PHAR0007
INTRODUCTION TO
PHARMACOLOGY
,INTRODUCTION TO DRUG TARGETS
CLASSIFICATION AND NAMES OF DRUGS
1. Therapeutic use (stating function of the drug)
a. Antihypertensive work against high blood pressure
b. Antiepileptic
2. Molecular mechanism of action
a. B-blocker beta adrenergic receptor blocker
b. Monoamine oxidase inhibitor stops breakdown of catecholamines
c. Ca2+ channel blocker stops stimulation of muscles or nerves
3. Chemistry
a. Benzodiazepine
b. Catecholamine
Approved name Brand name
Caprin (sinclair)
Aspirin Aspro (Roche)
Disprin (Reckitt & Colman)
Calpol
Paracetamol Panadol
Tylenol
Solpadein
Propranolol Inderal
Syprol
TARGETS OF DRUG ACTION
Drugs bind to more than one site with different effects
Selective toxicity
- Ehrlich realised importance of drug selectivity
- A drug will act selectively where its action is wanted
Drug selectivity achieved by:
I. Pharmacokinetics (Drug Motion): Using a higher concentration of the drug at the site of action
II. Pharmacodynamics (Drug Power): Using a drug with a higher affinity for desired site of action
Note: the target may be the patients own tissue or an invading organism
Drug Targets:
1. Drug action at a specific binding site
a. May exhibit high affinity for drug and high specificity due to stereochemistry of substrate cofactor binding
i. Hormone/neurotransmitter receptor bind agonists and antagonists specifically with high affinity
and specificity
ii. Enzymes (cholinesterase, monoamine oxidase) can be targeted by using pseudo substrates to
mitigate their effect
iii. Transporters shuttle substrates across membrane so the substrate selectivity is very high and
drugs can be targeted here to inhibit pumps
iv. Ion channels – local anaesthetics at Na+ channels
v. DNA binding to anticancer agents is based on specific helix and groove size of DNA
, 1. Anticancer agents fit into grooves of helixes or make bonds across different helices and
bases
2. Action not involving a specific binding site
a. Higher concentration of a drug needed to have a desired effect
i. General anaesthetic ether produces surgical anaesthesia only at concentrations above 20 mM
ii. Action of these drugs are less affected by changes in chemical structure
1. Wide variety of molecules produce general anaesthesis
BENEFIT AND RISK
Amount of risk acceptable influenced by severity of medical condition
- Benefit of drug is worth the risk is condition is severe
Ehrlich’s therapeutic index:
𝐦𝐚𝐱𝐢𝐦𝐮𝐦 𝐧𝐨𝐧 − 𝐭𝐨𝐱𝐢𝐜 𝐝𝐨𝐬𝐞
=
𝐦𝐢𝐧𝐢𝐦𝐮𝐦 𝐞𝐟𝐟𝐞𝐜𝐭𝐢𝐯𝐞 𝐝𝐨𝐬𝐞
Difficult to define what a non-toxic dose is
Improved measure:
Humans
𝑇𝐷50
𝑇ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝐼𝑛𝑑𝑒𝑥 =
𝐸𝐷50
Animals
𝑇ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝐼𝑛𝑑𝑒𝑥
𝐿𝐷50
=
𝐸𝐷50
, RECEPTOR STRUCTURE
TYPES OF RECEPTORS
Proteins that are the site of action of neurotransmitters, hormones, growth factors and other inter-cellular (cell-to-cell)
signalling molecules
I. Ligand-gated ion channels (transmembrane)
a. Nicotinic acetylcholine receptor
II. G-protein-coupled receptors (transmembrane)
a. Muscarinic acetylcholine receptor
III. Kinase-linked and related receptors (transmembrane)
a. Insulin receptor
IV. Nuclear receptors (intracellular)
a. Oestrogen receptor
b. Signalling molecules acting upon them can cross the lipid bilayer and act on the receptor inside the
membrane
LIGAND-GATED ION CHANNELS
AKA agonist-activated ion channels / neurotransmitter-gated ion channels / ionotropic receptors
FEATURES
- Multi-subunit (oligomeric) transmembrane proteins involved in rapid signal transduction
o Forms ring-like structure in the centre which is an ion channel
o Conformational changes that take place in protein subunits resulting in opening and closing of ion
channel
- Neurotransmitters bind to site on extracellular domain
- Binding of the agonist/neurotransmitter is coupled to a conformational change resulting in opening of an integral
ion channel
- Found in synapses in CNS, PNS or on effector tissues that need to respond rapidly (skeletal muscle)
o Physical gap between adjacent nerves and muscles at sites of chemical transmission are very small
allowing NT molecules to diffuse across the gap between pre and post synaptic cell
▪ Concentrations of NT molecules in cleft are high
• Receptor has low affinity for the ligand allowing it to dissociate rapidly helping to
terminate response rapidly
Neurotransmitter Receptor
Acetylcholine Nicotinic acetylcholine receptors (ionotropic):
- signal muscular contraction with stimulation
- Na influx/K efflux
- Depolarisation
- E.g. muscle contraction
- Found in the neuromuscular junction of skeletal muscle, in ganglia of both
sympathetic and parasympathetic nervous systems, and sympathetic
innervation of skeletal muscle
Muscarinic acetylcholine receptors (GPCR):
- nervous system in the regulation of smooth muscle activity, wakefulness,
hormone secretion, heart rate, etc.
