Receptors And Determinants Of Biologic Response

Drug Receptors & Determinants of biological responses

By:

Dr. Arlene Maceren Diaz Chairman Pharmacology Dept. S.W.U MHAM College of Medicine

Pharmacodynamics and Drug Receptors Definition of Terms:  Receptor – a macromolecular component of a cell that interacts with a drug leading to a chain of biochemical events resulting to an observable effects of drug action. They are mostly protein in nature.  Affinity – is the ability of a drug to bind to a receptor; or it is the ability of a drug to have full occupancy of the receptor.  Intrinsic activity – is the ability of the drug to activate the receptor site leading to a chain of biochemical events. (resulting to an observable effects of drug action).

 Efficacy – refers to the magnitude of the maximum effect. Produce by the drug when it bind to the receptors.  Potency – refers to the relative concentration required to produce a given magnitude of effects. It denotes the amount of drug needed to produce a given effect.  Agonist – is a drug that has affinity, intrinsic activity and efficacy.  Antagonist – is a drug that has affinity but lack intrinsic activity.  Pure Antagonist - is a drug that has affinity but lack intrinsic activity and has no efficacy. They inhibit or abolish the action of the agonist.  Partial Agonist/Antagonist – a drug that has affinity and produces little efficacy. They may reduce the effects of an agonist.

Features of Receptors  Protein : Lipoprotein, glycoprotein  Mol wt: 45-200 kilodaltons  Drug binding : reversible , specificity to binding is not absolute – leading to drug binding to several receptor types  Receptors are saturable because of finite number of receptors  Specific binding of receptors results in signal transduction via second messenger to intracellular site.  May require more than one drug molecule to bind to receptor to generate signal

Features of Receptors  Magnitude of signal depends on the number of receptors occupied.  Receptors must have properties of recognition and transduction  By acting on receptor, drugs can enhance, diminish or block generation or transmission of signal  Drugs are receptor modulators and do not confer new properties on cell or tissues  Receptors regulated

can

be

upregulated

or

down

2 Functions of a Receptor 1. Ligand binding – Receptor binds to endogenous regulatory ligand such as hormones, neurostransmitters and autocoids to produce physiological normal functions 3. Message Propagation – A receptor regulate the activity of a certain enzyme (Receptor – effector system) which is the effector – that synthesizes the second messenger which in turn propogate the signal or message.

Example: Receptor

Receptor

Effector Adenylyl cyclase

Synthesis of 3 adenosine 3’5’ monophosphate (cyclic AMP)

Effector Adenylyl system

Four Molecular Mechanisms by which Receptors Transduce Signals 1. Direct receptor control of ion – channel (ligand gated or voltage gated) 3. Receptor – controlled generation of second messenger (G-protein-cAMP and G-Proteinphosphoinositide system) 5. Receptor – initiated phosphorylation involving tyrosine kinase 7. Receptor initiated steroid hormones activity

I.

Ion – Channel Receptors

-the mechanism of action of several hormones and neurotransmitters is due directly to enhance movement of ions across the plasma membrane. The hormone or the neurotransmitter receptor (ligand bound receptor) is itself an ion channel. Ion Channel

Ion Selectivity

Effect

1.Nicotinic Acetylcholine Na+ / k+

Depolarize

2. GABA

Cl

Hyperpolarize

3. Glycine

Cl

Hyperpolarize

4. Glutamate a. N-methyl-D-aspartate b. Quisqualate c. Kainate

Na, Cl, k Na, k Na, k

Depolarize Depolarize

Nicotinic Acetylcholine Receptors – is found on the muscle cell end plate in the neurotransmitter junction at all autonomic ganglia and in the CNS. The role of the acetylcholine receptor is to convert the binding of the neurotransmitter acetylcholine into an electrical signal in the cells of the organ containing the receptor. It opens a pore for Na+ or K+ ions to pass through the cell membrane leading to depolarization of cell membrane potential.

GABA Receptor  is the major inhibitory neurotransmitter in the mammalian brain. It inhibits neuronal hyperpolarization resulting from increase chloride conductance and is attributed to the inhibitory actions are enhanced by the presence of barbiturate or benzodiazepine by the presence of barbiturate or benzodiazepine.

Gylcine Receptor  is the principal neurotransmitter in the mammalian spinal cord and brain stem. It is like GABA, inhibiting neuronal firing by activating a chloride ion conductance which hyperpolarize excitable membrane.

Glutamate Receptor  mediates Na-K ion depolarizing conductance and is responsible for most fast excitatory postsynaptic potential of brain and spinal cord

Receptor –G-protein Effector System or the Gprotein based Second Messenger Receptors -Dozen of pharmacologically important Hormone and neurotransmitter receptors are dependent on Gproteins to mediate their action on cells. This include: Adrenergic receptors Muscarinic acetylcholine receptors Serotonergic receptors Dopaminergic peptide receptors

G-proteins form a family of membrane assoc. proteins that serve a key role in receptor modification of the second messenger activity. The second messenger usually involve are: a. cAMP (cyclic adenosine monophosphate) b. Inositol triphosphate (IP3) c. Diacylclycerol (DAG)

How – G – Protein Receptor Effector System Works  Receptor is activated by a ligand  Activated receptor interacts with the ∝ subunit of the G protein  Release of bound GDP and binding of GTP  The active GTP bound form of the protein then interacts with adenylate cyclase  Adenylate cyclase – controls formation of the second messenger – cyclic AMP

R1 Gs α βγ

Adenylate Cyclase

R2 G1

ATP cyclic AMP Protein kinase (inactive)

Protein kinase (active)

Schematic diagram of surface receptor-second messenger system

Four Functional Group of G – Proteins I.

Gs- which couple stimulatory receptors to adenylate cyclase.

