neurotransmitters
AP originates at Axon hillock
52
what do local anesthetics block ?
the transmission of nociceptive stimuli (pain) from the peripheral nervous system through the spinal cord to the brain.
53
what do local anesthetics do?
Local anesthetics cause the loss of sensation to a limited region of the body.
LA selectively inhibit voltage-gated Na+ channels. (reversible)
Specificity of action achieved by location of injection/ application
Ability to reach axonal Na+ channels depends on LA chemical properties allowing rapid permeation through multiple membranes.
54
what are peripheral nerves
Peripheral nerves are bundles of axons wrapped in several membranes
55
what are the chemical properties of local anesthetics (LA)
Lipophilic aromatic ring
an amide or ester linkage, hydrolyzed by ester, have shorter range of action
a hydrophilic terminal amine.- helps blood water solubility
56
what are the requirements for local anesthetics for blood and membranes?
Local anesthetics must be in an uncharged (lipophilic) form to cross membranes, but in a charged (hydrophilic) form to diffuse to water filled compartments and act on Na+ channels
when injected it goes from charged and uncharged, which can go to nerve sheath and membrane
greater the lipid solubility allows the greater diffusion through membranes
57
what is the relationship between Local anesthetic and pKa ?
LA with lower pKa have a more rapid time of onset
higher the free base amount, the unprotonated form of the drug, allows it to diffuse faster
58
relationship between lipid solubility and relative potency?
The greater the lipid solubility, the greater the potency.
59
what is the difference between motor fibers and pain fibers in terms of Local anesthetic and action potentials ?
Pain fibers have high firing rates and relatively long action potential (3 ms) duration.
Motor fibers have slower firing rates and a shorter action potential duration (0.5 ms). Less sensitive to the LA
The action potential of cardiac muscle are several 100ms, thus heart is highly susceptible to the actions of LA.
pain fibers are more sensitive to local anesthetic
60
what are factors that affect the local anesthetic intensity and duration?
Intrinsic potency of anesthetic
Binding affinity for receptor
Lipid solubility of anesthetic
Tissue pH
Concentration of the solution
Length of nerve exposed to drug (2-3 successive nodes of Ranvier)
Vascularity of treated area (determines removal)
--Anatomy
--Concomitant administration of vasoconstrictor
61
when do we get unwanted local anesthetic adverse drug interactions?
what do local anesthetics block
occur if local anesthetic get into the circulatory system
- voltage gated sodium channels they function as full antagonists (full pore)
62
what are excitatory and inhibitory NT for ligand gated ion channels?
Inhibitory- Gaba, glycine (allow more cl- come into the cell)
Excitatory: acetylcholine, glutamate, seratonin (which allows Na+
63
what are 2 types of muscle relaxants?
1) competitive antagonists
-- non depolarizing blocker
2) depolarizing agonists
-- depolarizing blocker
64
what is a transmitter at the neuromuscular junction
Ach is the transmitter, it gets released at the junction and Ach receptors take it in,
Ache metabolizes it, then an action potential happens
65
Describe ligand-gates acetylcholine ion channel on skeletal muscle and how it initiates contraction
Ion channel opened by Ach
it depolarizes muscle cells generating AP, which opens voltage gated calcium channels
The increase in cytosolic Ca2+ triggers muscle contraction
66
what is the clinical use of a muscle relaxant acting on nicotinic Ach receptors
induce muscle paralysis for surgery, endotracheal intubation
67
what is a type of depolarizing neuromuscular blocker, and how does it function ?
SUX (succinylcholine) binds to and activates Ach receptors
it is resistant to AChe, so it remains bound to the receptor for a long period of time.
Depolarizing agonists causes muscle paralysis due to persistent depolarization, leading to inactivation of sodium channel .
68
what are the pros and cons of succinylcholine ?
Advantage: Very rapid onset and short duration of action (good for trauma care)
Disadvantage:
In overdose – paralysis of respiratory muscles – no
mechanism for reversing: must ventilate
AChE inhibitors only make paralysis worse
69
what is a competitive receptor antagonist function ?
opening of nAChR by its natural agonist-ACh
so as a competitive antagonist, it tried to keep the channel closed so there is no depolarization (non-depolarizing block)
it can be overcome by increasing amount of agonist (ACh)
clinical overdose- paralysis of breathing muscles
can be reversed with AChE inhibitors
70
what is the function of acetylcholinesterase (AchE) inhibitors
reduced the degradation of NT acetylcholine
71
what are clinical uses of AchE inhibitors?
Clinical use:
Can reverse actions of competitive receptor antagonist (muscle relaxants)
Myasthenia gravis – disease of decreased nAChR on skeletal muscle
Alzheimer’s disease
72
what is the relationship between Alzheimers and Ach ?
loss of Ach in neuron
early treatment is Ach esterase inhibitor
73
What does Donepezil do ?
Donepezil easily crosses the blood-brain barrier.
AChE inhibitor increases availability of ACh
Early on can slow progression of disease
Side effects-
-Inhibits all AChE
-Effects on CNS (hallucinations)
-Stimulates the autonomic nervous system resulting nausea, diarrhea, anorexia, abdominal pain, and frequent urination
74
What does Gaba do?
