Pharmacodynamic

• Anna Wiktorowska-Owczarek

• awiktorowska@tlen.pl

Pharmacodynamics

Mechanisms of drug action and the relationship between drug concentration and its effect

Pharmacodynamics

• Can be defined as:– the study of the biochemical and

physiological effects of drugs and their mechanisms of action

– the chemical or physical interactions between drug and target cell

Why do we want to know mechanisms of drug action?

• Such a complete analysis provides the basis for– the rational therapeutic use of drug– adverse effects– the design of new therapeutic agents

Mechanisms of drug action

• The effects of most drugs result from their interaction with macromolecular components of the organism.

• These interactions initiate the biochemical and physiological changes that the characteristic of the response to the drug.

Mechanism of drug action• Drug in site of action

↓

• Drug interaction with component of the organism

↓

• Alteration of function of the component

↓

• Initiation of the biochemical and physiological changes

Drug receptors• Proteins form the most important class of

drug receptors.• The term receptor denotes the component

of the organism with which the chemical agent was presumed to interact.

• Membrane receptors contain one or more hydrophobic membrane-spanning α-helical segments, linking the extracellular ligand-binding region of the receptor to the intracellular domain which is involved in signalling.

Membrane receptors contain one or more hydrophobic membrane-

spanning α-helical segments, linking the extracellular ligand-binding region

of the receptor to the intracellular domain which is involved in signalling.

Interaction with receptor

Agonist

↓

Receptor

↓

Generation of second message

↓

Change in cellular activity

Drug receptors

• Agonist combines with receptor and activate the receptor. Agonists initiate changes in cell function, producing effects of various types

• Antagonist may combine at the same site without causing activation. Antagonist blocks the binding of the endogenous agonist.

• Ligand is small molecule that may function either as an agonist or as an antagonist.

Ligands

Ligands

Hormones

Neurotransmitters

Exogenous substances (drug)

AntagonistAgonist

Drug receptors• Drugs acting on receptors may be

agonists or antagonists• Agonists initiate changes in cell

function, producing effects of various types; antagonists bind to receptors without initiating such changes.

• Agonist potency depends on two parameters: affinity (i.e. tendency to bind to receptors) and efficacy (i.e. ability, once bound, to initiate changes which lead to effects).

Drug receptors• For antagonists, efficacy is zero.

• Full agonists (which can produce maximal effects) have high efficacy; partial agonists (which can produce only submaximal effects) have intermediate efficacy.

Drug receptors

• Tolerance –this term is used to describe a more gradual decrease in responsiveness to a drug, taking days or weeks to develope.

• Tolerance to drug effects results in a decrease in response with repeated doses.

• Tachyphylaxis is a medical term describing a rapidly decreasing response to a drug following administration of the initial doses.

Drug receptors

• Desensitisation is used to describe both long-term or short-term changes in dose-response relationship arising from a decrease in response of the receptor.

• Desensitisation can occur by a number of mechanisms: – Decreased receptor numbers

(downregulation)– Decreased receptor binding affinity– Decreased G-protein coupling

Drug targets• Receptors (for hormones/neurotransmitters)

– adrenergic β-receptor blockers• Enzymes

– angiotensin converting enzyme inhibitors• Carrier molecules

– serotonin reuptake inhibitors• Ion channels

– GABA agonists• Idiosyncratic targets (metal ions, gastric content)

– cholestyramine• Nucleic acids

– antiviral agents

Types of receptors

• Receptor-operated channels

• G-protein-coupled receptors

• Tyrosine kinase receptors

• DNA-coupled receptors

Receptor-operated channels

• Subunits – 4 TMs each• Binding of ligand conformational changes

opening of ion-selective pore membrane depolarization or hyperpolarization

• Three states:– open– closed– inactivated

• Very rapid transduction (ms)

