PHARMACODYNAMICS

DRUG TARGETS
I. Receptors
II. Ion channels
III. Carrier molecules (transporters)
IV. Enzymes

RECEPTORS
● Receptor - a target molecule through which physiological mediators produce their effects
● Located in the cell membrane/ intracellular
● The binding of ligands to the receptor is specific like Lock & Key
- Exogenous ligands - drugs
- Endogenous ligands - neurotransmitters, hormones, growth factors

TYPES OF RECEPTORS

Types Mechanism Examples Time

Ligand-gated Coupled directly to an ion channel. The binding of Nicotinic ACh Milisecon
ion channels ligands activates and opens the channel, making a receptors; GABA ds
cell membrane permeable to specific ions receptors

G-protein Coupled to intracellular effector mechanisms via Muscarinic ACh Seconds

coupled G‐proteins that participate in signal transduction by receptors;
receptors coupling receptor binding to intracellular enzyme β-adrenoreceptors;
(GPCR) activation or the opening of an ion channel. dopamine receptors;
Secondary messenger systems include the enzymes, serotonin receptors;
 AC and GC, which generate cAMP and cGMP, opioid receptors
respectively

Kinase-linked Linked directly to an intracellular protein kinase that Insulin receptors; Hours
receptors triggers a cascade of phosphorylation reactions for cytokine receptors
protein synthesis

Nuclear Binding of a ligand that promotes/ inhibits synthesis Steroid hormone Hours to
receptors of new proteins receptors; thyroid days
hormone receptors; vit
D receptors

Ionotropic receptors Metabotropic receptors

A group of transmembrane ion A subtype of membrane receptors that do not form an ion
channels that open/close in channel pore but use signal transduction (G-proteins) to
response to the binding of a ligand activate a series of events using secondary messenger

Linked with ion channels Coupled with G-proteins

Second messenger-independent Second messenger-dependent

Short latency action Longer latency action

Rapid responses (milliseconds) Slower responses (seconds)

GPCRs
GENERAL MECHANISM OF ACTION
1. In the resting state, the Gα and Gβγ subunits are associated with one another, and GDP is
bound to Gα subunit
2. The binding of a ligand (agonist) to a GPCR causes the exchange of GTP for GDP on Gα
3. The Gβγ subunit dissociates from the Gα subunit, which diffuses to interact with effector
proteins and the GTP-Gα activates the effector
4. The GTP is hydrolysed to GDP due to the GTPase activity which causes the Gα subunit
to dissociate from the effector and reassociate with the Gβγ subunit

TYPES OF Gα SUBUNITS

Gα subunits Effects

Gsα Stimulates AC to increase cAMP formation

Giα Inhibits AC to decrease cAMP formation

Gqα Activates PL-C, increasing production of IP3 and DAG

SIGNALLING CASCADE OF Gq
1. A signal molecule activates the receptor and associated G-proteins
2. G-protein activates PL-C which converts membrane phospholipids, PIP2 into DAG
(remains in the inner layer membrane) and IP3 (diffuses into the cytoplasm)
3. DAG activates PK-C which phosphorylates proteins
4. IP3 stimulates the release of Ca2+ from ER and entry of Ca2+ across the membrane into the
cytosol, creating a Ca2+ signal

SIGNALLING CASCADE OF Gs
1. Signalling molecules (NE; E) activates the receptor (β-adrenoreceptors) and associated
G-proteins
2. Activated G-protein binds to and causes activation of AC in the plasma membrane
3. AC converts ATP molecules to cAMP molecules
 4. cAMP then activates PK-A which triggers the influx of Ca2+ into SR

SIGNALLING CASCADE OF Gi
1. Signalling molecules (ACh; Ado) binds to the receptor (M2 receptor; A1 receptor)
2. Activated G-protein inhibits the activation of AC which prevents the formation of cAMP
3. The decreasing level of cAMP cannot activate PK-A and the rest

SECONDARY MESSENGERS
● Relay signals received at receptors on the cell surface
● Amplify the strength of the signal
● 3 major classes:-
- cAMP and cGMP
- IP3 and DAG
- Ca2+

CYCLIC AMP
● Hormones that achieve their effects through cAMP:-
- Adrenaline
- Glucagon
- Luteinizing hormone
● cAMP is synthesized from ATP by the action of AC and hydrolysed to AMP
● Regulation of metabolism:-
- Increased lipolysis
 - Reduced glycogen synthesis
- Increased glycogen breakdown

CALCIUM IONS, Ca2+

● A rise in the concentration of Ca2+ in the cytosol triggers:-
- Muscle contraction
- Exocytosis
- Activation of T cells and B cells
- Adhesion of cells to the ECM
- A variety of biochemical changes mediated by PK-C
● 2 main depots of Ca2+ which are the extracellular fluid and ER in skeletal muscle
● The movement of Ca2+ into the cytosol is through:-
- Voltage-gated channels
- GPCRs

ADRENERGIC RECEPTORS

α-ADRENORECEPTORS
α1 α2

Potency order NE > E ≫ ISO E > NE ≫ ISO

Location Smooth muscle, liver Smooth muscle in GI tract, pancreatic

islet, nerve terminal

Transduction Gq Gi/o

Function Vasoconstriction, hypertensive, Decrease norepinephrine secretion,

mydriasis decrease insulin secretion

Agonist Phenylephrine, methoxamine Clonidine

Antagonist Prazosin, doxazocin Yohimbine, idozoxan

β-ADRENORECEPTORS
β1 β2

Potency order ISO > NE = E ISO > E ≫NE

Location heart Smooth muscle, liver

Transduction Gs Gs
Function Increase heart rate, lipolysis, Vasodilation, bronchodilation,
myocardial contraction glycogenolysis

