Pharmacology Flashcards
1
Q
Glucocorticoid
A
- endogenous steroid hormone produced and released by adrenal gland
- exogenous analogs are used anti-inflammatories and immunsuppressives
2
Q
3 classes of corticosteroids, their roles, and their endogenous sources
A
- mineralocorticoids - Zona glomerulosa
- salt/water retention
- glucocorticoids - Zona Fasiculata
- immunity and metabolism
- androgens/estrogens- Zona Reticularis
- sexual function
3
Q
Endogenous regulation of glucocorticoid production
A
- HPA: CRF–> Ant. Pit. –> ACTH–> corticosteroids
- negative feedback from glucocorticoids and ACTH
4
Q
Negative effects of glucocorticoids
A
- Metabolic: gluconeogenesis, lipolysis, lipgenesis
- Catabolic: protein catabolism, wasting, osteoporosis
- Other: Na homeostasis, behavior
5
Q
Anti-inflammatory effects of glucocorticoids
A
- decrease T cell production of IFN gamma
- reduce macrophage production of Il1 and TNFalpha
- reduce mast cell production of histamine, NO, prostaglandins
- inhibition of PLA2
- decrease mRNA Cox
- decrease IL2,3
- decrease antibodies
6
Q
Immunosuppressive effects of glucocorticoids
A
- cell mediated immunity
- reduced proliferation of lymphocytes, neutrophils, and monocytes
7
Q
Glucocorticoid Receptor and 4 domains
A
- intranuclear steroid hormone receptor family
- 4 functional domains
- ligand binding domain-gr interaction with chaperones Hsp90 and Hsp56
- DNA binding domain-binds to DNA GRE response element within promoter of target gene
- C terminal AF2-ligand dependent transactivation domain; interacts with co activator or cosuppressor proteins that optimize receptor induced gene transcription; recruited to ligand receptor complex after steroid binds GR
- N terminal AF1- ligand dependent transactivation domain; constitutive interaction with receptor complex
8
Q
Ligand-binding domain of glucocorticoid receptor binds to
A
chaperone proteins Hsp 90 and 56
9
Q
DNA binding domain of glucocorticoid receptor binds to
A
glucocorticoid response element (GRE) on promoter in DNA of specific gene
10
Q
C-terminal AF2 of glucocorticoid receptor binds to
A
coactivator/cosuppressor proteins that optimize receptor induced gene transcription
11
Q
N-terminal AF1 of glucocorticoid receptor binds to
A
constitutively to transcription machinery of the cell
12
Q
Glucocorticoid MOA
A
- GR/Hsp resides in cytoplasm in a ligand friendly complex
- binds to hormone in the cell and dissociates from chaperone
- steroid receptor complex translocates to the nucleus and binds target gene
13
Q
Lipocortin effect
A
when gene bound by glucocorticoid –> increased expression of lipocortin –> downregulates PLA2 –> decreased synthesis of PGs and leukotrienes
*gc can also inhibit IL6/8
14
Q
Factors optimized in synthetic production of glucocorticoids
A
- limit salt-retaining properties (a la mineralocorticoids which are endogenous)
- improve anti-inflammatory response (via double bonds, 3 keto and oh groups)
15
Q
Glucocorticoid-physiological doses
A
- replacement therapy to treat adrenal insufficiency (mimic physiology)
- need to maintain negative feedback loop –> otherwise disrupt homeostasis (e.g. interrupt growth and development in kids)
16
Q
Glucocorticoid-supra physiological doses
A
- anti-inflammatory effect
- immunosuppressive
17
Q
Glucocorticoid toxicities
A
- HPA suppression–> no endogenous cortisol
- electrolyte imbalance (Na retention/K excretion)
- Infection from immunosuppression
- Osteoporosis from inhibition of osteoblast activity
- Hyperglycemia
- Cataracts
- Growth retardation
- Behavioral changes
18
Q
Sudden withdrawal of therapeutic glucocorticoids can lead to acute adrenal insufficiency because of reduced endogenous cortisol production called
A
Addisonian crisis
19
Q
