Poma Introduction To Pharmacology

Mechanism of drug action:

 Selectivity: no drugs show complete specificity but rather selectivity, i.e. preference. At lower concentration the drug may only act on one receptor while at higher concentration, other receptor will be affected
 Affinity: the tendency of a drug to bind to a receptor measured by the concentration at which 50% of receptors are bound.
 Response and affinity: the relationship between receptor occupancy and response is not strictly proportional.
- considerable amplification may exist (low occupancy producing max response)
- other factors downstream from binding to produce the final response
- drug may bind strongly to receptor but produce no effect
 Potency: the strength of a drug to be able to produce a biological effect and is measured by the effective concentration (EC) at which 50% of the full biological response is achieved.
 Efficacy: the ability of a drug to bind to a receptor and cause a change in the receptor’s action
- agonists: a drug with positive efficacy (activate receptor)
- inverse agonists: a drug with negative efficacy (decrease basal receptor activity)
- antagonists: a drug that binds to receptor but have no efficacy
 Agonism:
- full agonist: drugs that is able to produce maximum tissue response
- partial agonist: drugs that can only produce less than maximum of the response, i.e. lower Emax. Hence even at 100% occupancy, maximal response is not reached.
 Antagonism: have affinity but no efficacy
 Effect of partial agonist:
- reversible: shifts response curve to right as higher concentration of full agonists is need to achieve the same biological effect (partially lowered by partial agonist)
- irreversible: lower Emax
 Effect of antagonist:
- reversible: shifts the response curve to the right
- irreversible: lower Emax (drug binds covalently and reduce number of available receptors)
- when there is low receptor occupancy, irreversible look like reversible antagonist
 Physiological antagonism: sometimes a drug can look like an antagonist for another enzyme without actually binding to that enzyme’s receptor. This is because antagonist itself binds to a receptor that produces an opposing effect to the enzyme.
 Inverse agonism: requires the system to be basally active so inverse agonists are clinically more advantage as it can reduce the functionality while antagonist does nothing.

Drug Targets

 Enzymes Drug Targets: drugs which act on enzymes are usually competitive inhibitors of the substrate, i.e. mimic
 Acetylcholine: neurotransmitter of the autonomic system. It’s synthesized from choline and acetyl CoA through the action of choline acetyl transferase. When released acetylcholine binds to its postsynaptic ligand receptor and induce an AP in postganglionic cell. Action of acetylcholine is short lived as acetyl-cholinesterase immediately breaks down acetylcholine into choline and acetate.
 Cholinesterase:
- the active site of the enzyme comprises an anionic site and an esteric site
- the esteric site contains a hisidine imadazole ring and a serine –OH group. The acetyl group from Ach is transfer to the –OH group leaving an acetylated enzyme molecule and a free choline.
- acetate is released and the anionic site helps in aligning the two molecules
- process repeats at a rate of 10,000 molecules/second
 Acetylcholinesterase inhibitors:
- physostigmine acts by donating a acetate mimic group to the serine which has a greater binding potential. Hence takes longer to detach and thus delay esterase action.
- DFP binds irreversibly to esterase hence inactivating it
 Noradrenaline synthesis:
- tyrosine to DOPA by tyrosine hydroxylase
- DOPA to dopamine by DOPA decarboxylase
- Dopamine to norarenaline by dopamine beta-hydroxylase
 False substrate: drugs which act as a mimic and competitively inhibits substrate but also get modified by the enzyme into a product that have a therapeutic effect
- Methyl DOPA: methyl DOPA is an example of false substrate where through the pathway of noradrenaline synthesis, methyl-NA is formed. This false transmitter is a potent alpha-2 adrenergic agonist hence causing powerful pre-synaptic inhibitory feedback while it is also a less potent agonist at the postsynaptic receptor. Can be used for hypertension.
 Carrier/transporter molecule drug targets: these protein facilitate transportation of large or polar molecules such as glucose, amino acids, ion, and neurotransmitters
- drugs that target enzymatic or allosteric sites will generally block the transporter
 Serotonin: neurotransmitter of the CNS involved in regulating, sleep, appetite, memory, sexual behaviour, and neuroendocrine function and mood. It is synthesized from tryptophan (through 5-HTP), packaged in vesicle and released with an AP stimulation.
 Serotonin receptors:
- 5HT1a: presynaptic GPCR that inhibits further serotonin release
- 5HT1,2,4: postsynaptic GPCR
- 5HT3: ligand ion channel
 Serotonin transporter: a sodium and chloride dependent transport protein with 12 transmembrane domains.
- Na+ binds first to carrier, change conformation, allowing 5HT to bind
- Cl- binds last to allow transportation of 5HT (not needed for binding)
- The molecules are translocated and dissociated within the cell.
- K+ binds immediately after and transported outside to complete the cycle
 SSRI: selective serotonin reuptake inhibitor. Fluoxetine is such a drop and it binds to serotonergic receptor in the presynaptic cell and prevent uptake thus prolonging serotonin action.
 Ion channel drug targets: ion channels are used to regulate the flow of ion across a cell membrane thus fundamental in processes such as neurotransmission, cardiac conduction and muscle contraction. They are controlled by:
- integral part of receptor: when ligand occupy the receptor
- enzyme activators: intermediates such as G-protein, cAMP
- voltage change: action potentials
 Ion channel drugs:
- Benzodiazepines and Barbiturates: enhancing action of GABAa receptors by allostery
- nicotine: nACh receptor agonist
- anaethestics: Na+ channel inhibitors to prevent depolarization of cells and transmission of pain signal
 GABA: an inhibitory neurotransmitter. It binds to GABAa receptors causing the opening of ion channel and inflow of Cl- cause hyperpolarization thus prevent transmission of AP.