Agonist Dobutamine, xamoterol Salbutamol, terbutaline, salmeterol,

formoterol, clenbuterol

Antagonist Atenolol, metoprolol Butoxamine

RECEPTORS DESENSITIZATION
● Receptor desensitization - repeated/ chronic exposure to agonists over a few minutes
causes a gradual decrease in the response of a receptor to a drug, resulting in a reduced
effect of the drug
● Due to a decrease in the number of receptors or a change in the way the receptors interact
with the drug
● Removal of the drug for an extended period allows the cell to recover its capacity to
respond
● Tolerance - gradual decrease in drug response which occurs over days/ weeks

TYPES OF DESENSITIZATION
● Homologous desensitization (agonist-dependent)
- loss of response solely to agonists that act at a particular GPCR subtype
- occurs rapidly at high agonist concentrations
- involve adaptive changes at the level of the GPCR itself
● Heterologous desensitization (agonist-independent)
- simultaneous loss of agonist responsiveness at multiple GPCR subtypes
- occurs rapidly at low agonist concentrations
- involve changes in signalling components downstream of the GPCR
MECHANISMS OF DESENSITIZATION
● Begins with receptor phosphorylation by an associated G protein-coupled receptor kinase
(GRK), specifically βARK
● Selectively modify activated receptors such that no heterogeneous desensitization will
occur

I. Uncoupling by phosphorylation and reversible binding of the β-arrestin

1. Agonist binds and activates the receptor
2. βARK is activated and phosphorylates the C-terminus of the β2 receptor
3. β-arrestin binds to the phosphorylated receptor resulting in the uncoupling of the
Gα subunit from the receptor, causing desensitization

II. Sequestration/ internalization by endocytosis (phosphorylation is not always necessary)

1. β-arrestin interacts with AP-2 which clusters clathrin-coated
2. Receptor internalization is initiated in clathrin-coated vesicles triggering new
signalling pathways by recruiting src/MAPK

III. Down-regulation due to increased receptor degradation and reduced synthesis

1. Upon sustained internalization, the internalized vesicles are targeted for fusion
with lysosomes for degradation
2. Or, the receptor is reinserted into the plasma membrane to recycle
UP/DOWN-REGULATION RECEPTOR
● Down-regulation - a decrease in the number of receptors due to increased exposure to an
agonist
● Up-regulation - an increase in the number of receptors due to increased exposure to an
antagonists

ALLOSTERIC MODULATIONS
● Allosteric modulators - a group of substances that bind to a receptor to change the
receptor's response to stimuli
● Allosteric binding site - a site that an allosteric modulator binds to
● Orthosteric binding site - a site that an endogenous agonist binds to
● Positive allosteric modulators (PAM) - increase agonist affinity and/or efficacy
- e.g. benzodiazepines, barbiturates
● Negative allosteric modulators (NAM) - decrease agonist affinity and/or efficacy
● Neutral allosteric modulators (SAM) - no effect on agonist activity but can stop other
modulators from binding to an allosteric site

1. Upon binding, modulators generally change the conformation of receptor

2. Often cause the orthosteric site to change, which can alter the affinity and/or
efficacy of the agonist
3. Some modulators act to stabilize conformational changes associated with the
agonist-bound state
4. This increases the probability of the receptor remaining in the active state for
longer for the agonist to bind
DOSE-RESPONSE CURVE
● Affinity - the intrinsic capability of a drug to bind to the receptor
● Potency - the concentration (EC50) or dose (ED50) of a drug required to produce 50% of
that drug’s maximal effect
- The smaller the EC50, the higher the potency
● Efficacy - the maximum effect which can be expected from a drug
- The higher the Emax, the greater the efficacy

AGONIST DOSE-RESPONSE CURVES

● Full agonist - achieves the maximal response effect at its maximally effective
concentration

● Partial agonist - has a lower maximal response than full agonist even at full receptor
occupancy
- In the presence of full agonist, the partial agonist will act as an antagonist,
competing with the full agonist for a finite number of binding sites. Thus, a high
concentration of full agonist is required to produce the same efficacy, but its
potency is reduced
 ● Inverse agonist - binds to the same receptor as an agonist but brings an opposite response
to that of an agonist (reduces the fraction of active receptors)
- Differ than antagonist, where it produces no effect on its own but blocks the
effects of both agonists and inverse agonists

ANTAGONIST-DOSE RESPONSE CURVES

● Antagonist - binds to prevent the activation of receptor
● Competitive antagonist - competes for the same binding site with an agonist and binds
reversibly
- The concentration of agonist is increased to produce a same maximal response
 - The potency of the agonist is reduced, but not the maximum efficacy
- Intensity of response depends on the concentration of both agonist and antagonist

● Non-competitive antagonist - does not compete with agonist for the same binding site and
binds irreversibly
- The maximal response is suppressed, thus reduced efficacy of agonist
- Maximal response depends only on the concentration of antagonist

QUANTAL DOSE-RESPONSE CURVES

● Median effective dose (ED50) - the dose at which 50% of individuals exhibit the specified
quantal effect
● Median toxic dose (TD50) - the dose required to produce a defined toxic effect in 50% of
subjects
● Median lethal dose (LD50) - the dose required to kill 50% of subjects
● Therapeutic window - the range between the minimum toxic dose and the minimum
therapeutic dose
● Therapeutic index - the ratio of the TD50 to the ED50
- The larger the value, the safer the drug
- Drugs with a narrow therapeutic index should be monitored more closely
- Drugs with a narrow index would need to be given more frequently and in smaller
doses