Immunosuppressives-indications
A
- organ/tissue transplant
- treatment of autoimmune diseases
- treatment of inflammatory conditions like asthma
20
Q
Immunosuppression most effective in
A
prophylaxis: primary/initial steps prior to immunologic memory
- antigen presentation
- cell proliferation
- lymphokine synthesis & differentiation *immunosuppressants don’t have a uniform effect on all steps of immune response *prophylaxis is key
21
Q
Stages of immunosuppression
A
- Induction - T cell depletion and prevention of activation
- Maintenance - prevention of T cell activation/cytokine production
- Treatment of Rejection or Disease Flare
- Tapering
22
Q
Key risks during immunosuppression
A
- Infection
- donor-derived opportunistic
- worsening of pre-existing conditions
- Malignancy
- donor derived pre-existing
- de novo
23
Q
of medications needed for immunosuppression
A
- 3 rejection
- 3 infection
- 3-5 non-immune and metabolic regulators (e.g. statins)
24
Q
IFN gamma, IL 2 and TNF alpha are produced by
A
Th1 –> cellular response
25
Il4, 5, and 13 are produced by
Th2 cells --\> B cell/humoral response
26
IL 17, 21, and 23 are produced by
Th17 --\> can mediate steroid resistant rejection
27
IL10 and TGF beta are produced by
Treg cells
28
Three signal model
1. MHC vs TCR
2. B7 vs. CD28
3. IL2 vs CD25/IL2R
29
Anti-CTLA4 Ig (against CD80/86)
* Belatacept --\> blocks B7 which allows CTLA4 to bind to CD28 --\> anergy/apoptosis
* compare to Ipilimumab --\> binds to CTLA4 --\> constitutively on
30
Anti-CD25 Ig
Basiliximab: targets CD25 chain in IL2 receptor on t-cell (induction but not rejection)
31
Polyclonals used in immunosuppression
1. equine anti-thymocyte globulin (eATG)
2. rabbit (rATG)
* bind to t-cells --\>deplete circulating lymphocytes --\> use for **induction and rejection**
32
Challenges to using polyclonals
1. mass production
2. toxicity/serum sickness
3. immunosuppression (profound)
33
34
Which kinds of patients do we give belatacept to?
EBV+
35
Toxicities and risk of Belatacept
* PTLD
* anemial, hypertension, UTI, GI, fever
36
MOA of calcineurin inhibitors
1. bind to immunophyllin (c-proteins)
2. drug-protein complex binds to calcineurin phosphatase
3. **prevents** dephosphorylation and t**ranslocation of nuclear factor of activated T cells**
37
What does the calcineurin inhibitor tacrolimus bind to?
FK binding protein 12
38
What does the calcineurin inhibitor cyclosporine bind to?
cyclophillin
39
Common toxicities of calcineurin
1. nephrotoxicity
2. hyperglycemia
3. hypertention
40
Neurotoxicity is associated with which calcineurin inhibitor?
tacrolimus
41
Gingival hyperplasia is associated with which calcineurin inhibitor?
cyclosporine
* hypertension/hyperlipidemia/hyperuricemia too
42
What class of drugs do we not want to administer with calcineurin inhibitors and mTOR inhibitors?
CYP3A-related drugs
43
MOA of mTOR inhibitors
1. bind to FKBP
2. inhibits mTOR
3. decrease cytokine dependent cell proliferation of T-cells
44
Common toxicities of mTOR inhibitors
leukopenia, thrombocytopenia, wound healing impairment, pneumonitis, peripheral edema
45
2 important mTOR inhibitors
tacrolimus and everolimus
46
3 drugs that prevent lymphocyte proliferation
1. Azathioprine --\>blocks de novo and salvage purine --\> S phase arrest
2. Mycophenolic mofetil --\> blocks de novo purine synthesis --\> S phase arrest
3. Methotrexate --\> DHFR blocker-pyrimidine --\> S phase arrest
47
What drug should we prescribe with azathioprine (low dose)
Allopurinol --\> blocks xanthine oxidase --\> need less azathioprine (which is broken down by xo)
48
Common toxicities of DNA blockers
leukopenia, anemia, thrombocytopenia, liver dysfunction, lung disease, skin cancer, GI
49
What drugs do we use for induction therapy?
