Exam Flashcards
2 types of ways drugs are made:
Drugs that come from natural resources- you have to extract it, purify it and use biotechnology
What is pharmacokinetics?
The way the drug moves through the body
1.) Absorption = how the drug enters to the blood stream from where it is administered
2.) Distribution = how the drug moves through the blood stream to target specific cells and molecules
3.) Mechanism = how drug is modified by enzymes to become effective
4.) Excretion = how the drug leave the body through urine/ feces
What is pharmacodynamics?
It is how the drug effects the body and the studies relating to it
What are the aims?
Administered drugs that are safe, acts with high specificity, potency at low dose acts with appropriate duration to give maximum advantage. Minimise the side effects and low cost availability.
What is drug action?
(Most drugs) =Specific action on recognition sites. (some drugs) = non specific action
Targets of drug action on specific macromolecules:
Known as proteins and they can be divided into
Receptors, carrier proteins, ion channels, enzymes, DNA
Specific action of drugs on receptors:
Most common site of drug action
Located in the cell membrane
Receptors for steroids is located inside the cell
Receptor structure and functions (classification):
1.) Selective agonists= bind to receptor and becomes activated
2.) Selective antagonists= blocks the receptor causing no effect
3.) Ligand binding studies= can track the drug in the body, can also calculate association and dissociation constants
4.) Transduction pathways= further info for receptors under investigation, mechanism and action of drugs done before drugs are sent into clinical trials.
5.) Molecular structure
Examples of drugs acting on receptors:
Histamine receptors:
H1 receptors-blockade by antihistamines results in treating allergic or inflammatory response
H2 receptors- blockhead by antihistamines results in treating peptic ulcers
Specific drug action on ion channels:
-There’s a pore in the cell membrane which opens and closes and allows or prevents passage of ions down a concentration gradient
-Opening and closing of channels, depends on the structure of the macromolecule protein which forms the pore
-Drugs may bind onto different sites of this macromolecule which affects the opening and closing of the channel
Examples of drugs acting on ion channels:
-benzodiazepines use as an anxiety, hypnotic and anti-convulsant agents = increases conductance of chloride ions by increasing the frequency of chloride channel
-Extending the opening time of the channel, making the inside of the cell more negative than the outside, which means it’s less likely for the cell to get excited
-Calcium blockers= stops calcium from going into the cardiac and vascular cells= contractions of the heart is reduced
-local anaesthetic = blocks sodium channels= no sodium is entering the cell; no positive charge so prevents cells from becoming excited —-> leads to it becoming numb.
Specific drug action on carrier proteins:
Located in the cell membrane or intracellular organelles
Transfer materials against concentration gradient by using energy
Example of drugs acting on carrier proteins:
-sodium pump = pumps Na+ out and K+ into the cells using ATP
The action of the pump is inhibited by cardiac glycolide, for example, Digoxin in patients with heart failure
-NaCl Transporters in kidney inhibited by thiazide diuretics, for example, chlorothiazide and loop, diuretics, or another example is frusemide. They are both used to treat heart failure.
Specific Drug action on enzymes:
Enzymes are macromolecular proteins, they catalyse and speed up the rate of chemical reactions.
Drugs can bind to enzymes and inhibit or interfere with action
Examples of drugs acting on enzymes:
-Aspirin inhibit cyclic-oxygenase leading to inhibition of formation of prostaglandins (local meditator)
-Some diuretics inhibit carbonic anhydrase leading to an increase in urine output
-Some antibiotics with the synthesis of DNA of bacteria
-Nitrates, which is used in patients with angina, activate the granulate cyclase enzyme in blood vessels, resulting in an increase formation of cyclic GMP lead to relaxation of the wall of blood vessels which means more blood flow to supply the heart muscles.
Drugs action on DNA:
Drugs may bind to DNA and modify the replication in the cell division process. An example of this is anticancer, drugs, or cisplatin.
Non specific action of drugs:
-Show poor structural relationship
-Required in high concentrations
Non specific action of drug examples:
-General anaesthetics work by diminishing the activity of the excitable tissues by dissolving in membrane
-The potency correlates well with a degree of line lipophilicity
-Brain areas with consciousness are very sensitive, -Some laxatives and diuretics bulking effects, methylcellulose, branmannitol diuretics and faecal lubricants
Drugs effects:
-Beneficial or therapeutic effect, results from binding of a drug to sites with high affinity. I.e. drugs that show high affinity for a specific site.
-Adverse effect, results when drugs bind to sites that are not desired, may be seen in some individuals depending on genetic factors
Drug effects: beneficial and adverse effects might be:
Mediated by the same mechanisms
In different tissues e.g. cancer drugs kills both cancer and healthy tissues; corticosteroids reduce inflammation but induce adverse effects by modifying metabolisms.
Drug effects : beneficial and adverse effects might be:
Mediated by different mechanisms
Drug effects : beneficial and adverse effects might be:
Mediated by different mechanisms
High or low therapeutic index:
A high therapeutic index is preferable to a low one, this corresponds to a situation in which one would have to take a much higher amount of a drug to do harm than the amount taken to do good, the narrower the margin the more likely it is that the drug will produce unwanted effects.