- Hyperpolarizes the membrane
- Gaba is inhibitory
Gaba hyperpolarizes the membrane
Valium doesn’t change the chlorine conductance
But use both together is is a greater effect
Benzos potentiate Gaba evoked Cl- channels
75
What is the relationship between Benzos and Gaba?
Benzos enhance the GabaA affinity receptor for GABA
76
what is the relationship between Gaba and and Barbiturates?
Increase the Duration of GABA channel opening
(they can be complete respiratory depressants)
(Liver can cause damage, due to high induced Cyp450 and acitivity)
77
what are MHC and function?
Allows T cells to recognize self from non-self
MHC proteins present peptides on the cell surface for recognition by T cells.
Immunogenic peptide–MHC class I (pMHCI) complexes are presented on all nucleated cells and are recognized by cytotoxic T cells (CD8+) .
Immunogenic peptide-MHC class II (pMHCII) complexes are presented on Antigen- Presenting Cells [e.g., dendritic cells, macrophages, or B cells] and activate CD4+ T cells, leading to the coordination and regulation of effector cells.
78
what are MHC1 proteins made of ?
They are in nucleated cells
single transmembrane proteins
made of alpha and beta peptides closed at both ends
79
What are MHC2 proteins made of?
alpha and beta peptides open at both ends
80
Describe innate immunity
Physical barriers- skin, mucous, tears.
Cellular/Biochemical barriers- specialized cells and secreted factors
Immediate response to an invader.
Does not require Immunologic Memory (i.e. prior exposure to an antigen).
Mainly recognizes broadly distributed antigen molecules rather than specific organism or cell- hence also called non-specific immunity
81
what cells are in the innate immunity ?
Phagocytic cells- ingest and invade antigens, can be facilitated when antigens have a coated antibody
Dendritic cells- (in skin, lymph nodes and tissues). Antigen Presenting Cell.
Natural killer cells -kill virus-infected cells and some tumor cells. Induce cell death (apoptosis) in host cells lacking MHC class I (sign of virus infection or cancerous cell).
Leukocytes-- neutrophils, eosinophils, basophils) and mononuclear cells (monocytes, macrophages, mast cells) release inflammatory mediators (cytokines).
82
what are NK cells
natural killer cells
- provide rapid response to virus infected cells and respond to tumor formation
- they have ability to recognize and kill stresses cells in absence of antibodies and MHC, allowing for a faster immune reaction
NK cells are identified in presence of CD56 and absence of CD3
83
Describe acquired/adaptive immunity?
Slower, second-level response to a novel antigen.
Requires prior exposure to an antigen.
Remembers prior response and is antigen-specific.
Mediated by Antigen Presenting Cells (APCs) and two types of
lymphocytes: T-cells and B-cells
84
Adaptive/acquired immunity is achieved by 2 types of immunity
- cell mediated immunity- using T cells CD8+ cytotoxic T cells, Helper T cells CD4+ cells, and memory T cells
Humoral (antibody mediated) immunty: using B cells
(plama B cells CD20+ and Memory B cells )
85
what happens in CTL
cytotoxic T cell recognizes infected cell with MHC 1 and antigen presentation on receptor,
CD8 are recruited interact with antigen, then release lysis of chemicals causing death to antigen cell
86
What is the role of APC in acquired/adaptive immunity?
- Exogenous antigen is phagocytosized, and mhc2 molecule is presenting it. on the AP
it processes it, and T cell recruits CD4 and then T helper cells bring T help cytokines, where there is B cell activation, T cell along with macrophage help.
87
what is in B cell mediated Humoral immune response?
Antigen binds to B cell
T helper cell comes (Th2 cytokines)
clonal proliferation
that can make 2 things
differentiate into plasma cell with antibody production happening
or Memory B cell happens for subsequent infection
88
what is the function of complemet cascade system
-The main function of complement proteins is to aid in the destruction of pathogens by cell lysis (via formation of the “membrane attack complex”)
- Or By recruiting phagocytic cells such as macrophages (via protein tagging- termed “opsonization”).
89
what is the Role of Tregs?
It functions to terminate immune response
it can do cell to cell contact and that can cause cell cycle arrest and apoptosis
It can reduce antigen presentation
It can reduce costimulation and prevent maturation
90
what are 2 types of immunization
active immunization-(long-lasting- adaptive immunity inducing) Covid, flu, chickenpox
passive immunization (short acting neutralizing antibodies) Natural artificial (mother to son) (Plasma or recombinant antibodies)
91
what is the purpose of a vaccine
Application of a vaccine that induces an adaptive immune response like a natural infection, but without associated disease.
92
what is the immune response when someone gets vaccinated ?
vaccine injected, macrophages are met, pick up antigens, migrated into lymph node, where we have T B cells.
T cells activate B cells then they bring in adaptive immune system
now there will be clonal expansion and immunological memory
93
what are 5 components of a vaccine?
Water
Residual traces
preservatives and stabilizers
active ingredient
adjuvants
94
what are 4 types of vaccines
Live-attenuated vaccine: weakened form of pathogens capable of replication,but not causing illness.
Inactivated vaccine: killed form of pathogens incapable of replication or infection.
Subunit vaccine: minimal antigenic element of a pathogen, for example, a protein, protein subunit or polysaccharides.
