unit 2: drug receptors & pharmacodynamics

Pharmacodynamics

* **effects of drugs** on biologic systems
* Actions/effects of the **drug on the body**
* Determines the **group in which the drug classified** and plays a major role in deciding **whether a group is appropriate therapy**
* How therapeutics will be applied

Receptors

* component of a cell or organism that **interacts with a drug and initiates the chain of events** leading to the __drug's observed effects__
* Specific molecules in a biologic system with which **drugs interact to** __**produce changes**__ in the function of the system

quantitative relations

**Receptors**:

Determine the ___ between dose or concentration of drug and pharmacologic effects

Selective

**Receptors**:

___ in choosing a drug molecule to bind to **avoid constant activation** by promiscuous binding of many different molecules

Changes its function

**Receptors**:

___ **upon binding** in such a way that the **function of the biologic system is altered** in order __to have pharmacological effect__

ligand-binding characteristics

**Receptors**:

Selective in ___

agonists and antagonists

**Receptors**:

**Mediate the actions of both pharmacologic ___**

proteins

**Receptors**:

Majority are ___ which provide the necessary **diversity and specificity of shape and electrical charge**

Receptor Site

**Receptors**:

* **Specific binding region** of the macromolecule
* **High and selective affinity** to the drug molecule
* **Interaction between the drug and the receptor** is the __fundamental event__ that **initiates the action of the drug**

drug binding

**Receptors**:

used to **identify or purify receptor proteins from tissue extracts**; consequently, receptors were discovered after the drugs that bind to them.

Orphan receptors

their natural ligands are presently **unknown**

Regulatory Proteins

**Classification of Receptors:**

* Proteins that have a **function on bodily physiologic mechanisms**
* **Best characterized** drug receptors
* **Mediates** the action of **endogenous chemical signals**
* **Mediates** the **effects** **of the most useful therapeutic agents**

Enzymes

**Classification of Receptors:**

* **Inhibited** (or less commonly, activated) by binding a drug
* Most of which are **metabolic** in nature

Transport Proteins

**Classification of Receptors:**

* Allows **passage** from one body compartment to another
* Can be useful **drug targets**

Na+/K+ ATPase

**Classification of Receptors:** *Transport Proteins*

* the membrane receptor for **cardioactive digitalis glycosides**
* prolong the phase wherein your heart muscles would be able to **return to their resting membrane potential**
* revert back the **normal polarized sodium/potassium concentration** inside and outside the heart muscles

Structural Proteins

**Classification of Receptors:**

* **tubulin**, the receptor for colchicine, an anti-inflammatory drug
* **stabilize the tubulin** present in our inflammatory cells so that **colchicine** will, somehow, **moderate or lessen the inflammatory process**

Effectors

* Molecules that **translate the drug-receptor interaction into a change** in cellular activity

adenylyl cyclase

**Effectors**:

one of the most common effector

**Lipid soluble drug** __crossing the plasma membrane and acts on intracellular receptor__

**Signaling Mechanisms:**

**inhibitory** **constraint** on the __transcription-stimulating activity__ of the protein

**Signaling Mechanisms:** *Intracellular Receptors for Lipid-Soluble Agents*

Mechanism of **glucocorticoid action**: **binding of glucocorticoid hormone to its normal receptor protein** relieves an ____

hsp90

**Signaling Mechanisms:** *Intracellular Receptors for Lipid-Soluble Agents*

Mechanism of **glucocorticoid action**: **heat-shock protein** binds to the receptor in the absence of hormone and __prevents folding into the active conformation__ of the receptor

Binding of a hormone ligand

**Signaling Mechanisms:** *Intracellular Receptors for Lipid-Soluble Agents*

Mechanism of **glucocorticoid action**: ___ causes **dissociation** of the hsp90 stabilizer and **permits conversion** to the active configuration.

__Transmembrane receptor protein-intracellular enzymatic activity__ is regulated by a **ligand** that **binds to the protein’s** __**extra**__**cellular domain**

**Signaling Mechanisms:**

* These are usually **water soluble drugs**

__Transmembrane receptor__ that binds and stimulates a **protein tyrosine kinase**

**Signaling Mechanisms:**

extracellular hormone-binding domain and a cytoplasmic enzyme domain

**Signaling Mechanisms:** *Protein tyrosine kinase*

These receptors are **polypeptides** consisting of an ___

hydrophobic segment

**Signaling Mechanisms:** *Protein tyrosine kinase*

two domains are connected by a ___ of the polypeptide that __resides in the lipid bilayer__ of the plasma membrane.

