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Flashcards in Pharmacology Deck (172):
1

Glucocorticoid

 

  • endogenous steroid hormone produced and released by adrenal gland
  • exogenous analogs are used anti-inflammatories and immunsuppressives

2

3 classes of corticosteroids, their roles, and their endogenous sources

 

  1. mineralocorticoids - Zona glomerulosa
    • salt/water retention
  2. glucocorticoids - Zona Fasiculata
    • immunity and metabolism
  3. androgens/estrogens- Zona Reticularis
    • sexual function

3


Endogenous regulation of glucocorticoid production

 

  • HPA: CRF--> Ant. Pit. --> ACTH--> corticosteroids
  • negative feedback from glucocorticoids and ACTH

4

Negative effects of glucocorticoids

  • Metabolic: gluconeogenesis, lipolysis, lipgenesis
  • Catabolic: protein catabolism, wasting, osteoporosis
  • Other: Na homeostasis, behavior

5


Anti-inflammatory effects of glucocorticoids

  1. decrease T cell production of IFN gamma
  2. reduce macrophage production of Il1 and TNFalpha
  3. reduce mast cell production of histamine, NO, prostaglandins
  4. inhibition of PLA2
  5. decrease mRNA Cox
  6. decrease IL2,3
  7. decrease antibodies

6

Immunosuppressive effects of glucocorticoids

 

  1. cell mediated immunity
  2. reduced proliferation of lymphocytes, neutrophils, and monocytes

7

Glucocorticoid Receptor and 4 domains

  • intranuclear steroid hormone receptor family
  • 4 functional domains
    1. ligand binding domain-gr interaction with chaperones Hsp90 and Hsp56
    2. DNA binding domain-binds to DNA GRE response element within promoter of target gene
    3. 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
    4. N terminal AF1- ligand dependent transactivation domain; constitutive interaction with receptor complex

8


Ligand-binding domain of glucocorticoid receptor binds to


chaperone proteins Hsp 90 and 56

9


DNA binding domain of glucocorticoid receptor binds to

glucocorticoid response element (GRE) on promoter in DNA of specific gene

10

C-terminal AF2 of glucocorticoid receptor binds to

coactivator/cosuppressor proteins that optimize receptor induced gene transcription

11

N-terminal AF1 of glucocorticoid receptor binds to

constitutively to transcription machinery of the cell

12

Glucocorticoid MOA

  1. GR/Hsp resides in cytoplasm in a ligand friendly complex
  2. binds to hormone in the cell and dissociates from chaperone
  3. steroid receptor complex translocates to the nucleus and binds target gene

13

Lipocortin effect


when gene bound by glucocorticoid --> increased expression of lipocortin --> downregulates PLA2 --> decreased synthesis of PGs and leukotrienes

 

*gc can also inhibit IL6/8

14

Factors optimized in synthetic production of glucocorticoids

  1. limit salt-retaining properties (a la mineralocorticoids which are endogenous)
  2. improve anti-inflammatory response (via double bonds, 3 keto and oh groups)

15

Glucocorticoid-physiological doses

  • 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

Glucocorticoid-supra physiological doses

  • anti-inflammatory effect
  • immunosuppressive

17

Glucocorticoid toxicities

  • 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

Sudden withdrawal of therapeutic glucocorticoids can lead to acute adrenal insufficiency because of reduced endogenous cortisol production called

Addisonian crisis

19

Immunosuppressives-indications

  1. organ/tissue transplant
  2. treatment of autoimmune diseases
  3. treatment of inflammatory conditions like asthma

20

Immunosuppression most effective in

prophylaxis: primary/initial steps prior to immunologic memory

  1. antigen presentation
  2. cell proliferation
  3. lymphokine synthesis & differentiation *immunosuppressants don't have a uniform effect on all steps of immune response *prophylaxis is key

21

Stages of immunosuppression

  • Induction - T cell depletion and prevention of activation
  • Maintenance - prevention of T cell activation/cytokine production
  • Treatment of Rejection or Disease Flare
  • Tapering

22

Key risks during immunosuppression

  1. Infection
    • donor-derived opportunistic
    • worsening of pre-existing conditions
  2. Malignancy
    • donor derived pre-existing
    • de novo

23


# of medications needed for immunosuppression

  • 3 rejection
  • 3 infection
  • 3-5 non-immune and metabolic regulators (e.g. statins)

24


IFN gamma, IL 2 and TNF alpha are produced by


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 translocation 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