Peptide-based vaccines: peptides are fundamental element of a protein subunit recognized by the immune system; all antigens described above contain peptide epitopes
95
what is an adjuvant?
a stimulatory agent designed to boost immune response toward a co-delivered antigen. Occurs as-
independent entities’ in a mixture with antigens.
‘conjugate-entities’ via chemical fusion directly to antigens
96
Vaccine administration methods ?
Syringe: hypodermic needle used for intramuscular, subcutaneous or intradermal delivery of vaccine.
Implant: slow-release device containing vaccine for sustained subcutaneous delivery.
Microneedle patch: array of micrometer-scale needles containing vaccine for slow release, sustained
intradermal delivery.
97
what are recombinant mRNA vaccines?
Take mRNA encapsulate it, helps nanoparticle, once inside cell, it can produce gene of interest, and its on the surface of the cell
98
how are antigens packed in the vaccine ?
Viral Nanoparticle: include live-attenuated and inactivated viral vaccines.
Mammalian Viral Nanoparticles: repurposed mammalian viruses engineered to deliver a gene encoding the antigen (examples include adenoviral vectors derived from chimpanzee and human).
Proteinaceous Nanoparticles: nanoscale protein biomaterial assemblies engineered with atomic precision and complexity to present a subunit vaccine or deliver a nucleic acid encoding the antigen (e.g. include protein nanocages and non-infectious viruses such as plant viruses or bacteriophages).
Synthetic Nanoparticles: nanoscale assemblies of synthetic materials engineered to present a subunit vaccine or deliver a nucleic acid encoding the antigen (e.g. include polymer, liposomal, or lipid nanoparticles).
99
what are the inproxy methods for vaccine testing in humans
1) Hemmaglutination inhibition assay
2)Single Radial hemolysis SRH assay
3) Virus microneutralization (Mn) assay
100
how does the hemagglutination assay work ?
- Antibody virus and RBC get put it all in one, and set up for interaction
more dilute the serum the less antibody you have,
101
what does the SRH assay measure
measures complement mediated lysis of RBC coated with whole virus
virus infects the RBC, then maakes wells and introduced serum in wells
antibodies will bind to the viral particles of the sensitised RBC, which recruits the complement system
larger the surface of hemolysis, greater the antibody concentration
102
what is virus microneutralization do and measure
analysis of neutralizing antibodies by VNA
Z cells are infected
103
What is parts of an antibody that are therapeutically relevant parts ?
FV- variable fraction
FC- crystallisable fraction
Fab- antigen binding fraction (1/3) of antigen this is where the antigen bind too
104
how are class of antibodies differentiated?
by the FC region
105
what happens when you activate a complement system?
- Antigen-antibody complex fixes and activates complement
- the complement system enhances phagocytosis and inflammation and leads to cell lysis
106
Describe the ADCC and CDC mechanisms
these two mechanisms used by antibody drugs to kill targeted tumor cells
ADCC- antibody dependent cell-mediated cytotoxicity
- antibodies bind antigens on the surface of target cell
- NK cell cd16 Fc receptors recognize the cell bound antibodies
- cross linking of cd16 triggers degranulation into lytic synapse
- tumor cells die by apoptosis
CDC- complement dependent cytotoxicity
-antibodies binds to membrane surface antigens on target cells
-complement cascade is elicited, complement binds to the antibodies
- binding of complement leads to induction of membrane attack complex
- target cell dies of cell lysis
107
how are polyclonal and monoclonal antibodies made?
have an antigen put it in rat cells.
Then isolates spleen cells
take the b cells which are plasma cells
then hybridize them with melanoma cells
the melanoma cells are hgprt negative
they then are in HAT medium, only ones with hgprt antibodies survive
108
how are antibodies cleaved?
Dipeptide bonds are cleaved 2 ways
pepsin cleavage- makes 2 Fab fragments
papain cleavage- creates 2 Fab fragments and one Fc fragment (the 2 fab is where the antigen binds)
109
how to make recombinant antibodies?
We have antibody library. We have isolated B cells, the business end get replicated and transform them in bacteria. Then we have phage infection, we have a phage library, and human antibody fragments.
Then you pick the phage, amplify it, then put it into a vector, and put it in a mammilan cell, translation happens.
It then gets secreted and purified
110
What are antibody drug candidate examples
Amantin it inhibits RNA polymerase 2, which results in apoptosis
It is an antibody that targets tumor antigen
111
what are bispecific antibodies?
- Bispecific antibodies are antibodies that can simultaneously bind to 2 separate and unique antigens.
The primary application of BsAbs have been to redirect cytotoxic immune effector cells for enhanced killing of tumor cells by antibody-dependent cell-mediated cytotoxicity (ADCC) and other cytotoxic mechanisms mediated by the effector cells.
112
how to make recombinant bispecific antibodies
The mammalian Chinese Hamster Ovary (CHO) cells are co-transfected with separate plasmids containing heavy or light-chain gene for a half-antibodies.
Secreted antibodies are assembled by GSH induction. GSH: reduced glutathione
113
what is the function of complement cascade system
-The main function of complement proteins is to aid in the destruction of pathogens by cell lysis (via formation of the “membrane attack complex”)
- Or By recruiting phagocytic cells such as macrophages (via protein tagging- termed “opsonization”).
