Different types of receptors can drugs affect the body through interacting with these receptors. this presentation is a part from special course in basics of pharmacology .. deep and simple

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3. Physical
a. Adsorption , kaolin adsorbs toxins in diarrhea
Chemical
a. Neutralization, antacids
b. Chelation, BAL dimercaprol with mercury
Inhibition of cell division
Cytotoxic drugs
MECHANISMS OF ACTIONS

4. interference with normal metabolic
pathways
e.g Sulphonamides inhibit bacterial folic acid synth
by competing with PABA
Actions on enzymes ( mostly inhibition)
NSAIDS inhibit COX
Neostigmine inhibits choline esterase E.
Allopurinol inhibits xanthine oxidase E.
MECHANISMS OF ACTIONS

5. Actions on receptors
 Receptor is a protein molecule usually found inside or on the surface of
a cell, that receives chemical signals from outside the cell.
 A molecule that binds to a receptor is called a ligand, and can be
a peptide (short protein) or another small molecule such as
a neurotransmitter, hormone, pharmaceutical drug, or toxin.
 The endogenously designated molecule for a particular receptor is
referred to as its endogenous ligand
 When a ligand binds to its corresponding receptor, it activates or
inhibits the receptor's associated biochemical pathway.
MECHANISMS OF ACTIONS

6. 1. GPCR
2. ION Channels
3. Transmembrane enzymes
4. Transmembrane non-enzymes
5. Nuclear receptors
6. Intracellular enzymes
TYPES OF RECEPTORS

8. •G protein refers to any protein which
binds to GDP or GTP and act as
signal transduction.
GPCR

10. SIGNAL TRANSDUCTION

11. Signaling molecule
Receptor of target cell
Intracellular molecule
biological effect
Signal
transduction

12. SIGNALING MOLECULES
1. Extracellular molecules
Protein & amino acids: Hormone, cytokine Gly, Glu,
adrenaline, thyroxine
Steroids: Sex Hormone, glucocorticoids
Fatty acid derivatives: prostaglandin
2. Intracellular molecule
• Ca2+ ( ions)
• DG(diacyl glycerol), ceramide ( lipid)
• IP3 (Inositol trisphosphate) (carbohydrate)
• cAMP cGMP (nucleotides)
• JAK (janus-activated kinase ) Ras- Raf (proteins)

13. SECOND MESSENGER
Small molecules synthesized in cells
in response to an external signal are the
second messengers, which are
responsible for intracellular signal
transduction.
Such as Ca2+, DG, Cer, IP3, cAMP, cGMP

14. C AMP AS A SECOND MESSANGER
http://www.studyblue.com/notes/note/n/endocrine-system1/deck/3907012

15. Smooth muscle
relaxation
V.D – B.D
Positive inotropic
effect in heart
Prevent platelet
aggregation
Reduces
inflammation

16. C GMP AS A SECOND MESSANGER

17. Main tissue localizationPDE
Brain, heart, vascular smooth muscle1
Adrenal cortex, brain, heart, corpus cavernosum2
Heart, corpus cavernosum, vascular smooth muscle, platelets, liver
pancreas
3
Lung, mast cells, vascular smooth muscle4
Corpus cavernosum, lung, vascular smooth muscle, platelets,
brain, esophagus
5
Retina6
Skeletal muscle, T cells7
Testis, thyroid8
Broadly expressed, not well characterized9
Brain, testes10
Skeletal muscle, prostate, liver, kidney, pituitary, testis11

18. PDEIs and
Indications

19. PHOSPHODIESTERASE
INHIBITORS
 Drugs that block subtypes of the enzyme
phosphodiesterase (PDE), therefore preventing the
inactivation of the intracellular second messengers
cyclic adenosine monophosphate (cAMP) and cyclic
guanosine monophosphate (cGMP) by the respective
PDE subtype(s).
 They are classified into non-selective PDE inhibitors
and selective PDE