Receptors and cell signaling:

 G-protein Coupled Receptor: the most abundant type of receptor in the body and it spans the cell membrane with an external drug/ligand binding domain and internal region interacts with G-protein.
 Intracellular G-protein domain: made up of alpha, beta and gamma units.
- Alpha units: the binding of agonist signals the alpha unit and it release GDP and take on GTP. The activated G-protein units proceed to phosphorylate adenylate cyclase and initiate a signal transduction.
- Beta-gamma unit: signal function units that work as one unit (dissociates after G-alpha unit activation) and stimulate inwardly rectifying K+ channels
 Types of G-protein: different alpha subunits for different function.
- Gi: inhibits adenylate cyclase
- G0: inhibits Ca2+ channel
- Gs: stimulates adenylate cyclase
- Gq: activate PLC
 Opioids: three types of receptors – DOR, KOR and MOR. They are used in:
- Nociceptive (pain) pathway: agonist are potent analgesics particularly MOR.
- Hypothalamus: influence temperature regulation and control of hormonal secretion
- Forebrain: involved in behavioral reinforcement, anxiety and emotion expression
- Others: GI and autonomic nervous system function
 Morphine: an agonist of the u-opioid receptor in the nociceptive pathway and can produce euphoria, analgesia, sleep and prevent diarrhea.
- morphine is coupled to Gi/G0 hence able to block Ca2+ channels to prevent the effect of action potential, and in addition inhibit adenylate cyclase.
 Tolerance: an increase in the dosage needed to produce a given pharmacological effect due to adaptation of the body to the drug.
- develops rapid between 12-24 hours and last for months
- possible mechanism is increase gene expression of G-proteins and adenylate cyclase
 Morphine tolerance and withdrawal:
- rapid increase of cAMP due to lack of inhibition of morphine leading to abstinence syndrome: yawning, pupillary action, fever, sweating, piloerection, nausea, diarrhea and insomnia
 Other mechanism of tolerance: receptors may be altered so that they no longer activate effectors, e.g. by phosphorylation of the receptor so it can’t couple to the G-protein.
 Down regulation: prolonged agonist exposure can decrease receptor number such as isoprenaline at beta2-adrenoceptors in the lung. Consequently lower receptor will mean less stimulation and response
 Up regulation: long term exposure to antagonists may result in up-regulation of receptor numbers so require more antagonist maintain previous effect, e.g. propanolol, an inhibitor of NA on beta1-adrenoreceptors.
- up regulation can produce tolerance and thus result in some withdrawal effects
 Tyrosine kinase receptor: enzyme receptors that phosphorylate tyrosine reside on intracellular target proteins and its function include mediating action of growth factors, cytokines and certain hormones, e.g. insulin.
 Insulin receptors: composed of two alpha extracellular units and two beta intracellular units linked by disulfide bond.
- Binding of the insulin to alpha subunits causes beta subunits to phosphorylate each other and activating the catalytic activity of the receptor. Signal transduction proceeds.
- Insulin receptor is already a dimer
 Vascular endothelial growth factor receptor: receptors that govern the action of VEGF such as angiogenesis during pregnancy, wound healing, and pathophysiological conditions, e.g. cancer, CV disease
 VEGFR2: Ligand stimulates receptor dimerization and autophosphorylation of tyrosine residue in cytoplasmic domain. Activated receptor can phosphorylate SH2 domain proteins and produce a multitude of biological functions:
- endothelial cell survival, proliferation and migration
- NO and PGI2 production
- increase vascular permeability
 Proliferation pathway of endothelial: receptor activation activates PLC by phosphorylation. PLC-gamma hydrolyses PIP2 to DAG and IP3, DAC activates PKC, PKC activate ERK via Raf and MEK, ERK activation leads to increased gene transcription.
- angiogenesis inhibitors negatively impact the heart but prevent tumours
- angiogenesis stimulators conversely promote tumours but easier on the heart
 Intracellular steroid receptors: receptors localized in the cytoplasm that is activated by lipophilic ligands to alter transcription of DNA directly. Biological action activated through this pathway is usually slow as new proteins are made.
 Glucocorticoid receptor signaling:
- lipophilic ligand cortisol diffuse through cell membrane and binds to glucocorticoid receptor
- GR dissociates and dimerises
- GR enters the nucleus and acts as a regulatory factor and alter gene transcription

