Mechanisms of Drug Action Flashcards
Learning Outcomes •Describe the different types of drug receptors (e.g. ion channel receptors, G-protein coupled receptors, membrane-bound enzymes)review •Explain the necessity for second messengers •Describe the basic processes of drug-receptor interactions •Describe the concepts of agonist, antagonist and receptor •Explain the dose-response relationship
What is pharmacodynamics?
‘What the drug does to the body’
Modes of action
Interaction with receptors and signaling pathways
Dose response relationships Biochemical and physiological effects of drugs
What are the 4 molecular mechanisms of Action?
- (Direct physicochemical effect)
- Transport systems
- Enzymes
- Interaction with the 4 major types of receptors (Cell signalling Part II)
Others: adhesion molecules, organelles and structural proteins
What are the three main transport systems?
- Ion Channels
- Cell membrane ion pumps
- Transporter (carrier proteins)
Give two examples of Ion Channels (see also Cell Signalling lecture)
Voltage (and Ligand-gated) ion channels Second-messenger-regulated – a second messenger regulated by a G-coupled protein receptor
Give three examples of Cell membrane ion pumps (see also Fundamentals of Physiology lecture)
Active transport of ions against their concentration gradients
Proton pump inhibitors (e.g., omeprazole) - K+/H+-ATPase in gastric parietal cells
Digoxin - Na+/K+-ATPase (cardiac tissue)
Give two examples of Transporter (carriers) proteins (see also Fundamentals of Physiology lecture)
Symport, Antiport
Thiazide diuretics - Block Na+ /Cl− co-transport in the renal tubule (symport)
Enzymes are involved in intracellular and extracellular synthesis and degradation of substrates, how?
A drug can inhibit the enzyme by:
- Binding to the active site – enzyme not able to bind to substrate
- Binding to another site in the enzyme, changing its conformation – enzyme not able to bind to substrate
(Drugs might be able to activate enzyme / increase its genetic transcription)
What are the 4 major types of receptors?
- Ligand gated ion channels (iontropic receptors)
- GPCR
- Kinase Linked receptors
4 Nuclear receptors
What 3 major types of receptors are transmembrane surface receptors, order by speed
- Ligand gated ion channels (iontropic receptors)
- GPCR
- Kinase Linked receptors
Which major type of receptor is cytoplasmic/ Nuclear receptor?
- Nuclear receptor
Brief outline of Ligand gated ion channels (iontropic receptors)
- Hyperpolarisation or depolarisation
- milliseconds
- Nicotinic/ACh receptor
Brief outline of GPCR (metabotropic)
- G-proteins
- Second messenger
- ions change in excitability
- protein phosphorylation
- Ca2+ release
- seconds
- Muscarinic/ACh receptors
Brief outline of Kinase Linked receptors
- Receptor/enzyme
- protein phosphorylation
- gene transcription
- hours
- cytokine receptors
Brief outline of Nuclear receptors
- nuclear receptor
- gene transcription
- protein synthesis
- hours
- oestrogen receptor
Gas, Gai, Gaq
Ga proteins coupled with intracellular signalling pathways. Can be stimulatory or inhibitory depending on the second messenger systems activated.
What are the three second messenger systems?
Intracellular chemicals:
- (GAS) Adenyl Cyclase–> cAMP–PKA
- (GAQ) PLC (phospholipase c)—> InsP3/DAG—> +ca2+—>PKC
- GC —> cGMP
What are the 3 GPCRs and their function and locations?
- GAS: AC–>cAMP–>PKA (Adrenergic receptors in lungs, asthma drugs (salbutamol act here)
- GAQ: PLC (phospholipase c)—> InsP3/DAG—>+Ca2+—>PKC (Muscarine acetylcholine receptors)
- GAI: inhibits AC thus no cAMP and no PKA
What are enzyme linked receptors? How do they work?
- Cytoplasmic enzymes that induce signalling are normally PROTEIN TYROSINE KINASES.
- Extracellular ligand binding, single transmembrane helix, cytoplasmic region containing PTK activity.
Receptor Tyrosine Kinases
- Single dimer molecule Ligand binds activating RECEPTOR TYROSINE KINASE, by receptor dimerization.