114
in what phases do you study people
Phase 1 studies (20 to 80 healthy volunteers) (PK and toxicity evaluation).
Phase 2 studies (few dozen to about 300 patients).
Phase 3 studies (several hundred to about 3,000 patients).
115
what are the goals of drug design?
The goal is to have strong, selective target binding and functional efficacy
- Structure based design
- structure- activity relationship
The goal is to overcome in vivo barriers
116
what are some drug absorption barriers
pH
Efflux transporters
Cell membranes
Metabolic enzymes
Binding proteins
117
absorption in stomach is limited due to ?
Relatively low surface area (~ 1 m2).
Relatively low blood flow around the stomach.
Relatively short stay (0.5 – 1 hour).
Acidic environment which can cause chemical instability.
Hydrolytic gastric enzymes which could breakdown the drug.
118
what are barriers in the bloodstream
Enzymatic hydrolysis
Plasma protein binding
Red blood cell binding
119
what does plasma enzymatic hydrolysis do ?
Large number of enzymes present in blood
Substrate specificity and amounts varies with species, gender, age, race and disease state
Most common reaction is hydrolysis
Functional groups that are susceptible include- ester, amide, carbamate, lactam, lactone, sulfonamide
120
what does plasma protein binding do in terms of sequestering barriers in the bloodstream?
Approximately 6 to 8% of plasma is protein.
Three types of binding proteins are-
-->Albumin
-->1-acid glycoprotein
-->lipoproteins
Drugs bind reversibly to these proteins.
Reduces drug available for binding to target receptor
Affects drug clearance rate
121
what does RBC cell binding do in terms of sequestering barriers in the bloodstream
RBC comprise about 95% of the total blood cells.
There are three major components in the erythrocyte capable of binding drugs-
-Hemoglobin,
-Carbonic anhydrase
-Cell membrane
Drugs can bind and/or be transported into RBCs reversibly.
Impacts PK characteristics-
-Reduces drug available for binding to target receptor
-Affects drug clearance rate.
122
what are barriers in the kidney
Solubility
Permeability
Paracellular transport
Passive diffusion
Efflux transport
Uptake transport
123
what is a dissolution rate? and how do you increase it?
Dissolution rate is how fast a compound can dissolve into solution. Enhances absorption.
strategies
Reduce particle size (increase surface area)
Prepare an oral solution
Formulate with surfactants
Prepare a salt form
124
what are some problems low solubility compounds have ?
Poor absorption and bioavailability after oral dosing
Insufficient solubility for intra venous (IV) dosing
Artificially low activity values from bioassays
Erratic assay results
Expensive formulations and increased development time
Frequent high-dose administrations which is not ideal
125
what are physicochemical properties that affect solubility?
Size: molecular weight and shape (smaller more soluble)
pKa: functional group ionizability (ionized more soluble)
Lipophilicity: hydrophobicity (less lipophilic more soluble)
Crystal lattice energy: crystal stacking, melting point (lower lattice energy more soluble)
126
what is the relationship between solubility and permeability?
- as solubility increases with more ionized forms at higher pH, permeability goes down
127
what are strategies to improve solubility?
add ionizable groups; basic amine or carboxylic acid
Reduce Log P
Add hydrogen bonding: donors (OH) and acceptors (NH2)
Add polar group
Reduce molecular weight
Out of plane substitution: disrupts crystal packing
Construct prodrug: cleaved in vivo to release drug
128
describe solubility in the GI tract
(function of pH and pKa)
Basic compounds are charged (ionized) in the stomach and upper intestine.
Acidic compounds are charged (ionized) as the pH increases through the intestine.
The ionized forms are soluble.
Lipophilic compounds are solubilized by bile acids (acts like detergent) from the gall bladder.
129
what is efflux
energy dependent removal of drug from cells back into lumenal space (reduces drug concentration)
Done by efflux transported
Facilitates the export of drugs from the cell which minimizes the exposure of the drug to the therapeutic target.
They belong to the ATP-binding cassette (ABC) family which include-
-P-glycoprotein (Pgp) efflux transporter (also called MDR1 or ABCB1)
-Breast Cancer Resistance protein (BCRP, ABCG2)
-Multidrug Resistance protein 2 (MRP2, ABCC2)
130
what are permeation pathways in the GI tract
Efflux transport and passive diffusion
paracellula transport through tight junctions
endocytosis
131
what is the predominant permeation mechanism for most drugs?
Passive diffusion is the predominant permeation mechanism for most drugs (~ 95%).
-Molecular weight (size) of compound (small pass easier)
-Lipophilicity of compound (lipophilic compounds pass easier)
-pH and pKa plays a major role in permeability. (ionized molecules are less permeable)
132
what is pgp efflux transporter
wide spread expression
very broad substrate specificity
133
what are the rules for pgp substrates
A drug is more likely to be a Pgp substrate if its structure has-
N+O > 8 (number of hydrogen bond acceptors)
MW > 400
Acids with pKa> 4
A drug is less likely to be a Pgp substrate if its structure has-
N+O < 4 (number of hydrogen bond acceptors)
MW < 400
Base with pKa < 8
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what is permeability ?
