pharmacology lecture 4
Post on 06-Apr-2018
219 Views
Preview:
TRANSCRIPT
-
8/3/2019 Pharmacology Lecture 4
1/13
1
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
-
8/3/2019 Pharmacology Lecture 4
2/13
2
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
-
8/3/2019 Pharmacology Lecture 4
3/13
3
G-protein link
receptors
G-protein linkedreceptors
Binding
sites ofG protein
G-protein
linked receptor
signaling
-
8/3/2019 Pharmacology Lecture 4
4/13
4
-
8/3/2019 Pharmacology Lecture 4
5/13
5
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
-
8/3/2019 Pharmacology Lecture 4
6/13
6
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
-
8/3/2019 Pharmacology Lecture 4
7/13
7
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
-
8/3/2019 Pharmacology Lecture 4
8/13
8
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)
-
8/3/2019 Pharmacology Lecture 4
9/13
9
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
-
8/3/2019 Pharmacology Lecture 4
10/13
10
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
-
8/3/2019 Pharmacology Lecture 4
11/13
11
-
8/3/2019 Pharmacology Lecture 4
12/13
12
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
-
8/3/2019 Pharmacology Lecture 4
13/13
13
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
top related