Examples of Receptors that stimulate adenylate cyclase:

1. β-adrenergic II.

2. Histamine H2

3. Dopamine D1

G1- which couple inhibitory receptor to adenylate cyclase

III. G0- believe to couple ion channel (calcium channels) IV.

Gq – which couples receptors to activation of phospholipaseC– this phosphodiesterase type of enzyme catalyzes the hydrolysis of membrane phospholipids known as phosphoinositides. The hydrolysis releases inosital 1,4,5 triphosphate (IP3) and 1,2 diacylglycerol (DAG) which function as second messengers.

Examples of receptor using the phosphorinositides signaling system Alpha (∝) adrenergic receptors Muscarinic M 1 or M 2 receptors Serotonin 5 HT2 receptors Thyrotropin releasing hormone (TRH) (4a) receptors

Major Receptor Types for Autonomic Transmitters Transmitter

Receptor Type

G – Protein

Effect

Acetylcholine

Nicotinic

None (Ion-channel receptor)

Opens Na+ - K+ depolarizes cell

Muscarinic

Gq (smooth muscle and some glands

 2nd messenger IP3 and DAG

G1 Cardiac muscle

 cAMP opens K+ channels

Norepinephrine

Alpha ∝1

Gq  2nd messenger (smooth muscle and some IP3 and DAG glands)

∝2

G1 (smooth preganglionic CNS)

β1, β2, β3

Gs Increases Smooth and cardiac muscle, second juxtaglomerular apparatus, messenger cAMP adipocytes

 second muscle messenger cAMP

Receptors Tyrosine Kinases 

Are critical proteins in the control of cell growth differentiation

 The activation of receptor tyrosine kinases results when the agonist binds to the receptor which then undergoes phosphorylatio0n on specific tyrosine residues. 

This results to an increase tyrosine phosphorylations on cytosolic substrate and there is activation of cellular protein kinases and enhanced transport of ions and nutrients across the plasma membrane.

Agonist Molecules

OUT IN

P Protein Kinase (inactive)

P

Protein Kinase

Protein Kinase

(inactive)

(active)

This includes group of receptors for:  Insulin  Epidermal growth factor  Platelet derived growth factor  Hepatocyte growth factor

Steroids Hormone receptors  are important in the regulation of development and homeostatic processes.

diverse

Mechanism of Action of Steroid Hormone is attributed to their penetration into cells and their high affinity binding to intracellular receptors.

Receptors Desensitization  the loss of response of a receptor on exposure to an agonist on continuous basis.

Down regulating of receptors  when the receptors are exposed to agonist the receptors move in the plane of the membrane and appear to concentrate in the coated pits where they may be degraded by lysosomes. This results in smaller number of receptors and eventually desensitization

Upregulation of receptors  results from exposure of receptor to an antagonist. This will result to supersensitivity

Presynaptic terminal

Postsynaptic

Normal Synapse

terminal DECREASED STIMULATION INCREASED STIMULATION

Receptor desensitization / down regulation

Receptor supersensitivity

Determinants of response to drugs  Biologic variation 1. Hypersusceptibility / Drug intoleranceExaggerated response to an ordinary dose of a drug (Supersentivity) 3. Idiosyncrasy – extreme susceptibility of an individual to an expected pharmacologic action. 5. Drug allergy – is a response that results from a previous exposure to a drug; it is mediated by an immunologic mechanism

Drug Acts as antigen

 Disease process or pathological condition that influence response a. Liver disease b. Renal disease

 Presence of other drugs I. Summation 1. additive effect – when 2 drugs are given and half of each dose used simultaneously elicits the same effect as the full dose of either drug use alone.

Example: 1. Additive Effect = ½ + ½ = 1 Codeine = Narcotic Analgesic = 60 mgs Aspirin = Non-steroidal Anti-inflammatory Analgesic = 325mg Combine: Aspirin 160 mg

Lesser GIT irritation

+

Codeine 30 mg Lesser resp. depression

=

Paralgin or Codalgine

Stronger analgesic with Anti-inflammatory effect

2. Synergism – if the response is greater than that of the full dose of either drug. Example: Synergism = 1 + 1 = 3 Sulfamethoxazole Narrow Spectrum

+ Trimethoprim

Extended Spectrum

-

Co-trimoxazole

Broad Spectrum

3. Potentiation - a drug that appears to have no action when given alone increases the potency of a second drug. Example: Potentiation = 0 + 1 = 2 Clavulanic Acid

Beta Lactamase inhibitor no Antibacterial activity

+

Amoxycillin

Antibacterial activity but easily destroyed by Betalactamase producing Bacteria

=

Co-Amoxyclav (Augmentin)

Antibacterial and resistant to the destruction of Beta lactamase

II. Antagonism 1 + 1 = 0 - Diminishing response by opposing actions of 2 drugs ST I N GO

A

AGONIST

Physiological Effect

AG

ANTAGONIST

No Effect

ON

IS

T

Kinds of antagonism 3. Chemical – one drug is rendered inert or inactive by precipitation, conjugation, oxidation 5. Physiological antagonism – 2 drugs have opposing action on the same physiologic sites 7. Competitive antagonism – when 2 drugs will compete on a certain receptor cell and the antagonist displaces the other drug from the receptor site.

IV. Pharmacokinetic antagonism – drugs may affect efficacy of other drugs by: a. b. c. d. e.

Altered absorption from GIT Reduce binding to plasma protein Altered renal excretion Inhibition of metabolic degradation Induction of metabolic degradation

Altered dose – response metabolism.

due

to

special

features

of

drug

a. Cumulative or cumulative effect b. Tolerance c. Tachyphylaxis

I will praise you, for I am fearfully and wonderfully made. Psalm 139:14