1. Basilixumab
2. rATG/eATG
50
What drugs do we use for maintenance immunosuppression?
1. corticosteroids
2. calcineurin inhibitor
3. mTOR inhibitors
4. belatacept
5. azathioprine/mmf/mpa
51
What drugs do we use to manage acute rejection?
1. high dose pulse steroids
2. rATG, eATG
52
Drug
chemical entity that affects living protoplasm
53
medicine
chemical entity used to treat, cure, prevent, and diagnose disease
54
Pharmacokinetics
what happens to a drug when given to a patient
55
Pharmacodynamics
the body's response to a given drug
56
Routes of administration
* Enteral- oral, rectal, sublingual
* Parenteral- IV, IM, SubQ
* Other- transdermal, topical, inhalation, intranasal
57
Key advantages and disadvantages of oral administration
* Advantages: ease, cost, outpatient
* Disadvantages: complicated, variable response, gastric pH, food, first pass effect, biotransformattion
58
First pass effect
* concentration of a drug is greatly reduced before it reaches the systemic circulation
* the fraction of lost drug during the process of absorption w/biotransformation--\> hepatic/gut wall
59
Key advantages and disadvantages of rectal administration
* Advantages: ease, outpatient, cost, tolerability
* Disadvantages: some first pass effect, slightly complicated/variable response, hepatic biotransformation
60
Key advantages and disadvantages of sublingual administration
* Advantages: ease, outpatient, no first pass
* Disadvantages: cost, taste, limited formulations
61
Which modes of administration avoid the first pass effect?
Sublingual, Parenteral, Transdermal, Topical, Inhalation, Intranasal
62
Key advantages and disadvantages of IV administration
* Advantages: no first pass, control of dose, rapid onset
* Disadvantages: invasive, cost, overdose, inpatient
63
Key advantages and disadvantages of IM administration
* Advantages: no first pass, fast onset aqueous/slow response non aqueous
* Disadvantages: pain, cost, supervision
64
Key advantages and disadvantages of SubQ administration
* Advantages: no first pass,aqueous fast onset, slow sustained (nonaqueous)
* Disadvantages: invasive, cost, supervision
65
What factor determines absorption of transdermal drugs?
Lipid solubility
66
What is a limiting factor in inhalation-based administration?
molecular size of drug
67
What mode of administration guarantees 100% bioavailability?
IV
68
What does the HH equation tells us about drug delivery?
what proportion of drug is uncharged at a given pH --\> how much of drug will be absorbed
69
Bioavailability
Proportion of drug that reaches systemic circulation in an unchanged form:
[AUC]/AUCiv \* 100
70
Distribution
process by which drug reversibly leaves blood stream and enters interstitium and/or cells of tissues
71
3 body compartments
1. plasma
2. interstial fluid volume
3. intracellular fluid volume
+bone, adipose, fetus
72
4L
Plasma
73
14L
ECF = plasma + IF
74
42L
Total body water = Plasma + IF + ICF
75
Factors affecting drug distribution
1. blood flow
2. capillary permeability
3. hydrophobicity
4. binding to plasma proteins
76
If Vd is small and drug is displaced from binding site on plasma protein
concentration in plasma is high and high risk of toxicity
77
If Vd is large and drug is displaced from plasma proteins
drug can distribute to other compartments and risk of toxicity is lower
78
Volume of Distribution Vd
hypothetical volume of fluid into which a drug is disseminated
Vd = bioavailable dose/concentration in plasma @ t= 0 (L/kg)
79
Large molecular weight drugs can be found in ________ because \_\_\_\_\_\_\_\_\_.
