Pharmacology basics Flashcards
What experiments first introduced the idea of receptors? How?
Langley’s experiments with pilocarpine and atropine
Application of pilocarpine resulted in decreased heart rate and increased saliva production
Both were prevented by pre-application of atropine
Later on- nicotine application mimics effects of innervation but curare stopped this
stimulation of a nerve produced a substance the mimicked the effects of nicotine
What is the modern definition of affinity?
Tendency of a chemical/molecule to bind to a receptor
Ehrlich’s early experiments on blood cells
Proposed chemical interactions occurred between dyes and cells
There was a specificity which is governed by cell type and the chemical structure/solubility of the dye
What are chemical mediators?
Extracellular signal molecules that are detected by target cells by receptors
generate intracellular changes that alters the cells behavior
Why do cells express different kinds of receptors?
Integration of information
Coordination of responses
Amplification of signalling
What is the difference between endocrine and paracrine signalling?
Endocrine- over long distances to target organs through the bloodstream, distributed widely over the body (signalling molecules, mediators)
Paracrine- extracellular signals acting locally without diffusing too far, may be stored in vesicles or produced on demand
What does it mean when a cell is autocrine?
When a cell responds to paracrine signalling molecules that it produces itself
What are common examples of paracrine signalling?
Inflammation, controlling cell proliferation and wound healing
Smooth muscle relaxation and dilation by nitric oxide
Eciosanoids and endocannabinoids
What is contact dependent signalling?
Shortest range of all types of communication
When a cell surface bound molecule binds to a receptor on an adjacent cell
What are examples of contact dependent siganlling?
Used widely by the immune system
Immunotherapy to treat cancers
What is a bioassay?
Experimental assay in which the concentration or potency of a substance is determined by the biological response it produces
How is a mediator defined?
A chemical, peptide or protein that conveys information from one cell to another in response to a stimulus of some kind
What are the criteria for a mediator?
It is released from cells in sufficient amounts to produce a biological action on target cells within an appropriate time frame
Application of an authentic sample of the mediator reproduces the original biological effect
Interference with the synthesis, release or action ablates or modulates the original biological response
How is regulating the synthesis of small molecule mediators different to synthesis of peptide mediators?
Small molecule- regulated by specific enzymes
Peptide- regulated by transcription
What are the two types of chemical mediators?
Preformed mediators- stored in vesicles from which they are released by exocytosis allowing for rapid communication
Mediators produced on demand- released by diffusion or constitutive secretion which are slower and take minutes/hours to act
What are examples of preformed mediators and ones that are produced on demand?
Preformed- neurotransmitters, hormones, cytokines, growth mediators and neuromodulators
Produced on demand- nitric oxide, lipid mediators like prostanoids
How can drugs effect chemical communication?
Targeting transporters
Increasing release of neurotransmitters by displacing it from vesicles (sympathomimetic action)
Targeting ion channels involved in regulation of neurotransmission
What are the 4 classes or ‘super families’ of receptors targeted by synthetic drugs?
Ligand gated ion channels
G-protein coupled receptors
Kinase linked receptors
Nuclear receptors
What classes of receptors are found on the cell surface? What features do they have in common?
Ion channels, GPCRs and kinase linked
Transmembrane spanning segments composed of hydrophobic amino acids
Possess extracellular ligand binding domain
What type of receptor isn’t found on the surface of a cell membrane? What features do they possess?
Nuclear receptors as they are DNA linked
Regulate gene transcription#
Ligand must be able to cross plasma membrane
What are agonists? What are some examples?
Drugs or chemical mediators that bind to a receptor and produce a response
Pilocarpine, nicotine, acetylcholine, morphine
What are antagonists? What are some examples?
Drugs that inhibit or prevent the response of an agonist, they may bind to a receptor but they don’t elicit a response
Majority of clinically useful drugs: atropine, curare, naloxone
What are the features of ligand gated ion channels?
Involved in fast synaptic transmission
Composed of 3-5 subunits and each subunit has 2-4 transmembrane spanning domains
Central aqueous pore
Agonist binding leads to channel opening
What are the features of G-protein coupled receptors?
Formed from a single protein, receptor protein spans the membrane 7 times
Signal transduction occurs via a heterotrimeric GTP binding protein (G protein)
Effectors may be an enzyme or an ion channel
What are secondary messengers?
Small diffusible molecules that spread the signal
Structure of G proteins
3 subunits- alpha, beta and gamma
GPCRs activated by encouraging alpha unit to release it’s GDP and replace it with GTP
What are the three different types of enzyme G proteins? How do they allow signal transduction?