- second messenger signalling
5-HT 5-HT type 3 receptor
INTRODUCTION TO
PHARMACOLOGY
,INTRODUCTION TO DRUG TARGETS
CLASSIFICATION AND NAMES OF DRUGS
1. Therapeutic use (stating function of the drug)
a. Antihypertensive work against high blood pressure
b. Antiepileptic
2. Molecular mechanism of action
a. B-blocker beta adrenergic receptor blocker
b. Monoamine oxidase inhibitor stops breakdown of catecholamines
c. Ca2+ channel blocker stops stimulation of muscles or nerves
3. Chemistry
a. Benzodiazepine
b. Catecholamine
Approved name Brand name
Caprin (sinclair)
Aspirin Aspro (Roche)
Disprin (Reckitt & Colman)
Calpol
Paracetamol Panadol
Tylenol
Solpadein
Propranolol Inderal
Syprol
TARGETS OF DRUG ACTION
Drugs bind to more than one site with different effects
Selective toxicity
- Ehrlich realised importance of drug selectivity
- A drug will act selectively where its action is wanted
Drug selectivity achieved by:
I. Pharmacokinetics (Drug Motion): Using a higher concentration of the drug at the site of action
II. Pharmacodynamics (Drug Power): Using a drug with a higher affinity for desired site of action
Note: the target may be the patients own tissue or an invading organism
Drug Targets:
1. Drug action at a specific binding site
a. May exhibit high affinity for drug and high specificity due to stereochemistry of substrate cofactor binding
i. Hormone/neurotransmitter receptor bind agonists and antagonists specifically with high affinity
and specificity
ii. Enzymes (cholinesterase, monoamine oxidase) can be targeted by using pseudo substrates to
mitigate their effect
iii. Transporters shuttle substrates across membrane so the substrate selectivity is very high and
drugs can be targeted here to inhibit pumps
iv. Ion channels – local anaesthetics at Na+ channels
v. DNA binding to anticancer agents is based on specific helix and groove size of DNA
, 1. Anticancer agents fit into grooves of helixes or make bonds across different helices and
bases
2. Action not involving a specific binding site
a. Higher concentration of a drug needed to have a desired effect
i. General anaesthetic ether produces surgical anaesthesia only at concentrations above 20 mM
ii. Action of these drugs are less affected by changes in chemical structure
1. Wide variety of molecules produce general anaesthesis
BENEFIT AND RISK
Amount of risk acceptable influenced by severity of medical condition
- Benefit of drug is worth the risk is condition is severe
Ehrlich’s therapeutic index:
𝐦𝐚𝐱𝐢𝐦𝐮𝐦 𝐧𝐨𝐧 − 𝐭𝐨𝐱𝐢𝐜 𝐝𝐨𝐬𝐞
=
𝐦𝐢𝐧𝐢𝐦𝐮𝐦 𝐞𝐟𝐟𝐞𝐜𝐭𝐢𝐯𝐞 𝐝𝐨𝐬𝐞
Difficult to define what a non-toxic dose is
Improved measure:
Humans
𝑇𝐷50
𝑇ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝐼𝑛𝑑𝑒𝑥 =
𝐸𝐷50
Animals
𝑇ℎ𝑒𝑟𝑎𝑝𝑒𝑢𝑡𝑖𝑐 𝐼𝑛𝑑𝑒𝑥
𝐿𝐷50
=
𝐸𝐷50
, RECEPTOR STRUCTURE
TYPES OF RECEPTORS
Proteins that are the site of action of neurotransmitters, hormones, growth factors and other inter-cellular (cell-to-cell)
signalling molecules
I. Ligand-gated ion channels (transmembrane)
a. Nicotinic acetylcholine receptor
II. G-protein-coupled receptors (transmembrane)
a. Muscarinic acetylcholine receptor
III. Kinase-linked and related receptors (transmembrane)
a. Insulin receptor
IV. Nuclear receptors (intracellular)
a. Oestrogen receptor
b. Signalling molecules acting upon them can cross the lipid bilayer and act on the receptor inside the
membrane
LIGAND-GATED ION CHANNELS
AKA agonist-activated ion channels / neurotransmitter-gated ion channels / ionotropic receptors
FEATURES
- Multi-subunit (oligomeric) transmembrane proteins involved in rapid signal transduction
o Forms ring-like structure in the centre which is an ion channel
o Conformational changes that take place in protein subunits resulting in opening and closing of ion
channel
- Neurotransmitters bind to site on extracellular domain
- Binding of the agonist/neurotransmitter is coupled to a conformational change resulting in opening of an integral
ion channel
- Found in synapses in CNS, PNS or on effector tissues that need to respond rapidly (skeletal muscle)
o Physical gap between adjacent nerves and muscles at sites of chemical transmission are very small
allowing NT molecules to diffuse across the gap between pre and post synaptic cell
▪ Concentrations of NT molecules in cleft are high
• Receptor has low affinity for the ligand allowing it to dissociate rapidly helping to
terminate response rapidly
Neurotransmitter Receptor
Acetylcholine Nicotinic acetylcholine receptors (ionotropic):
- signal muscular contraction with stimulation
- Na influx/K efflux
- Depolarisation
- E.g. muscle contraction
- Found in the neuromuscular junction of skeletal muscle, in ganglia of both
sympathetic and parasympathetic nervous systems, and sympathetic
innervation of skeletal muscle
Muscarinic acetylcholine receptors (GPCR):
- nervous system in the regulation of smooth muscle activity, wakefulness,
hormone secretion, heart rate, etc.
- second messenger signalling
5-HT 5-HT type 3 receptor