Velocity of compound passage through a membrane barrier
135
what are modifications to improve permeability?
Reduce ionizability: convert ionizable groups to non-inoizable groups
Increase lipophilicity: increase Log P
Esterify carboxylic acid
Isosteric replacement of polar group. Add nonpolar side chain
Reduce molecular weight
Reduce hydrogen bonding and polarity
Construct prodrug: cleaved in vivo to release drug
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what are in vitro models for testing permeability ?
MDCK
Caco-2
PAMPA- uses as a non cell based in vitro model of passive, transcellular permeability
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what is pardridge rules of 2 for CNS drugs
Poor drug CNS penetration if
– H-bonds > 8-10
– MW > 400-500
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pka relationship with BBB penetration
low pka have poor brain ependratoin
CNS drugs tend to contain basic nitrogen, allowing for greater penetration
139
what is the relationship of H bonds on BBB penetration
Reducing total number of H bonds increases BBB permeation
140
what is drug stability ?
the susceptibility of a compound to break down?
141
what is a stability barrier in the Gi tract
Drug molecules can be metabolized by the cytochrome P450 3A4 (CYP3A4) isozyme present in the intestinal epithelial cells.
Wide variety of GI enzymes from pancreas, stomach, saliva etc. can catalyze drug hydrolysis.
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stability barriers in the liver?
Metabolism
Phase I
Phase II
High rate of metabolism results in rapid clearance, low exposure and low bioavailability
Biliary excretion
Part of metabolized/unmetabolized drug moves into bile by passive diffusion and active transport.
Moves to the gall bladder from where it is released into the small intestine and eventually excreted
143
what are stability barriers in the bloodstream?
Plasma has large number of hydrolytic enzymes that decompose drugs
144
what modification strategies improve plasma stability
Substitute an amide for an ester
Increase steric hindrance
Eliminate the hydrolyzable group
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Difference btw phase 1 and phase 2 metabolism
Phase I Metabolism: (oxidation and reduction) Mediated by
-The cytochrome P450 (CYP) family
-The flavine monooxygenase (FMO) family
Phase II Metabolism: (addition of polar moieties) Include-
Glucuronidation
Sulfation
Acetylation
Amino acid conjugation
Glutathione conjugation
Methylation
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how to make a drug more metabolically stable for phase 1 metabolism?
Add fluorine, chlorine or nitrile
Remove labile functional group
Change ring size and/or chirality
Reduce lipophilicity
- remove fucntional group that is targeted by cp450,or change size so it wont fit in pocket of cp450
147
how to make a drug more metabolically stable for phase 2 metabolism?
Introduce electron-withdrawing groups & steric hindrance
Change phenolic hydroxyl to cyclic urea or thiourea
Change phenolic hydroxyl to prodrug
148
what is lipinski's rules
Rules derived by examining the structural properties of compounds that passed Phase I human clinical trials (involves toxicity and PK studies
Experimental and computational approaches for estimation of absorption of new drug candidates.
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what is lipinski's rules
Rules derived by examining the structural properties of compounds that passed Phase I human clinical trials (involves toxicity and PK studies
Experimental and computational approaches for estimation of absorption of new drug candidates.
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in lipinski rule, there is poor absorption when what?
There are more than 5 H-bond donors.
The molecular weight is over 500.
The LogP is over 5.
There are more than 10 H-bond acceptors
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what is toxicity defined by
duration and frequency of exposure
151
how is toxicity affected?
- by routes and sites of deliver/ exposure
152
what is toxication and how is it done
Toxication: Biotransformation to harmful products
Increased reactivity due to conversion into-
electrophiles: positively charged species
free radicals: unpaired electrons
nucleophiles: can donate electron-pair
redox-active reactants: electron accepting transition metals and organic molecules
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what is an example of toxication?
- superoxide happens makes hydrogen peroxide
free raidcals are made like nitrogen dioxide, carbonate anion radical, hydroxyl radical
154
example of toxication with biotransformation
tylenol and cyp3a4 makes NAPQO
too much of that results in hepatic toxicity and reaction with proteins and nucleic acids
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what is detoxication
Biotransformation that eliminates or prevents formation of harmful products
Detoxication of -
toxicants with no functional groups
electrophiles (positively charged groups that are attracted to electron rich groups)
nucleophiles (compounds that can provide electron pair)
free radicals
protein toxins
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what is an example of detoxication?
Detoxication of superoxide anion radical by
superoxide dismutase (SOD),
Glutathione peroxidase (GPX)
catalase (CAT)
156
what is an example of detoxication?
Detoxication of superoxide anion radical by
superoxide dismutase (SOD),
Glutathione peroxidase (GPX)
catalase (CAT)
157
Give a break down of the allergic reaction?
1) initial contact with allergen on B cell
2) plasma cell relased IgE antibodies
3) mast cell comes
4) subsequenct contact with allergen
Chemical allergy (hypersensitivity) is an immunologically mediated adverse reaction that results from previous sensitization to a particular chemical or to one that is structurally similar.
Once sensitization has occurred, allergic reactions may result from exposure to very low doses of chemicals.
