Lecture 5

Front 1

Where can Toxicity result from?*

Back 1

Toxicity can result from:

Unintended activation of inhibition of intended target (on-target adverse effects);

or

Unintended activation of inhibition of unintended target (off-target adverse effects).

Front 2

what is on-target effects?

Back 2

If a drug target is expressed in more than one cell type.

Front 3

what is the use of

Diphenhydramine?

Back 3

Diphenhydramine

is a H1receptor antagonist, used to mediate the effects of histamine release in allergic conditions.

Front 4

what are the adverse effects of Diphenhydramine?

Back 4

It can have adverse effects is it crosses the blood brain barrier and can affect the CNS.

This lead to the development of terfenadine(2ndgen anti-histamine), which doesn’t cross the blood brain barrier, but does lead to off target effects by interacting with cardiac potassium channels increasing the chance of cardiac death!!!!

Front 5

what is Statinsare designed for?

Back 5

Statinsare designed to block HMG-CoA reductase in the liver.

Front 6

what is the rare adverse

effect of Diphenhydramine?*

Back 6

A rare adverse affect is muscle toxicity and myositis, revealing a role for HMG-CoA reductase in regulating post translational modification of several muscle proteins.

Front 7

Inhibition of potassium current carried by Iκr channels (aka. hERGchannels) can lead to what?

Back 7

Inhibition of potassium current carried by Iκr channels (aka. hERGchannels) can lead to repolarization of cardiac myocytes.

Front 8

Delayed repolarization can lead to what?

Back 8

Delayed repolarization can lead to increased heart rate.

Front 9

example of Enantiomers of a drug

Back 9

Enantiomers of a drug.

e.g. thalidomide.

Front 10

difference between

r-enantiomer and

s-enantiomer

Back 10

R-enantiomer is an effective sedative, the S-enantiomer is a potentmutagen/teratogen that causes serious birth defects, such as loss of limbs.

Front 11

what happens If therapeutic

Index (TI) is low ?*

Back 11

If therapeutic Index (TI) is low then toxicity may occur.

Front 12

Administration of a drug that inhibits or is a substrate for P-glycoprotein (Pgp) encoded by MDR1 gene, can lead to what?

Back 12

Administration of a drug that inhibits or is a substrate for P-glycoprotein (Pgp) encoded by MDR1 gene, can lead to increased plasma levels of drugs normallly exported by this mechanism.

Front 13

how can A pharmacokinetic effect can have positive effects?*

Back 13

A pharmacokinetic effect can have positive effects:
Penicillin half life can be increased by coadministration with probenecid, which inhibits renal tubullar transport
.The other example given is the antibiotic imipenem, which is inhibited by dehydropeptidase I,with cilastatin, which is a selective inhibitor of dehydropeptidase I.

Front 14

what happens when antibiotic imipenem, which is inhibited by dehydropeptidase I,with cilastatin, which is a selective inhibitor of dehydropeptidase I?*

Back 14

antibiotic imipenem, which is inhibited by dehydropeptidase I,with cilastatin, which is a selective inhibitor of dehydropeptidase I, leads to

therapeutic plasma levels o f imipenem.

Front 15

what happens when a drug that binds to plasma proteins may outcompete drugs that bind plasma proteins?

Back 15

Finally, a drug that binds to plasma proteins may outcompete drugs that bind plasma proteinsincreasing the bioavailability of a drug.

Front 16

How can the bio-availability of a drug be enhanced?

Back 16

This can be enhanced where circulating albumin is low, as occurs during liver failure ormalnutrition.

Front 17

when does Pharmacodynamic effects occur?

Back 17

Pharmacodynamic drug-drug interactionsPharmacodynamic effects can occur when one drug changes the response of a target (or nontarget) tissue to another drug.

Two drugs activating complementary pathways leading to exaggerated effects. 1+1=3????

Front 18

example of drugs where

Pharmacodynamic effects occur?

Back 18

e.g. sildenafil (erectile dysfunction) and nitroglycerin (for angina)

Front 19

effect of sildenafil

Back 19

Sildenafil prolongs the action of cGMP, by inhibiting phosphodiesterase5 (PDE5), and nitroglycerin stimulates cGMPin vascular smooth muscle cells.

Front 20

Warfarin and heparin can synergize leading to?*

Back 20

Warfarin and heparin can synergize leading to bleeding. Supratherapeutic levels of anti-coagulation.

Front 21

Drug-Herb Interactions lead to?

Back 21

Rarely tested. Can lead to toxic effects.

Front 22

example of Drug-Herb Interactions

(no. 1)

Back 22

e.g. gonkgo biloba inhibits platelet aggregation. If taken in conjunction with Non-steroidal anti-inflammatory drugs it can increase risk of bleeding.

Front 23

example of Drug-Herb Interactions (no. 2)*

Back 23

e.g.Echinacea

contains alkaloids which may deplete hepatic glutathione stores, increasing risk of toxicity.