- Tyrosine residues in the intracellular domains are auto-phosphorylated in response to the signal
- Activates intracellular signalling proteins in the cytosol
- Typically, responses are slow (hours)
Enzyme linked receptors terminology
- Phosphorylation: the addition of a phosphate (PO43−) group to a protein or other organic molecule: turns many proteins on and off
- Dephosphorylation: turns some proteins on and off
- Kinases: is a type of enzyme that catalyses the transfer of phosphate groups
- Autophosphorylation: the phosphorylation of a protein by itself
Nuclear Receptors (cytoplasmic)
For signals that can cross the cell membrane, huge family of receptors such as oestrogen, thyroid, retinoic acid, and steroid hormone receptors ALTER gene transcription and hence protein levels directly
What are AGONISTS?
Give two examples of agonists
- Bind and simulate physiological regulatory effects of endogenous compounds
1. Full agonist(morphine)
2. Partial agonist (buprenorphine)
What are ANTAGONISTS?
Give 2 examples of antagonist
Bind but do not have regulatory effects and prevent the binding of the endogenous compounds
- Competitive Reversible (Beta blockers, atropine, naloxone, prazosin)
- -agonist will reach maximum peak, but s curve can move right or left - Non-competitive (phenoxybenzamine)
a. Irreversible: Binds irreversibly to the receptor (but interacts with same part of the receptor
b. Allosteric effect/ antagonist: Interacts with a different part of the receptor
- -agonist cannot reach maximum occupancy
What are the two other types of antagonism?
- Functional (or physiological)Drugs that have opposing physiological actions at different receptors. (E.g. Effects of histamine and adrenaline on arterial pressure)
- Chemical Binds to and inactivates the agonist (not the receptor), (E.g. Dimercaprol (chelating agent) and heavy metals (arsenic, mercury, antimony))
What is DRUG SELECTIVITY?
Give three examples
Drug selectivity: drug’s ability to bind to particular receptor, types or subtypes, such as β1 or β2-adrenoceptors
- Propranolol (a β-blocker) binds equally well to β1- and β2-adrenoceptors
- Metoprolol (a cardio selective β-blocker) binds selectively to β1-adrenoceptors
- Salbutamol (a β-agonist) binds selectively to β2-adrenoceptors
no drug is completely selective and may depend on dose
What is drug DESENSITISATION AND TOLERANCE?
What are the various mechanisms?
- Desensitisation or Tachyphylaxis: effect of a drug gradually diminishes when it is given continuously or repeatedly (minutes)
- Tolerance: term used to describe a more gradual decrease in responsiveness to a drug (hours / days / weeks)
E.g., opiates, benzodiazepines, barbiturates, stimulants
- Change in receptors (conformational changes, phosphorylation, neuromuscular junction)
- Translocation of receptors (e.g., β-adrenoceptors – up and down-regulation!)
What are Concentration / Dose-response curves?
How pharmacodynamics of a drug is quantified?
X axis: concentration•
Y axis: response
•Receptor binding – any drug needs affinity
•Agonists produce a response – need to be effective (how effective is measured with the max response (Rmax))—>potency
What is EC50 and how is it measured?
A measure of drug activity expressed in terms of the amount required to produce an effect of given intensity
•A measure of potency: half maximal effective concentration (EC50)
•The concentration of a drug, antibody or toxicant which induces a response halfway between the baseline and maximum after a specified exposure time
•In vivo, this is called an ED50(half maximal effective dose
Important terms: cmax, tmax, half life, area under curve, EC50, ED50, TD50, LD50
Cmax and tmax
•Half Life of a drug (t1/2)
Time for plasma drug concentration to reduce by half
Useful to know time taken to reach steady state and time required for drug elimination
•Area Under the Curve
Represents overall drug exposure
EC50(half maximal effect in an individual) / ED50(50% subjects respond to a drug) •Toxic Dose 50 (TD 50)
•Lethal Dose (LD50)
- Therapeutic Index Therapeutic Window
What is the therapeutic window?
The range of drug concentrations within which the drug exhibits maximum efficacy (desired effect) and minimum toxicity in the majority of patients •Quantified by the therapeutic index •TI = TD50 / ED50 Large TI = Wide Therapeutic window Small TI = Narrow Therapeutic Window