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what is a idiosyncratic reaction and give an example?
abnormal reactivity to a chemical we dont know why it happened.
hemoglobin interacts with nitrate
makes methemoglobin that does not carry o2, then use cytochrome b5 reductase to reverse that back to normal hemoglobic
Genetic mutations that reduce Cytochrome-b5 reductase activity in some individuals- makes them more sensitive to nitrites – suffer tissue hypoxia
hot dog supermarket nitrate free goods
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what is a idiosyncratic reaction and give an example?
abnormal reactivity to a chemical we don't know why it happened.
160
local vs systemic toxicity
Local Toxicity
--Occurs at the site of first contact
--Can be caused by ingestion of caustic substances or inhalation of irritant materials. e.g., chlorine gas reacts with lung tissue
systemic toxicity
Requires absorption and distribution of a toxicant from its entry point to a distant site, at which toxic effects are produced.
The target organ of toxicity is not necessarily the site of accumulation
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what are agonistic interactions?
Additive effect
The combined effect of 2 chemicals is equal to the sum of effects of each agent, i.e., 2+3 =5.
Synergistic effect
Combined effects are much greater than the sum of each, i.e., 2+3 =20
Potentiation
One chemical is not toxic, but makes another much more toxic
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what are antagonistic intereractions
Functional (Physiologic) antagonism
Two chemicals produce opposite effects on the same physiologic function
Chemical antagonism
Reaction between 2 chemical to neutralize the effects, i.e., inactivation
Dispositional antagonism
– alteration of the disposition (absorption, biotransformation, distribution, excretion) of a substance so that the concentration or duration of the agent at the target organ is reduced
Receptor Antagonism (blockers)
– Two chemicals that bind to the same receptor produce less of an effect when given together or one chemical antagonizes the second chemical
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describe small molecule pharmaceuticals and what is its main toxicity concerns ?
oral administration
short half life, frequent dosing
Main toxicity concerns:
-off-target toxicity
-metabolites
-drug-drug interactions
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what are large molecule pharmaceuticals (biologics) and their main concerns?
Isolated from a variety of natural sources - human, animal, or microorganism. e.g., vaccine, recombinant proteins, antibodies.
Are complex mixtures that are not easily characterized
Usually not by oral admin (b/c breakdown by GI enzymes)
Regulated by FDA CBER (center for biologics evaluation and research)
Main concerns:
species restriction (should use relevant species, i.e., expresses the receptor or epitope)
immunogenicity (e.g., antibody response)
exaggerated pharmacologic effects
long half-life → chronicity of exposure and toxicity
cross-react with normal tissue
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what is in silico toxicity methoiuds
Algorithms that encompass information derived from in vivo and in vitro studies; they consider molecular interactions, biological data, pharmacological results and toxicological endpoints;
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what is invitro toxicity methods
Cytotoxicity
Is the killing of viable cells by the test compounds. Hepatocytes are typically used because both the test compound and its metabolites can cause toxicity
- LDH is released from damanged cells
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what is in vitro toxicity methods with drug- drug interactions
Drug-Drug Interactions:
When one drug alters the pharmacokinetics of a co- administered drug. This effect is most often the result of drug- induced induction or inhibition of cytochrome P450 enzymes
CYP inhibition/ CYP induction
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What is in vitro toxicity with cardiac
cardiac toxicity- long QT and arrhythmia
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what is hERG pottasium ion channel
Contributes to the electrical activity of the heart that coordinates the heart's beating- specifically the hERG channel mediates the repolarizing IKr current in the cardiac action potential.
if inhibited by drug or by rare mutations, it results in long QT syndrome.
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In vitro toxicity methods chemical carcinogens can be broken into 2 groups
genotoxic carcinogens interact with DNA (directly affect)
- found in broiled goods, cigarettes smoke, they are unreactive themselves, but are converted to electrophilic intermediates and they cause DNA mutations
non-genotoxic carcinogens (promoters)
- do not produce tumors alone, but do potentiate the effects of genotoxic carcinogents
171
what are genotoxicity and carcinogenicity tests
Genotoxicity tests:
Can detect genotoxic carcinogens but not promoters
Short-term, can be completed within a few days
Carcinogenicity tests
- can detect both promoters and genotoxic carcinogens
-Chronic. Treat rodents for their entire life span. Autopsies and histopathological examinations are performed after the treatment to determine the incidence of tumors in treated vs control animals.
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what go geneotoxiciy tests see ?
Genetic alterations can be gene mutations or changes in chromosome structure and number
ames test
172
what go geneotoxiciy tests see ?
Genetic alterations can be gene mutations or changes in chromosome structure and number
ames test
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what is the chromosomal aberration assay
Treat cells (e.g., Chinese hamster ovary (CHO), human peripheral lymphocytes) during a sensitive period of cell cycle, analyze aberrations at the first mitotic division after treatment.
Cells are stained and chromosomal aberrations are recorded, e.g., chromosome breaks, terminal deletions, rearrangements, and translocations. Through karyotype analysis
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what is a type of in vivo test
In vivo micronucleus tests (MNT):
Treat animals with chemicals, the frequency of micronucleated cells is determined microscopically at specified time after treatment
if you have a micronucleus, then you have a toxic component
micronuclei- are chromatin containing bodies that represent chromosomal fragments that were not incorporated into nucleus during mitosis
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compare contrast neonates and elderly drug distribution
Neonates and infants have
-increased percetange of body water
- decreased body fast
- increased volume Distro for water soluble drugs
elderly
- decreased percent body water
- increased body fat
- increased VD for lipophilic drugs
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as you get older what happens to drug metabolism and excretion
It gets slower
177
what is polypharmacy
use more drugs that any other age group, increased potential for durg drug inreaction and makes adherance more difficluy.