1. plasma
2. too big to pass to IF or bound to PP
80
Low molecular weight hydrophilic drugs can be found in ________ because \_\_\_\_\_\_\_\_\_.
1. ECF
2. can move to IF and stay in solution
81
Low molecular weight lipophilic drugs can be found in ________ because \_\_\_\_\_\_\_\_\_.
1. total body water
2. can move through cell membranes and slit junctions
82
Receptor bound drugs can be found in \_\_\_\_\_\_\_\_.
Tissues
83
Biotransformation purpose
* method of inactivating drug in order to excrete
* can be used to activate prodrugs
* occurs primarily in liver
84
Main locations of biotransformation enzymes
1. extrahepatic microsomal enzymes: oxidation, conjugation
2. hepatic microsomal enzymes
3. hepatic non-microsomal enzymes: acetylation, sulfation, GSH, dehydrogenase, hydrolysis, ox/red
85
Phase 1 metabolism
oxidation involving cyt P450
86
Phase 2 metabolism
* coupling of an endogenous substrate to a drug or its Phase 1 metabolite
* can come before, with, not at all, or after Phase 1
87
Which CYP is implicated in metabolism of many drugs?
*
* CYP3A4 --\> oxidation of drugs
* altered activity in GI tract an change bioavailability of drug
* differences between people can generate different metabolizing profiles
88
2 drugs that can increase metabolic function of CYP3A4
Rifampin, St. John's Wort
89
How does increased metabolism effect efficacy of a drug
Decreased
90
1 substance that reduces CYP3A4 activity
Grapefruit juice --\> increased absorption --\> prolonged effect and/or toxicity
91
Which CYPs are responsible for the major differences in drug metabolism between people
* 2D6
* 2C19
92
Which ethnocultural groups tend to overexpress CYP2D6, resulting in high metabolism of drugs?
Ethiopians, Saudi Arabians
93
3 consequences of altered drug metabolism
1. reduced = toxicity, death
2. increased = loss of efficacy
3. drug-drug interactions
94
Are prodrugs or metabolites easier to clear? Why?
metabolites; they are more polar
95
Modes of drug excretion
1. bile
2. urine
3. air
4. sweat
5. saliva
96
Processes implicated in renal excretion
1. glomerular filtration (if bound to PP, won't work)
2. active tubular secretion (competitive inhibition can prevent this)
3. passive tubular reabsorption (nonionized lipids)
97
Amount of drug excreted renally is the sum of
amount filtered and secreted minus amount reabsorbed
98
Elimination
process by which body terminates drug action: metabolism/biotransformation (liver, muscle) + excretion(kidney)
99
Clearance
* rate of elimination
* proportional to concentration of drug = **1st order kinetics**
* elimination is not saturable
100
For which drugs is elimination saturable (capacity limited elimination)
Alcohol, phenytoin = 0 order kinetics
101
Half Life
* time required to eliminate half drug in body or reduce plasma concentration by 505
* useful only in 1st order kinetics
102
How long does it take to reach steady state?
4-5 half lives of a 1st order drug b/c
rate of elimination = rate of administration
103
**time** to reach steady state is independent of
* dose
* frequency of administration
104
steady state concentration is dependent on
* drug dose/time
* elimination half life
105
continuous infusion reaches steady state faster/slower/same rate as intermittent drug administration
same rate but with more fluctuation of plasma level
106
Loading dose
used to rapidly achieve a therapeutic plasma concentration --\> then maintenance dose to sustain steady state
107
Which age groups have higher volumes of distribution for water-soluble drugs?