Receptor-operated channels

• Examples– GABAA receptor

• benzodiazepines

– nicotinic cholinergic receptor– glycine receptor

– 5-HT3 serotonin receptor

G-protein-coupled receptors

• Membrane proteins with 7 transmembrane helical domains– 7-TM receptors

• N-terminal part extracellular binds ligands

• C-terminal part intracellular binds G-proteins

G-protein-coupled receptors• G-proteins trimeric proteins

– three subunits: α, β, γ– ligand binds to receptor G-protein separates

from the receptor and α separates from βγ dimer– α and βγ stimulate intracellular signalling

pathways (depending on subtypes)• adenylate cyclase (AC) (+) or (-) cAMP protein kinase A (PKA)

• phospholipase C-β (PLC) DAG, IP3 PKC, Ca2+ channel

The G-protein system

• The α-subunit binds GDP/GTP, it also has GTPase activity. The α-subunit/GTP complex is active while GTP is bound to it. The α-subunit/GTP complex is inactivated when the GTP is hydrolysed to GDP.

• The β-subunits remains associated with the γ-subunit when the receptor is occupied and the combined βγ-subunit may activate cellular enzyme.

• The γ-subunit

Second messenger systems

• Cyclic nucleotide system. This system is based on cyclic nucleotides such as cyclic adenosine monophosphate (cAMP), which is synthesised from ATP via enzyme adenylate cyclase. The cAMP is inactivated by hydrolysis by a phosphodiesterase enzyme to give AMP.

Second messenger systems

• The phosphatidylinositol system. This system is based on inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG), which are synthesised from the membrane phospholipid phosphatidylinositol 4,5-bis-phosphate (PIP2), by the enzyme phospholipase Cβ.

Types of G-proteins

• Gs stimulates membrane-bound adenylate cyclase to increase cAMP

• Gi (and Go) inhibits adenylate cyclase to decrease cAMP

• Gq (and G12) activates phospholipase C

The intracellular consequences of receptor activation and G-protein

dissociation.

Receptor linked to G-protein

Gi

Gs

+

- Adenylate cyclase

cAMP Protein kinase A

Phospholipase C

DAG

IP3

Protein kinase C

Release of calcium from sarcoplasmic reticulum

Intracellular enzymes

Ion channels (Ca and K)

Contractile proteins

Gq

+

G-protein-coupled receptors

• Examples:– adrenergic receptors

• α-adrenomimetics vasoconstriction– muscarinic cholinergic receptors– dopamine receptors

• antipsychotic drugs antagonists

Tyrosine kinase receptors

• Three domains– extracellular (ligand binding) domain– transmembrane domain– intracellular (catalytic) domain tyrosine kinase

activity

• Ligand binding autophosphorylation binding and phosphorylation of other target proteins

Tyrosine kinase receptors

• Examples:– insulin receptor– epidermal growth factor receptor– VEGF -receptor

DNA-coupled receptors

• Binding to nuclear DNA fragments when activated by ligands– promote or inhibit gene expression– sometimes ligand binding causes

dissociation of inhibitory protein (e.g., HSP90)

– stay in the cytoplasm agonist must enter the cell

• when activated migrate to the nucleus – slow process

DNA-coupled receptors

• Examples:– Corticosteroids:

• Glucocorticoid receptor• Mineralocorticoid receptor

– Thyroid hormone receptor– Vitamin D receptor– Retinoic acid receptor

Other sites of drug action

• Specific enzymes: – Acetylcholinesterase (AChE) →

anticholinesterase drugs– Cyclo-oxygenase → NSAIDs (Non

Steroidal Anti-Inflammatory Drugs )– Angiotensin-converting enzyme → ACE

inhibitors– Phosphodiesterase →

Phosphodiesterase inhibitors

Other sites of drug action

• Specific enzymes and nucleic acid. The anticancer drugs inhibit enzymes involved in purine, pyrimidine or DNA synthesis.

Other sites of drug action

• Specific cell membrane ion pumps. – For example, Na/K-ATPase in the brain

is activated by the anticonvulsant phenytoin whereas that in cardiac tissue is inhibited by digoxin;

– K/H-ATPase (proton pump) in gastric parietal cells is inhibited by omeprazole.

Other sites of drug action

• Ion channels– Voltage-gated Na channels → Local

anaesthetic– Voltage –gated Ca channels →

Dihydropyridines