an **active dimeric** state

**Signaling Mechanisms:** *Protein tyrosine kinase*

Mechanism of **activation of the epidermal growth factor**:


1. Upon **binding of EGF** (circle), the receptor converts from its **inactive monomeric state** (left) to ___

phosphorylated (P)

**Signaling Mechanisms:** *Protein tyrosine kinase*

Mechanism of **activation of the epidermal growth factor**:


2. The **cytoplasmic domains** become ___ on **specific tyrosine residues (Y)**

3. phosphorylation of substrate proteins (S)

**Signaling Mechanisms:** *Protein tyrosine kinase*

Mechanism of **activation of the epidermal growth factor**:


3. Their **enzymatic activities** are __activated__, catalyzing ___

**JAK** (janus kinase)

**Signaling Mechanisms:** *Protein tyrosine kinase*

**one of the biggest group** of type of receptors; tyrosine kinase associated receptors

phosphorylation of signal transducers and activation of transcription (STAT) molecules

**Signaling Mechanisms:** *Protein tyrosine kinase*

**JAK** (janus kinase): *Cytokine receptors*

after activation by an appropriate ligand, (JAK) are activated, resulting in ___

**high energy reactions** (ADP-producing or consuming reactions)

**Signaling Mechanisms:** *Protein tyrosine kinase*

Kinases catalyze ___

binding of ligand

**Signaling Mechanisms:** *Protein tyrosine kinase*

The receptor tyrosine kinase signaling function begins with ___, typically a polypeptide hormone or growth factor, **to the receptor’s extracellular domain**

**dimerize**: bind to one another

**Signaling Mechanisms:** *Protein tyrosine kinase*

The resulting change in receptor conformation causes two receptor molecules to ___

dimerization

**Signaling Mechanisms:** *Protein tyrosine kinase*

drug **binds to the extracellular domain** of your receptor

dimers

**Signaling Mechanisms:** *Protein tyrosine kinase*

**activate the tyrosine kinase enzyme** __intracellularly__

phosphorylation of **tyrosine residues**

**Signaling Mechanisms:** *Protein tyrosine kinase*

Activated receptors catalyze ___ on different target signaling proteins, thereby allowing a **single activated receptor** complex to __modulate a number of biochemical processes__

Inhibitors

**Signaling Mechanisms:** *Protein tyrosine kinase*

used in treating **neoplastic disorders** in which **excessive growth factor signaling** is often involved

monoclonal antibodies

**Signaling Mechanisms:** *Protein tyrosine kinase*

bind to the extracellular domain of a particular receptor and **interfere with binding of growth factor**

membrane-permeant small molecule chemicals

**Signaling Mechanisms:** *Protein tyrosine kinase*

inhibit the **receptor’s kinase activity** in the cytoplasm

receptor down-regulation

**Signaling Mechanisms:** *Protein tyrosine kinase*

process that **limits** the **intensity and duration of action** of EGF, PDGF, and other agents that act via receptor tyrosine kinases

accelerated endocytosis

**Signaling Mechanisms:** *Protein tyrosine kinase*

Ligand binding often induces ___ of receptors from the cell surface, followed by the **degradation** of those receptors

**responsiveness to ligands**

**Signaling Mechanisms:** *Protein tyrosine kinase*

Receptor down-regulation:

When this process occurs at a rate **faster than de novo synthesis** of receptors, the total number of cell-surface receptors is **reduced**, the **cell’s ___** is correspondingly **diminished**.

limit the strength and duration of the growth factor signal

**Signaling Mechanisms:** *Protein tyrosine kinase*

down-regulation process is essential physiologically to ___

translocated in endocytic vesicles

**Signaling Mechanisms:** *Protein tyrosine kinase*

**Internalized nerve growth factor receptors** are __not__ __rapidly__ __degraded__ but are ___

**Ligand-gated transmembrane** **ion channel** which __regulates the opening of the ion channel__

**Signaling Mechanisms:**

* **mimic or block** the actions of natural agonists

inhibitory

**Signaling Mechanisms:** *Ligand-gated transmembrane ion channel*

Opening of chloride channel

excitatory

**Signaling Mechanisms:** *Ligand-gated transmembrane ion channel*

● Opening of sodium channel

nicotinic acetylcholine (ACh) receptor

**Signaling Mechanisms:** *Ligand-gated transmembrane ion channel*

* receptor molecule is depicted as embedded in a rectangular piece of plasma membrane
* receptor **opens a central transmembrane ion channel** when ACh binds to sites