Neonates and infants because of incomplete BBB
108
Which age groups have higher volumes of distribution for fat soluble drugs?
elderly//lower Vd for water-soluble
109
Full agonist
drug that if given in sufficient quantity to saturate receptor pool binds to receptor and induces Ra form at large %
110
Partial agonist
has intermediate affinity for Ra/Ri and generates partial response
111
Antagonists
have equal affinity for Ri/Ra and maintain same level of constitutive activity as receptor on its own
112
Inverse agonists
have higher affinity for Ri and reduce constitutive activity
113
Potency
concentration of drug required to achieve EC50
114
Efficacy
magnitude of drug's action at Emax
115
The dose response relationship and selectivity of drug action are dependent on
receptors
116
5 transmembrane signaling mechanisms
1. GPCR
2. ion channel
3. steroid receptor
4. cytokine receptor
5. RTK
117
Gs
epinephrine --\> B1 adrenergic receptor --\> adenylyl cyclase --\> camp
118
Gi
ACh --\> M2 muscarinic receptor --\> reduce adylyl cyclase activity
119
Gq
binding --\> PLC --\> PIP3 formation --\> IP3--\>Ca2+ release
120
Histamine receptor effect
bronchioles: Gq --\> H1 receptor --\> Ca2+ --\> constrict
vessels: Gs --\> B2 receptor --\> cAMP --\> dilation
121
Platelet receptor effect
TxA2: Gq --\> TP --\> Ca2+ --\> aggregation
PGI2: Gs --\> cAMP --\> relaxation
122
Importance of receptor subtypes
subtle differences in structure and anatomic distribution can provide unique points of pharmacological attack --\> **therapeutic leverage**
123
GPCR desensitization occurs via
Barrestin recruitment to phosphorylated GPCR carboxyl tail
124
Two types of dose response curves
* graded
* quantal: all or nothing
125
4 types of antagonism
1. competitive - same receptor//reversible
2. noncompetitive-different receptors on same pathway
3. chemical-drug drug binding
4. physical-different receptors with opposite effects
126
Therapeutic index formula
LD50/ED50
127
Safety Index
LD1/ED99
128
ACH, muscarine, and pilocarpine are agonists for
muscarinic cholinergic receptors
129
ACH and nicotine are agonists for
nicotinic cholinergic receptors
130
Norepinephrine and epinephrine are agonists for
Alpha 1 adrenergic receptors
131
Epinephrine is an agonist for
Beta 1 adrenergic receptors
132
Atropine and scopalamine block
muscarinic cholinergic receptors
133
Curare and succinylcholine block
nicotinic cholinergic receptors
134
Prazosin and phentolamine block
Alpha-1 adrenergic receptors
135
Propanolol and metoprolol block
Beta-1 adrenergic receptors
136
NSAIDS
* weak acids
* variable selectivity for isoforms of COX
* older NSAIDS inhibit both forms of COX
* newer NSAIDS selectively block COX2
137
New NSAIDS (**-coxibs)** block
COX2
138
Prostanoid biosynthesis pathway
PLA2 -\> Arachidonic Acid --\> COX1 or COX2 --\> prostanoids, prostacyclin, TxA2, prostaglandins D,E,F
139
Aspirin MOA
acetylate Ser530 in COX --\> **irreversible inhibition**
140
All NSAIDs except aspirin MOA
**reversible** competitive inhibition of COX
141
Clinical utility of NSAIDs
1. anti-pyretic
2. analgesic
3. anti-inflammatory
4. antiplatelet
4As
142
NSAID toxicities
1. gastropathy -blocking cytoprotection
2. bleeding time increase
3. hypertension -decreased PGE production --\> renoconstriction
4. gestation prolongation -decrease PGE,F
143
NSAID induced gastropathy
COX 1 hypothesis:
COX1 inhibition --\> reduced PGE --\> less mucous, low pH, reduced TxA2 --\> erosion, ulceration, bleeding
\*COX 2 also produces PGE but doesn't have anything to do with TxA2 compounding effect
144
Why were coxibs developed?
To bypass the gastropathy and other side effects associated with COX1 inhibition by older NSAIDs
145
What are the deleterious consequences of coxibs?