Autonomic Neurotransmission:

 Autonomic system: involuntary innervation of the body
- sympathetic: ergotropic (affinity for work) which prepares the body for stress and activities
- parasympathetic: trophotropic (related to food) which relaxes body for accumulation of resources and resting.
 Sympathetic neurotransmission: short preganglion synapses with a long postganglion with acetylcholine and nicotinic receptor at the ganglion and NA and adrenergic receptor at innervation (except sweat gland)
 Parasympathetic neurotransmission: long preganglion synapses with a short postganglion and acetylcholine and nicotinic receptor at ganglion and acetylcholine and muscarinic receptor at innervation.
 Skeletal muscle and adrenal medulla innervation: skeletal muscle uses nicotinic receptor at the postganglion for stimulation and adrenal medulla received stimulation directly from preganglionic nerve.
 Possible site of drug action:
- mimic Ach (e.g. nicotinic or muscarinic agonist) to enhance effect
- prevent the action of Ach on the receptor (postsynaptic is inhibition of AP, presynaptic is stimulate release)
- prevent the synthesis of Ach by stopping uptake (drug hemicholinium) , inhibiting transferase or stopping release
- prevent release of Ach by botulinuim toxin (stops vesicle fusing) or Ca2+ channel blockers
- prevent vesicular storage, e.g. vesamicol
- prevent the breakdown of Ach, e,g, neostigmine
 Carbidopa: inhibitor of dopa decarboxylase. This drug is usually prescribed along with L-dopa as a cure for parkinsons as only Dopa can cross the blood-brain barrier into brain whereas dopamine can’t. Hence peripheral dopa decarboxylase must be inhibited to prevent break down of dopa into dopamine before entering the brain.
 Noradrenaline inhibitory feedback: NA is released with ATP in a fixed ratio of 1 to 4. When released NA may act on alpha 2-adrenergic receptor, a Gi linked GPCR, to inhibit adenylate cyclase, cAMP and down-regulate further release of NA.
 Homotropic: when the neurotransmitter feedback on the inhibition of its own release, e.g. acetylcholine binding to M2 receptor.
 Heterotropic: when the neurotransmitter feedback on the inhibition of its own release in addition to the inhibition of other neurotransmitters as well. For example in the heart, parasympathetic stimulation of the heart acts through acetylcholine where the neurotransmitter will need to limit its own release while inhibit NA release to prevent sympathetic stimulation.
 Presynaptic receptor: these receptors are pharmacologically distinct form the post-synaptic receptors thus require specific agonist and antagonist for them. Advantage of a presynaptic receptor drug is that effect of drug only used when the neurotransmitter is released.
 NANC transmission: non-adrenergic non-cholinergic transmission.
 Co-transmission: NA is packaged in vesicles with ATP and released together in vesicle for neurotransmission functions.
- Benefits: able to reach targets further and produce longer lasting effects. Also inhibition of one component will not completely impair function but rather partially.

Unless otherwise stated, the content of this page is licensed under Creative Commons Attribution-ShareAlike 3.0 License