Regulation of levels of secondary messengers
Gs- increase in adenylyl cyclase leads to an increase in cAMP
Gi- decrease in adenylyl cyclase leads to a decrease in cAMP
Gq- increase in phospholipase C leads to increase in IP3, DAG, Ca2+ conc
What is PKA? how is it regulated by cAMP?
Protein kinase A
PKA regulated by phosphorylation of target proteins, which in turn regulates their functions
What happens when phospholipase C is activated by GPCRs?
Generation of secondary messengers IP3 + DAG
Increased intracellular Ca2+
Activation of protein kinase C
What parts of the body are innervated by the sympathetic nervous system only, unlike most tissues?
Sweat glands, hair follicles, blood vessel smooth muscle and the adrenal medulla
Neuronal organisation of the ANS
Preganglionic neurons are always short and cholinergic
Postganglionic neurons have nicotinic receptors for ACh, are long and are adrenergic
Target tissue expresses alpha and beta adrenergic receptors for norepinephrine
Where are chromaffin cells located? How do they work?
Adrenal medulla
Function similar to postganglionic neurons but release mainly epinephrine
Target alpha and beta adrenergic receptors
Allows diffuse sympathetic activity
Neuronal organisation of the parasympathetic NS
Long cholinergic preganglionic neurons from brain stem and sacral spinal cord
Short cholinergic postganglionic neurons
Target tissue expresses muscarinic ACh receptors
What are the essential components of the ANS in the CNS?
Spinal cord- mediates autonomic reflexes, receives sensory afferents and brain stem outputs
Brain stem nuclei- mediate autonomic reflexes
Hypothalamus- integration and coordination of behavioral processes
Forebrain and visceral inputs control cortical functions
How do drugs directly and indirectly target ANS receptors?
Direct- agonists and antagonists
Indirect- synthesis, storage, breakdown
What blocks muscarinic ACh receptors?
Atropine
How do M1, M3 and M5 work?
Gq protein coupled receptors
Increase in phospholipase C
Increase in IP3 and intracellular Ca2+
How do M2 and M4 receptors work?
Gi protein coupled receptors
Decrease in adenylyl cyclase so decrease in cAMP
Increase in GIRK
Decrease in voltage gated Ca2+ channels
Where are M1 receptors found in the body?
Autonomic ganglia
Gastric oxyntic glands
Lacrimal and salivary glands
Cerebral cortex
Where are M2 receptors found in the body?
Atria of the heart
Widely distributed in the CNS
Where are M3 receptors found in the body?
Exocrine glands Smooth muscle Gastrointestinal tract Eye, airways, bladder Endothelium of blood vessels
Where are M4 receptors found?
CNS
Where are M5 receptors found?
Substantia nigra
Salivary glands
Iris and ciliary muscles
What does M2 activation cause?
Cardiac slowing
Decreased force of contraction in the atria
Inhibition of atrioventricular conduction
What does the activation of M1 and M3 receptors cause?
Stimulation of smooth muscle- bronchoconstriction and GI motility
Stimulation of secretion from endocrine glands- increase in mucus in the lungs
What is the effect of muscarine poisoning?
Decrease in blood pressure
Increase in saliva, tear flow, sweating
Abdominal pain, death from cardiac/respiratory failure
What can pilocarpine be used to treat?
Glaucoma
reduces pressure in the eye
What are the effects of atropine?
Inhibition of secretion Smooth muscle relaxant Pupillary dilation Decrease in GI motility Increase in body temp
What are examples of muscarinic antagonists and what do they treat?
Pirenzipine- M1 selective and used to treat peptic ulsers
Darifenacin- M3 selective and used to treat overactive bladders
Atropine can be used to reverse poisoning by anticholinesterases
What are cholimimetic drugs? How do they do this?
Drugs that act indirectly to enhance cholinergic transmission
Inhibition of cholinesterase, can be topic and used in medicine (physostigmine) or long lasting (sarin, organophospates and pesticides)
Where are noradrenergic receptors found?
Tissues responding to postganglionic sympathetic neurons
Clinical uses of adrenoceptor agonists
Adrenaline- cardiac arrest, anaphylaxis
B2 selective- ephedrine used for nasal decongestants, salbutamol used for bronchial dilation
How do amphetamines work?
Structurally related to noradrenaline, sympatomimetic drug
Indirectly acting- increase endogenous release of noradrenaline
Also work on dopamine and 5HT
Repeated use leads to tolerance due to depletion of neurotransmitter
Clinical uses of adrenoceptor antagonists?
Hypertension- prazosin (a1 selective)
Heart failure- carvediol (a + b selective)
Anxiety- propanolol (B1 + B2 selective)