Front 24

example of Drug-Herb Interactions (no. 3)*

Back 24

e.g. St Johns wort may also lead to serotonergic syndrome when taken in conjunction with selective serotonin uptake inhibitors (SSRIs).

Front 25

Moderate doses of a potentially toxic drug activate what?

Back 25

Kupffer cells and are metabolized by hepatocytes.

The resulting stress may be exacerbated by: reactive oxygen species (ROS) and reactive nitrogen intermediatesibrosis.ibrosis.De

Front 26

high doses of toxic drug can lead to?

Back 26

High doses of a toxic drug metabolized by hepatocytes can induce cell injury.

Front 27

Factors released by the injured hepatocytes activate?

Back 27

Kupffer cells and , endothelial cells, whichelaborate toxic ROS and RNI.

Front 28

what happens When a drug binds to a protein?

Back 28

Hapten it is then capable of eliciting an immune response

>>Indirect.

Front 29

Direct induction of the immune system, can result in

Back 29

hypersensitivity & autoimmunity.>>direct.

Front 30

Type I hypersensitivity (aka intermediate).

Back 30

>Wheel and Flair in the skin, hay fever symptoms.

Front 31

Type II hypersensitivity (antibody dependent)

Back 31

>rare adverse responses (e.g. Penicillin)

Front 32

Type III hypersensitivity (immune complex mediated)

Back 32

>IgG& IgMcomplexes aggregate in tissues (e.g. lungs etc).

>>>Serum sickness.Can be caused by administration of antivenins.

Front 33

Type IV hypersensitivity (delayed –type)

Back 33

>activation of cytotoxic t-cells.Repeated exposure following initial insult….can lead to the cytokine storm

>>fever, hypertension, and even organ failure.

Front 34

explain the Mechanisms of Hypersensitivity Reactions

Back 34

......................................................

Hint 34

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Front 35

A.

Type I hypersensitivity reactions occur when

(continued).....

Back 35

a haptenbinds to a protein (1).The antigen crosslinks IgEantibodies on the surface of a mast cell, leading to mast cell

degranulation (2).

Front 36

(continued)......

these Mast cells release what?

Back 36

Mast cells release histamine and other inflammatory mediators.

Front 37

B.

Type II hypersensitivity reactions occur when

(continued)......

Back 37

an antigen binds to the surface of a circulating blood cell(1).

Front 38

(continued).....

Antibodies to the antigen then bind the surface of the RBC (2), attracting

Back 38

cytotoxic T cells (3), which release mediators that lyse the RBC.

Front 39

(continued).....

Binding of antibody to RBCs can also directly stimulate

Back 39

complement-mediated RBC lysisand RBC removal by the reticuloendothelialsystem.

Front 40

C.

(continued).....

Type III hypersensitivity reactions occur when

Back 40

antibodies bind to a

soluble toxin, acting as an antigen (1).

Front 41

(continued).....

The antigen–antibody complexes are then deposited in the tissues (2), attracting

Back 41

macrophages (3) and starting a complement-mediated reaction sequence (not shown).

Front 42

D.

(continued).....

Type IV hypersensitivity reactions occur when

Back 42

a hapten

binds to a protein (1) and the hapten-

bound

protein is phagocytosed

by a

Langerhans cell (2).

Front 43

(continued).....

The Langerhans cell migrates to a regional lymph node, where it

Back 43

presents the antigen to a T cell, thereby activating the T cell (3).

Front 44

Autoimmunity is

Back 44

(lack of self recognition)

e.g. Methyldopa can cause haemolytic reactions by initiating autoimmunity against Rhesus antigens (Rh Factors)Some drugs can induce antibodies against myuelpoperoxidase(eg. Hydralazine) and even DNA (procainamide).

Front 45

Red man syndrome is

Back 45

(anaphylactoidshock)

e.g. I.V. introduction of vancomycin. Direct effect on mast cells.Head neck and shoulders (upper trunk).Can be alleviated by use of antihistamines.

Front 46

Chemotherapies

targeting cancer are designed for what?

Back 46

Designed to target proliferating cancer cells, also damage the bone marrow/ and bone marrow originating immune cells.

Front 47

Chemotherapies associated with?

Back 47

Associated with increased risk of infection. Various ways to stimulate leukocyte production such as filgrastin.

Front 48

Some therapies target specific cells Rituximab is a monoclonal antibody which targets

Back 48

CD20+ B-cells, which are important in lymphoma and arthritis.

Front 49

Chemotherapies can lead to?

Back 49

Can lead to opportunistic infections that rely on an immunocompromised patient.

Another example is efalizumabwhich targets CD11a, blocking leukocyte adhesion.

Front 50

Drugs metabolized in the liver can produce

Back 50

toxic by-products damaging the liver. e.g. acetaminophen.