Pharmacology Lecture 4

8/3/2019 Pharmacology Lecture 4

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Receptor signaling

Signal transduction transducers A complicate pathway, with a large spectra

of regulating keypoints

Existence of antagonist pathways

A BASIC LAW OF HOMEOSTASIS

A wide number of pathways, with

alternative and if then type substitutions

Drugs influence quantitatively the physiologic functions of the

target cell, but they do not initiate new functions

Because the concentration(s) ofendogenous(natural) ligand(s) is(are) variable

Because the cell exhibits a lower number of

receptors on the cell

Because the receptors respond less for thesame intensity of stimulus (desensitization,down-regulation)

Why is the cells response variable in

physiologic and pathologic conditions? Because there is an agonist and an antagonist present:

-different response depends of

Concentration

Affinity

Intrinsic activity

Because pharmacodynamic tolerance is activated

Because the cell exhibits less receptors(internalization)

Because receptors respond less at the samestimulus (desensitization)

Because receptors respond the same, buttransductors respond less

Why is the cells response variable when the

receptor is activated during the treatment?

Ion channel

linked (gated)

receptor

signaling


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On-off effects on ion-channel linked receptors

Numberofopenchannels

GABA A RECEPTOR

Cl- channel activity hyperpolarization of the membrane

Some channelsare notactivated byligands;

But by voltage

Protein tyrosine kinase

receptor signaling


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G-protein link

receptors

G-protein linkedreceptors

Binding

sites ofG protein

G-protein

linked receptor

signaling


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Inhibitory

receptor

Stimulatory

receptor

Target

enzyme

Adenylyl

cyclase

1 - receptor M2-receptor

Some surpizes regarding G protein linkedreceptors

Sometimes they dimerize, and this changes theiractivity

There are proteins which can change the receptorsactivity (RAMP)

they can transduce without G-protein


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Adrenergic receptor can mediate theactivation of Src kinase pathwayindependently form G protein (after theactivation of G-protein by the ligand and G-protein mediated transduction).

Metabotrophic Glutamate receptors mediate Ca++ release in neuronsindependently of G-proteins with the participation of Homer-family proteins

Intracellularreceptorsignaling

Response

Protein

CytoplasmNucleus

Transcription

mechanisms,

RNA

polymerase

etc

Homodimer

Steroid

receptor

(activated)

Processing

Intracellular

receptor

signaling

C

N

Zn Zn

Zinc Fingers

Tau1

DNAbinding

GCS binding

Tau 2

Hsp 90

Nuclearlocalization

GRE: GGTACAnnnTGTTCT

nGRE: ATYAnnTnTGATCn

Taf-2


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Non-tyrosin-kinase type receptors

cytokine receptors cell adhesion receptors TNFR superfamily

Resemblences: they have a transmembrane domain they are activated by an adaptative protein

+ GCH

GR

Raf

14-3-3 p53

hs

p70

hsp56Raf

hsp90

p23

PI-PLC

Src-1

p53

GR

PI-PLC

Src-1

GR

GR mdm2

PI-PLC

Src-1

APOPTOSIS

Non-transcriptionalactivity of the intracellularreceptor

Pharmacodynamic effects Desired effect

Side effect:

Interaction between more drugs(and/orsubstances): Additive

Synergism

Antagonism

Indifference


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Adverse effects

Toxic effects

Side effects

Amount of active substance causing death in a given

period of time, and route of administration at 50% oftreated lab animals

Amount of substance which inhaled leads to death in a

given period of time at 50% of treated lab animals

DL50 (lethal dose50)

CL50 (lethal concentration50 )

Adverse effectsA damaging or unpleasant sensation

caused by a medical substance which

predicts a risk and suggests caution for

future use, implying:

- prevention

- specific treatment- changing dosage regimen

- withdrawal

Classification of adverse effects

Non correlated to

the mechanism of

action

Type B

Correlated to the

mechanism of

action

Type A

Classification of adverse effects

Non Correlated to the mechanism of

actionType B(Bizarre)

(Cma) During chronic treatmentType C(Chronic)

(Cma) Occurs or becomes

appearant after a while of useType D(Delayed)