20. PDE
FAMILY
SUBSTRATE INHIBITORS CLINICAL
APPLICATIONS
PDE 1 cAMP/cGMP Vinpocetine
Nicardipine
Dementia, memory
loss
PDE 2 cAMP/cGMP EHNA (erythro-9-(2-
hydroxy-3-
nonyl)adenine)
Sepsis, acute
respiratory distress
syndrome, memory
loss
PDE 3 cAMP/cGMP Milrinone
Cilostazol
Congestive heart
failure, Intermittent
claudication,
pulmonary
hypertension
PDE 4 cAMP Rolipram
Denbufylline
Cilomilast
Roflumilast
Asthma, COPD,
Bipolar depression,
Autoimmune
Encephalomyelitis,
Organ transplantation
PDE 5 cGMP Sildenafil Zaprinast
Dipyridamole
Erectile dysfunction,
hypertension

21. PDE
FAMILY
SUBSTRATE INHIBITORS CLINICAL
APPLICATIONS
PDE 6 cGMP
PDE 7 cAMP Dipyridamole
Thiadiazole
Airway and
immunological
diseases.
PDE 8 cAMP Dipyridamole
immunological
diseases.
PDE 9 cGMP Zaprinast Possible
hypoglycemic
effects
PDE 10 cAMP/cGMP Dipyridamole
Papaverine
psychosis
PDE 11 cAMP/cGMP Tadalafil
Zaprinast
Dipyridamole
Proposed
improvement
of human

22. Classification:
Nonselective phosphodiesterase inhibitors
 caffeine
 aminophylline
 IBMX (3-isobutyl-1-methylxanthine)
 paraxanthine
 pentoxifylline,
 Theobromine,
 Theophylline.
They act as competitive nonselective phosphodiesterase inhibitors which
raise intracellular cAMP, activate PKA, inhibit TNF-alpha and leukotriene
synthesis, and reduce inflammation and innate immunity and nonselective
adenosine receptor antagonists

23. Selective phosphodiesterase inhibitors
PDE1 selective inhibitors
 Vinpocetine
PDE2 selective inhibitors
 EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine)
 Anagrelide
PDE3 selective inhibitors
 Enoximone and milrinone, used clinically for short-term
treatment of cardiac failure.
 These drugs mimic sympathetic stimulation and increase
cardiac output.
 PDE3 is sometimes referred to as cGMP-inhibited
phosphodiesterase.

24. b1 adrenergic receptors function through Gs to stimulate the effector adenylyl
cyclase to produce the 2nd messenger cyclic AMP
Activated Gs:
- stimulates adenylyl cyclase to produce
cAMP
- enhances activation of voltage gated Ca2+
channels in the plasma membrane
cAMP:
- activates protein kinase A, which directly
phosphorylates proteins (e.g. troponin I)
essential for cardiac muscle contraction
- stimulates sodium/potassium influx which
opens voltage-gated Ca2+ channels
- inhibits uptake of Ca2+ into cellular stores
- cAMP hydrolyzed by phosphodiesterases
Overall effect: increased intracellular Ca2+ concentration and phosphorylation of
contractile proteins. Result: cardiac muscle cells expressing b1 receptors
contract in response to epinephrine or norepinephrine.

25. b2 Receptors
 Gs: Activation of adenylyl cyclase and increased cAMP levels.
 Relaxes vascular, bronchial, gastrointestinal and
genitourinary smooth muscle, stimulates the uptake of
potassium into skeletal muscle, stimulates glycogenolysis
and gluconeogenesis in the liver.
 Agonist: Terbutaline
 Antagonist: Propranolol
Why does b1 stimulation cause contraction in cardiac muscle while b2
stimulation causes relaxation of smooth muscle – both elevate cAMP?
BETA RECEPTORS

26. protein kinase A
EPI, b1, cardiac muscle
Phosphorylation of contractile
machinery proteins: e.g. Troponin I
CONTRACTION
EPI, b2, smooth muscle
Troponin I absent from smooth
muscle. PKA phosphorylation
of a different target, myosin light
chain kinase, inhibits myosin
function.
RELAXATION
Different downstream effectors:
different responses

27. Gs→ s→ AC→ cAMP↑
Gi→ i→ AC→ cAMP↓
Gq→ q →PI-PLC→IP3+DAG
Go→ o→ ion channel
Gt→ t → cGMP PDE → cGMP → Rhodopsin
CLASSES OF G PROTEINS