**sodium** to enter

**Signaling Mechanisms:** *Ligand-gated transmembrane ion channel*

**Nicotinic acetylcholine (ACh) receptor:**

Once the **acetylcholine binds** to it, it would be able to allow the ___ the excitable tissue.

depolarization

**Signaling Mechanisms:** *Ligand-gated transmembrane ion channel*

**Nicotinic acetylcholine (ACh) receptor:**

Na+ to flow down its concentration gradient into cells, producing a **localized excitatory postsynaptic potential**

transient opening of a central aqueous channel

**Signaling Mechanisms:** *Ligand-gated transmembrane ion channel*

**Nicotinic acetylcholine (ACh) receptor:**

When acetylcholine binds to sites on the α subunits, a **conformational change** occurs that results in the ___

glutamate

**Signaling Mechanisms:** *Ligand-gated transmembrane ion channel*

receptors that **mediate excitatory neurotransmission** at central nervous system synapses bind ___

“flytrap”

**Signaling Mechanisms:** *Ligand-gated transmembrane ion channel*

receptors that **mediate excitatory neurotransmission:**

physically closes around the glutamate molecule; the glutamate-loaded domain then moves as a unit to control pore opening

uniform response

**Signaling Mechanisms:** *Ligand-gated transmembrane ion channel*

**nicotinic synapse controlling diaphragmatic respiration** maintain a ___

synaptic plasticity

**Signaling Mechanisms:** *Ligand-gated transmembrane ion channel*

regulation mechanisms can produce **long-term changes in the magnitude of the response** and contribute to ___ involved in learning and memory

**Voltage-gated** ion channels

**Signaling Mechanisms:** *Ligand-gated transmembrane ion channel*

__do not bind neurotransmitters__ directly but are **controlled by membrane potential**

“voltage sensor”

**Signaling Mechanisms:** *Ligand-gated transmembrane ion channel*

**Voltage-gated** ion channels:

**Drugs** that regulate voltage-gated channels typically bind to __a site of the receptor different from the charged amino acids__ that constitute the ___ **domain** of the protein used for channel opening by membrane potential.

**Transmembrane receptor is coupled with an effector enzyme G protein** which __modulates production of an intracellular second messenger__

**Signaling Mechanisms:**

* A transmembrane receptor protein that stimulates a **GTP-binding signal transducer protein**

**release of GDP** from the G protein

**Signaling Mechanisms:** *effector enzyme G protein*

guanine nucleotide-dependent activation-inactivation cycle of G proteins:


1. **agonist activates the receptor**, which promotes ___, allowing **entry of GTP** into the nucleotide binding site

effector enzyme or ion channel

**Signaling Mechanisms:** *effector enzyme G protein*

guanine nucleotide-dependent activation-inactivation cycle of G proteins:


2. In its GTP-bound state, the G protein **regulates** activity of

G protein-coupled receptors

**Signaling Mechanisms:** *effector enzyme G protein*

Receptors that signal via G proteins

G**s:** G Stimulatory Proteins

**G Proteins:**

**ß-Adrenergic amines**, histamine, serotonin, glucagon, and many other **hormones**

↑cAMP

**G Proteins:** *G****s***

↑Adenylyl cyclase

G**i1** , G**i2** , G**i3:** G Inhibitory Proteins

**G Proteins:**

**⍺2-Adrenergic amines**, acetylcholine (muscarinic), opioids, serotonin, and many others

↓cAMP

**G Proteins:** *G****i1*** *, G****i2*** *, G****i3***

↓Adenylyl cyclase

decreasing or inactivating adenylyl cyclase

**G Proteins:** *G****i1*** *, G****i2*** *, G****i3***

Primary mechanism

↓ Heart Rate

**G Proteins:** *G****i1*** *, G****i2*** *, G****i3***

Open cardiac K + channels

G**olf**

**G Proteins:**

**Odorants** (olfactory epithelium)

**↓** cAMP

**G Proteins:** *G****olf***

↑ Adenylyl cyclase

G**0**

**G Proteins:**

**Neurotransmitters** in brain

G**q**

**G Proteins:**

Acetylcholine (muscarinic), bombesin, serotonin (5-HT2), and others

↑IP3 , diacylglycerol, cytoplasmic Ca

**G Proteins:** *G****q***

↑Phospholipase C

G**t1** , G**t2**

**G Proteins:**

**Photons** (rhodopsin and color opsins in retinal rod and cone cells

↓cGMP (phototransduction)