MI risk
* COX2 blocks PGI2 --\> no more vasodilation
* COX1 remains unblocked --\> TxA2 --\> thrombosis
Possible renal
* NSAIDs increase blood pressure due to PGE induced renin --\>renal reabsorption --\> both COX1 and 2
146
Aspirin dose scale
1. low = COX1
2. medium - analgesis
3. high - anti-inflmmatory (can be toxic--\> not used)
147
Aspirin toxicities
* Reyes syndrome-hepatic toxicty in kids
* Salicylism-headache, tinnitus, dizziness, nausea
148
What are eicosonaids and what are their families?
* naturally occuring autocoids derived from arachidonic acid in the cell membrane
1. prostanoids - from cyclooxygenase
2. leukotriene - from lipoxygenase
3. HETE and ETE - from monoxygenase
149
What do we call eicosanoids produced without enzymes?
Isoeicosanoids - formed from free radicals
150
What are the 6 prostanoids?
1. Prostaglandins
* PGD2
* PGE1&2
* PGF2/alpha
2. prostacyclin PGI2
3. TxA2
151
chemical mediators that are formed in cells and released to act as local mediators are
autocoids
152
Which cells have arachidonic acid, phospholipase A2, and COX?
All cells
153
What is the role of PLA2?
catalyzes the release of AA from the cell membrane
154
Which two factors affect the kind of prostanoids produced?
1. tissue
2. enzyme isomers
e.g.
1. platelets = thromboxane synthase = TxA2
2. GI endothelia = PGE2 isomerase = PGE1 & 2
3. Vascular endothelia = PGI2 isomerase = PGI2 prostacyclin
155
Which isoform of PLA2 is responsible for the housekeeping functions of healthy cell life?
constitutive form: cytosolic PLA2
156
Which PLA2 is expressed during inflammation and in response to chemical and physical stimuli?
inducible form: sPLA2
157
Which COX is constitutively expressed?
COX1 (PGE1&2 protection in GI, platelet aggregation)
\* still contributes to prostanoid formation in inflammation
158
Which COX is found in platelets?
COX1
159
Which COX is found in endothelial cells?
COX2 (prostacyclin)
160
How is COX2 downregulated endogenously?
Glucocorticoids
161
Where is COX2 found?
kidney
brain
synovial
macrophages/monocytes
162
Function of TxA2
* produced by platelets, kidney, macrophages
* COX1
* induces **platelet aggregation, vasoconstriction, and smooth muscle cell proliferation**
163
Function of Prostacyclin PGI2
* vascular endothelial cells
* COX2
* inhibits platelet aggregation and smooth muscle cell proliferation
* vasodilator and proinflammatory
164
Function of PGE1 and 2
* cytoprotection in GI tract/stomach (COX1)
* inhibition of gastric acid secretion, increased mucous production
* Proinflammatory (COX2)
* Cox 1 and 2
* regulate renal blood flow through vasodilation
* regulate salt homeostasis via renin
* uterine and GI smooth muscle contraction
165
Function of PGF2alpha
* COX 1 and 2
* induces vascular smooth muscle, luteal regression, and uterine contraction
* vasoconstrictor
166
Function of PGD2
* COX1 and 2
* produced by mast cells
* cutaneous vasodilation, inhibition of platelet aggregation
* sleep, chemotaxis of Th2 lymphocytes, hair follicle activity
167
Carboprost MOA
PGF2alpha analogue used as an abortifacient and post partum bleeding
168
Misoprotol MOA
PGE1 analogue used with RU486 for abortion and on own for gastric cytoprotection
169
Dinoprostone MOA
PGE2 analogue used to induce labor
170
Alprostadil MOA (dont need for exam)
PGE1 analogue used for eriectile dysfunction and maintain PDA
171
Latanoprost MOA (dont need for exam)
PGF2alpha analogue used to reduce intraocular pressure in glaucoma
172
Epoprostenol MOA
PGI2 analogue used to treat primary pulmonary hypertension by inducing pulmonary vasodilation