28. Gs vs. Gi
Regulation of Adenylate Cyclase Activity
Gs stimulates adenylate cyclase
Gi inhibits adenylate cyclase
e.g. epinephrine can increase or decrease intracellular cAMP concentrations,
depending upon the receptor to which it binds
b adrenergic receptors couple to Gs, whereas
2 adrenergic receptors couple to Gi

29. PLC Gq
1
Interstitial fluid
PIP2
DAG
IP3
IP3
IP3R
Ca2+
GTP GDP
Intracellular calcium pools



Epi, NE
Contraction of
vascular and
genitourinary
smooth muscle

30. Different downstream 2nd messengers and
effectors: different responses
e.g. vascular or genitourinary
smooth muscle
RELAXATION
EPI, b2, Gs
EPI, 1, Gq
CONTRACTION

31. IMPORTANT…..direction of response depends upon
ligand concentration
e.g. in vascular smooth muscle
Gs, cAMP,
VASODILATION
1 b2
b21
b21 Gq, Ca2+, overcomes
cAMP effects,
VASOCONSTRICTION

32. ION CHANNELS
 Changes in the flux of ions across plasma membrane are a very
critical regulatory event in excitable and non excitable cells
through electrochemical gradient
 This criteria used by excitable cells (nerve and muscle) to
generate and transmit electrical impulse
 Used by non excitable cells to trigger biochemical and secretory
events

34. VOLTAGE GATED

35. LIGAND GATED

37. e.g., the insulin receptor that
forms disulfide-linked dimers
in the presence of
hormone(insulin); moreover,
ligand binding to the
extracellular domain induces
formation of receptor dimers.
TRANSMEMBRANE ENZYMES
TYROSINE KINASE

39. Intracellular
insulin effectsCytosol
Insulin

40. The JAK-STAT system consists of three main
components: (1) a receptor (2) Janus
kinase (JAK) and (3) Signal Transducer and
Activator of Transcription (STAT)
Many JAK-STAT pathways are expressed in
white blood cells, and are therefore involved
in regulation of the immune system.
 e.g interferones
TRANSMEMBRANE NON-ENZYMES
CYTOKINE S RECEPTORS

41. The phosphorylated STAT protein binds to another phosphorylated STAT protein
(dimerizes) and translocates into the cell nucleus. In the nucleus, it binds to DNA and
promotes transcription of genes responsive to STAT

42. NUCLEAR RECEPTORS
STEROID H, VIT D3, THYROXINE

44. INTRACELLULAR ENZYMES
GUANYLYL CYCLASE

45. 1. GPCR
2. ION Channels
3. Transmembrane enzymes
4. Transmembrane non-enzymes
5. Nuclear receptors
6. Intracellular enzymes
TYPES OF RECEPTORS

46. Effect by
membrane
receptors
Effect by
intracellular
receptors
Intracellular
molecules
Extracellular
molecules
Signal
molecules
cAMP, cGMP, IP3, DG, Ca2+
Proteins and peptides:
Hormones, cytokines
Amino acid derivatives:
Catecholamines
Fatty acid derivatives:
Prostaglandins
Steroid hormones,
Thyroxine, VD3

48.  Receptors are subjected to feedback regulation by their own
signaling outputs
 Continuous stimulation of cells with agonists generally results in
a state of desensitization(adaptation) or tachyphylaxis e.g beta2
agonist bronchodilator
 a decrease in the number of receptors to a message sited on
the cell membrane reduces the cell's sensitivity to the
message.That's called down-regulation.
 Similarly if the cell receives a weak signal, it can up-regulate by
pumping out more receptors such as to increase
the sensitivity to the weak message. So an increase in the
number of receptors to a message sited on the cell
membrane increases the cell's sensitivity to the message.That's
called up-regulation. For example, there is an increase in uterine
oxytocin receptors in the third trimester of pregnancy, promoting
the contraction of the smooth muscle of the uterus.
RECEPTORS DESENSITIZATION AND
REGULATION

49. Examples
Autonomic receptors
1. Adrenergic ( alpha – beta)
2. Cholinergic (muscarinic – nicotininc)
serotonergic receptors
Dopaminergic receptors
RECEPTORS AND NEUROTRANSMITTERS

50. 50
Parasympathetic
Effector
organ
Types of Autonomic Nerves
Adr.
Sk.m
Somatic N.
Sympathetic
Pre- ganglionic N
Post- ganglionic N.
M