**G Proteins:** *G****t1*** *, G****t2***

↑ cGMP phosphodiesterase

“**seven-transmembrane**” (7TM) or “**serpentine**” receptors

**G protein-coupled receptors:**

the receptor polypeptide chain “**snakes**” across the plasma membrane 7 times

Agonist binding

**G protein-coupled receptors:**

**stabilizes a conformational state** of the receptor’s **cytoplasmic surface** that __binds a critical regulatory surface of the G protein__

Primary Messenger

**Intracellular 2nd Messengers**:

drug )agonist or antagonist)

Secondary Messenger

**Intracellular 2nd Messengers**:

effectors inside the cell produced by the drug-receptor interaction

**cAMP** (Cyclic Adenosine Monophosphate)

**Intracellular 2nd Messengers**:

* Mediates **hormonal** responses
* Mimic epinephrine
* regulates the **production of adrenal and sex steroids**
* Most common
* product of enzyme adenylyl cyclase

catecholamines

**Intracellular 2nd Messengers**: *cAMP*

* breakdown of carbohydrates in the liver

vasopressin

**Intracellular 2nd Messengers**: *cAMP*

* Conservation of water by the kidneys

parathyroid hormone

**Intracellular 2nd Messengers**: *cAMP*

* Calcium homeostasis

beta-adrenomimetic catecholamines (beta-agonists)

**Intracellular 2nd Messengers**: *cAMP*

* Heart rate and contraction

Arginine & vasopressin

**Intracellular 2nd Messengers**: *cAMP*

* antidiuretic hormones for conservation of water

Phosphodiesterase Enzyme

**Intracellular 2nd Messengers**: *cAMP*

mechanism to stop cAMP

Phosphatase

**Intracellular 2nd Messengers**: *cAMP*

* catalyzes the **reverse** reaction
* cleaves phosphate from phosphorylated substrate which was initiated by cAMP
* **phosphorylated** substances are capable of **becoming** **substrates/products of metabolism**

Phosphodiesterase Inhibitors

**Intracellular 2nd Messengers**: *cAMP*

* can un-cyclize cAMP
* will not remove phosphate

Calcium and Phosphoinositides

**Intracellular 2nd Messengers**:

* Involves **hormonal stimulation of phosphoinositide hydrolysis**

Phospholipase C (PLC)

**Intracellular 2nd Messengers**: *Calcium and Phosphoinositides*

* crucial step is the stimulation of membrane enzyme

diacylglycerol (DAG) and (inositol-1,4,5-trisphosphate (IP3 or InsP3 )

**Intracellular 2nd Messengers**: *Calcium and Phosphoinositides*


1. PLC will cleave **phosphatidylinositol-4,5-bisphosphate (PIP2** ), into two second messengers, ___

Calcium

**Intracellular 2nd Messengers**: *Calcium and Phosphoinositides*

* IP3 is **water-soluble and diffuses through the cytoplasm** to trigger release of ___ by **binding to ligand-gated calcium channels** in the limiting membranes of internal storage vesicles

**increase in Ca2+** intracellularly

**Intracellular 2nd Messengers**: *Calcium and Phosphoinositides*

neurotransmitters are pushed to be exocytosed

Pyruvate Kinase-C (PK-C)

**Intracellular 2nd Messengers**: *Calcium and Phosphoinositides*


2. **Diacylglycerol** is confined to the membrane, where it activates a phospholipid- and calcium sensitive protein kinase called ___

Ca2+

**Intracellular 2nd Messengers**: *Calcium and Phosphoinositides*


3. binds with CaM

Phosphorylated Substrate

**Intracellular 2nd Messengers**: *Calcium and Phosphoinositides*


4. produces a response; caused by PK-C

cGMP (Cyclic Guanosine Monophosphate)

**Intracellular 2nd Messengers**:

* Ligands detected by **cell-surface receptors** stimulate **membrane-bound guanylyl cyclase**
* few signaling roles in a few cell types like the **intestinal mucosa and vascular smooth muscle cells**

kinase-mediated mechanism

**Intracellular 2nd Messengers**: *cGMP*

Increased cGMP concentration causes relaxation of vascular smooth muscles by a ___

Graded Dose-Response Curve

* **Response** of a particular receptor-effector system is measured __against increasing concentration of a drug__
* **Graph of the response** versus the **drug dose**
* **Sigmoid** curve

Emax

**Graded Dose-Response Curve:**

* **maximal response** that can be produced by a drug
* **all receptors are occupied,** no added effect
* **efficacy** of drug