(Cma) Occurs right after withdrawalType E(End of use)

Correlated to the mechanism of action

(Cma)Type A(Augmented)


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Ineficcacy(Failure, F)

Defects and counterfeit

Inappropiate use (or lack of compliance)

Interactions

Resistance

Tolerance

Inaproppiate use

Wrong dosageWrong duration

Wrong route

Wrong indication

Wrong expectation

Type A adverse effects

Dose-dependent

Relatively common

Very rarely fatal

Predictable

They can occur at 1 administration orprolonged therapy

Type A adverse effects: risk situations

Children

Elderly

Renal failure

Pregnant women

Breastfeeding women

Other types of adverse effects Idiosyncratic intolerance, unpredictable,

very severe, dose-dependent

Tachyphylaxis very fast tolerance

Both may vary in time of onset

Type B1 adverse effects: allergies

Mediated by the immune system

- dose-independent

- relatively rare (< 1%)

- almost always more severe than type A adverse

effects

- they never occur at the prime contact (first

administration) of the drug


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Allergic reactions

Type 1: anaphylaxis IgE mediated: e.g.urticaria, rhinitis, asthma, shock

Type 2: cytotoxic IgG mediated: anti-tissue antibody+complement e.g. hemoliticanemia, trombocytopenia

Type 3: immune complex mediated (IgG,IgM) e.g. lupus-like syndrome

Type 4: delayed hypersensitivity -cytokine mediated- e.g.contact dermatitis

URTICARIA

IgE-mediated

circulating immune complexes

or anaphylactoid reactions

Stevens-Johnson syndrome toxic necrolysis of the skin (Lyellsyndrome) are related:

multiform eritema

systemic diseases (artritis, nephritis, myocarditis and CNS lesions)Drug-induced FIX ERITEMA

NSAIDs and antibiotics

Drug-

induced

psoriasis

Betablockers,

Li, NSAIDs

DRUG-INDUCED ALLERGIC CONTACT DERMATITIS Hematologic adverse effects

TrombocytopeniaAgranulocytosisHemolytic anemiaAplastic anemia

Liver

Cholestatic hepatitisHepatocellular hepatitis


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KidneyInterstitial nephritisGlomerulonephritis

LungPneumonia (alveolar and interstitial eosinophylia)

Systemic reactionsAnaphylaxisVasculitisSerum diseaseSystemic lupus erithematosus (SLE)

TERATOGENS

A substance whichdamages theembryonaldevelopment andcauses embryo flaw

Spontaneous teratogenesis inpregnancy is 3%

- Approx. 10% of congenital defects are

caused by environmental factors

-Miscarriage

-Malformation

FDA Classification of TeratogensCategory A: No teratogenic risk has beendemonstrated in humans

Category B: No risk in animals but no human studiesare available.

Category C: Terotogenic or embryocidal effects inanimals but no human data.

Category D: Definite human fetal risk but the drugis needed to save the mother. Benefits outweigh therisks.

Category X: Definite human or animal risk or both.Risk outweighs the benefit.

Thalidomide was originally manufactured by Grunenthal Pharmaceuticals in

Germany.

They were hoping to make a sedative (studies on cats confirmed the hypothesis only

partially). Thalidomide was not addictive (barbiturates are) and it seemed safe (but in

sugar syrups it could kill dogs).

Thalidomide was marketed as an over the counter medication (i.e., non-

prescription) in Germany and other European countries as a sedative.

Some patients complained thalidomide caused severeconstipation. Some claimed it

caused peripheral neuritis. Grunenthal responded with a form letter saying it was

news to them because millions of users had no complaints.

Some women (1961) used thalidomide to prevent nausea during pregnancy.

Grunenthal said it was safe to do so because nursing mothers who used thalidomide

did not produce unusually drowsy babies.

Thalidomide


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Thalidomide

Amelia or phocomelia

Thalidomide

Cases of Phocomelia Year

0 1940-1959

1 1959

30 1960

154 1961

University clinic in Hamburg

Approximately 5,000-7,000 malformed infants were born

to women who ingested thalidomide during pregnancy

Pharmacology Lecture 4

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