177
what is polypharmacy
use more drugs that any other age group, increased potential for durg drug inreaction and makes adherance more difficluy.
178
describe pharmacokinetics of infants
- rapid drug delivery usually accompanied by slow elimination
- slow drug delivery results in high peak concentration as well as slow elimination
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what leads to drug toxicity for children/infants
- depressed renal function and decreased rate of biotransformation
- drugs accumulate to toxic levels, need to keep spacing doses
example adult have chloramphenicol, it is conjugated and excreted rapidly due to kidneys
in newborn- most chloramphenicol is free, poorly eliminated urine.
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what are drugs that are toxic to children
- phenobarbital/ morphone
opiods such as these penetrate brain in much higher concentrations because of poorly developed BBB
180
what are drugs that are toxic to children
- phenobarbital/ morphone
opiods such as these penetrate brain in much higher concentrations because of poorly developed BBB
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why are drug affects unpredictable in mothers?
-absorption and distribution increased
-- but there is one aspect of distribution which is protein binding is decreased, due to decrease plasma proteins
biotransformation can have increased levels or decreased
excretion is increased, due to increased glomerular filtration.
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Thalidomide relevance on fetus?
- it was a OTC medication for morning sickness.
babies were born with missing or badly malformed limbs
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General disease symptoms with effect on PK
Body temperature (e.g. fever)
Water content – e.g. Overhydration (edema) or dehydration affects volume of distribution
pH – acidosis or alkalosis (metabolic or respiratory)
Altered rate of distribution or excretion
184
break down the allergic reaction severties
Minor: immediate response to histamine release
-Similar to hay fever or food allergy;
-Respiratory and GI, blood vessels,
-hives (IgE mediated)
intermediate
-Maculopapular rash (T-cell mediated)
-Difficulty breathing, swelling of mucous membrane, fall in blood pressure.
Major anaphylaxis
Anaphylactic shock – death can occur within few minutes from complete obstruction of respiratory passages and precipitous drop in blood pressure
185
Describe drug tolerance and drug resistance
Tolerance is a subject’s diminished response to a drug after prior or repeated use.
Characterized by requiring increasing doses to achieve
same effect.
tolerance disappears when administration is discontinued
Resistance is a property of the drug target. It is the ability of pathogens, cancer cells, or organisms to withstand the effects of drugs or pesticides usually effective against them
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Describe drug disposition tolerance
Decrease in effective concentration of drug at site of action
Drug may reduce its absorption or transfer across biologic barrier or increase its rate of elimination
-Phenobarbital, ethanol, opioids increase their own rates of biotransformation through stimulation of microsomal enzyme systems, particularly of CYP family
-Alcohol induces synthesis of alcohol dehydrogenase
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Describe cellular tolerance
This is Pharmacodynamic
develops more slowly
Accounts for most tolerance in CNS mood-behavior
Often caused by adaptation in neurons which makes them
insensitive (e.g. decreased number of receptors)
Or changes in circuitry (e.g. increased glutamate neuron activity with alcohol or other general CNS depressants acting through GABA neurons)
Cross Tolerance
Individual who develops tolerance to one drug may be tolerant to
drugs acting on same receptor or same system
e.g. Individual tolerant to opioids is cross-tolerant to heroin, oxycodone, etc but not alcohol or barbiturates
e.g. Alcoholics are partially tolerant to barbiturates, but not to opioids
188
How to overcome drug tolerance pharmacodynamic vs phamarco kinetic?
pharma kinetic- increased drug amount
pharmadynamic- you cannot
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what does methotrexate do?
It causes resistance due to decreased intracellularly availability
- resistance due to decreased entry
methotrexate is a inhibitor, cancer cells can become resistant to it, due to mutations in reduced folate carrier
190
describe drug Resistance due to efflex
Increased expression of a drug (efflux) transporter
ATP-binding cassette (ABC) family
-Facilitate export of drugs from cell
-Very broad substrate specificity
191
causes of drug resistance in microorganisms
Decreased intracellular drug availability
-Decrease rate of entry
-Increase in efflux transporters
-----Chloroquine resistance malaria
Increase of specific inactivating enzymes
--Resistance to penicillin: bacteria (microorganism) produces enzyme penicillinase which hydrolyzes penicillin to inactive metabolite
Decreased affinity of drug for its target
--Genetic modification that alters protein which is specific target of drug
---TB resistance to Rifampin - mutations in alpha-subunit of RNA polymerase
---TB resistance to Isoniazid - mutations in enzyme that builds cell wall
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Describe MDR-TB
Definition of MDR-TB: TB that is resistant to one of 2 front-line drugs: rifampin (rifampicin) and isoniazid
Example: Rifampin resistance is due to mutation in
beta subunit of bacterial RNA polymerase.
Isoniazid interferes with cell wall synthesis. At least two separate mutations makeup MDR-TB
193
what are 2 ways drug resistance happens
natural selection
infectious drug resistance
194
drug drug interaction can be broken into
Pharmacodynamic interaction
the pharmacological actions of one drug are affected by another drug.
Pharmacokinetic interaction
one drug can affect the absorption, distribution, biotransformation or excretion
195
drug drug interactions can enhance the beneficial effect how?
Additive or summation effects
-Codeine (opioid analgesic) and aspirin (anti-
inflammatory) – both relieve pain, 2 different mechanisms
-Aspirin and acetaminophen – both inhibit
cyclooxygenase and prostaglandin synthesis resulting in reduction of fevers.
Synergism – joint effect greater than algebraic sum
-Two drugs acting at different sites and one drug, the synergist, increases the effect of the second drug by altering its pharmacokinetics
-e.g. probenecid (reduces renal excretion) and ß- lactam antibiotics; e.g. ampicillin
196
describe drug- drug interactions that are catastrophic
unanticipated toxicity
Treating depression with selective serotonin reuptake
inhibitors (SSRI), e.g. Prozac and monoamine oxidase (MAO) inhibitors can cause “Serotonin Syndrome”.
MAO metabolizes monoamines (dopamine, norepinephrine, serotonin (5HT))
MAOI and SSRI together: YDA / NE/ 5HT neurotransmitters at synapses in CNS ➔ Seizures, delirium, high fever, and death
Opioid analgesics (fentanyl) are also SSRIs.
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what are types of drug antagonism?
1. Pharmacologic antagonism
2. Physiological antagonism
3. Chemical antagonism
4. Biochemical antagonism
198
what is pharmalogic antagonism?
Drugs compete for binding at same receptor
e.g. Naloxone reverses effects of opioid drugs (fentanyl) by binding to μ-opioid receptors – naloxone is a pure antagonist.
199
what is physiologic antagonism
Two agonists, acting at different receptors, produce opposite effects on same physiologic function
e.g. α1-adrenergic agonists increase blood pressure by constricting blood vessels, whereas histamine is a vasodilator and decreases blood pressure. Each agonist acts on own receptor producing opposing actions on BP
200
what is chemical antagonism
Agonist and antagonist react with each other to form an inactive product
-bicarbonate and gastric secretions
heparin and protamine sulfate
201
what is biochemical antagonism?
Opposite of synergism: one drug indirectly
decreases the circulating levels of a second drug.
Modifies Pharmacokinetics – ADME
-Example 1: Barbiturates and some antibiotics (rifamycins) are inducers of CYP450 enzymes in the liver. Increases in the
clearance of drugs metabolized by the same CYP450 enzyme,
e.g. HIV antiretroviral drugs.
– Example 2: Laxatives increase GI motility & result in
decreased absorption of other drugs
202
how can food can affect drug absorption
Presence of food often decreases drug bioavailability
Co-administration of some drugs with acidic beverages such as coke (pH<3) can alter absorption
grapefruit contains furanocoumarin which decreases intestinal protein levels of cyp3a4 which potentiates activity of various drugs
(calcium channel blockers, immunosppressants)
203
Foods can increased metabolism explain now
Indole-3-carbinol from cruciferous vegetables (broccoli, bok choy family) is a strong inducer of the liver microsomal cytochrome P450 enzymes, CYP1A1 and CYP1A2. CYP1A1 and CYP1A2 metabolizes tricylic antidepressants, some anti-psychotics.
204
describe the relationship between MAO inhibitors and tyramine
The combination MAO inhibitors and eating foods rich in tyramine can have toxic, potentially lethal, effects
Tyramine is produced by the breakdown of an amino acid called tyrosine and helps to regulate blood pressure.
Tyramine rich foods include:
Certain cheeses (Camembert, Cheddar, Stilton,
Roquefort)
Pickled herring, red wine, chicken liver
MAO (Monoamine oxidase) metabolizes norepinephrine
and serotonin and other monoamines including tyramine
In presence of MAO inhibitors, tyramine levels increase, causing sharp rise in blood pressure, including fatal cerebral hemorrhage
205
What can SNP mutations do ?
affect any stage of biotransformation process
6-MP – 6-mercaptopurine
Alcohol metabolism
Adverse drug reactions to Cyp-450 family of enzymes
-Tamoxifen
-Isoniazid – a TB drug
206
SNP mutation in 6MP does what
it affects TMPT, an enzyme involved in 6MP metabolism. It affects the levels of active and inactive metabolites
6MP is usually inactive, that requires bioactivation into a cytotoxic, immunosuppressive drug
- used to treat leukemia and IBD
ig mutation in TMPT happens it covertes 6MP into 6TGN an active form that inhibits purine synthesis, and others will be inactive.
TMPT usually converts 6MP to inactive metabolites.
207
CYP2D6 polymorphisms and response to tamoxifen cause what?
so a higher cyp2d6 activity produces levels of endoxifen, which is an active metabolite to be above therapeutic threshold
208
how is isoniazid metabolism in 2 pathways
Isoniazid acetylated by NAT2 enzyme results in rapid metabolism and non-toxic metabolites
Isoniazid metabolized through CYP450 is slower and
results in toxic metabolites