Generally a drug narrow therapeutic range (i.e. with little differences between toxic and therapeutic doses) may have it’s dosage adjusted according to measurements of the blood levels achieved in the person taking it
CAN BE ACHIEVED THROUGH THERAPEUTIC DRUG MONITORING (TDM) protocols
What is therapeutic index:
Therapeutic index is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects
Therapeutic ratio:
(It is the ratio given by the toxic dose divided by the therapeutic dose. A commonly used measure of therapeutic index is the toxic dose of a drug for 50% of the population (TD50) divided by the minimum effective dose for 50% of the population (ED50))
Examples of drugs with a narrow therapeutic range:
They may require drug monitoring both to achieve therapeutic levels and minimize toxicity include:
Digoxin
Dimercaprol
Theopphylline
Lithium carbonate
Drug effect:
Positive or negative effect- receptors
Magnitude of effects- amount of drugs and number of receptors
Type of effect- what the receptor does
agonists:
Drugs that interacts with the receptors and resulting in a complex that creates a response
Can alter the activity of a receptor (drug efficacy)
-can be positive which causes an increase in the receptor activity
-can be negative which causes a decrease in receptor activity
occupancy:
Occupancy occupied= number of receptors/ total number of receptors
Relationship between occupancy and concentration of a drug:
Explains the relationship between occupancy and agnostic concentration:
As the agonist concentration increases the occupancy increases sigmoidally (means occupancy increases fast to start with but slows down as most receptors start to become occupied)
Free receptor + agonist
K1
Free receptor ——>Agonist R complex ——>Activatiion of
<——
K2
Rates
Forward rate= k1 [free receptor][agonist]
Backward rate= k2 [agonist-R complex]
At equilibrium: Forward rate= backward rate
K A
As Ka increases the backward rate of a reaction increases
A drug with higher Ka has higher backward reaction and tend to form fewer complex at a particular concentration
As Ka increases, affinity decreases
K1 (N total - Na)= k2 (Na)
Na= number of receptors occupied by agonist
N total= total number of receptors
N total- Na= number of free receptors
[A]= concentration against agonist
Occupancy= [A]/ [A] +k A
Equation describes how occupancy varies with the concentration of the agonist
KA is an important constant and numerically equal to the concentration of drug at which HALF the receptors are occupied
Different types of agonists
Full agonists- they bind and activate receptor , 100% efficacy at receptor e.g. isoproterenol (which mimics action of adrenaline at B adrenoreceptor) e.g morphine mimics the action of endorphins at N-oploid receptors in the CNS
Measuring occupancy experimentally
It’s hard to measure how occupancy varies with agonist concentration so we measure how a biological response varies with agonist concentration e.g.contraction or relaxation of a muscle
This is done by plotting concentration response curves which allows us to see differences between agonists
3 Factors that determine dose response curves
Efficacy (Emax)- it’s the maximum possible effect for the agonist. Below a certain concentration of A, the response becomes too low to measure but at higher concentrations it becomes appreciable and rises with the increasing A concentration until it reaches really high concentrations where it cannot be further increased by the increase of A concentration and a max response/effect is achieved which is Emax
Antagonist
Antagonists are a type of receptor, ligand or drug that does not bind to a receptor, but blocks or dampens agonist mediated responses.
They are drugs which have affinity but NO efficacy
For their receptors and binding will disrupt the interaction and inhibit the function of an agonist
Most important antagonisms
Physiologically and pharmacologically, most important antagonisms are:
1. Physiological antagonism
2. Competitive antagonism
3. Non-competitive antagonism.
There are other types:
*Chemical antagonism; two drugs, interact in a solution *Pharmacokinetic antagonism; one drug modifies ADME of another drug
Physiological Antagonism:
~ Substances which have opposing physiological actions but act at different receptors
-the 2 drugs are both agonists and aid in regulating organ function in the body.
-eg. histamine lowers arterial presture through vasodilation
At the histamine H1 receptor, While adrenaline raise arterial pressure through vasoconstriction mediated by B-adrenergic receptor activation
Competitive antagonism:
the antagonist reversible binds to receptors at the same binding site as the endogenous ligand or agonist, but without activating the receptor.
~Agonist and antagonist compete for the same binding site and once bound an antagonist will block agonist binding
Characteristics of competitive antagonism:
1.)Concentration response curve to an agonist remains parallel with original (control) curve
2.)Concentration response curve to agonist to an agonist will be shifted to the right
3.)The maximum response will still be obtained
4.) The effects of a competitive antagonist by may be overcome by increasing the concentration of agonist
5.)Often (not always) these antagonists possess a very similar chemical structure to that of the agonist
Response curve to an agonist by a competitive agonist and what it depends on:
Extend of the right shift of concentration, response curve to an agonist by a competitive antagonist depends on
1. Concentration of the antagonist used.
2. Affinity of the antagonist for a particular Receptor
Find sample to antagonist with equal concentration, antagonist with high affinity water cause a big shift to the right
Concentration Ratio:
The concentration of agonist producing a defined response in the presence of an antagonist, divided by the concentration producing the same response in absence of antagonist.
Concentration ratio= Ec50 for curve B (d2) / Ec50 for curve A (D1)
Affinity of antagonist:
Determined using Schild plot
Schild plot equation -> (concentration ratio-1) = (antagonist
concentration)/ KB
Concentration ratio- concentration ratio for the agonist KB= dissociation equilibrium constant for the antagonist; the concentration which would occupy 50% of the receptors at equilibrium. The reciprocal (1/Kb) is called affinity constant or the association constant
When slope= 1 then PA2= pKB
Range of antagonist concentration:
A plot is made of the log (dose ratio-1) vs the log concentration of antagonist for a range of antagonist concentrations.
~The intercept on the x axis is called pA2 and the slope gives info about nature of antagonism
Slope= 1, indicates of competitive antagonism
pkb:
it’s a measure of the potency of a competitive antagonist
~it’s the negative log of the molar concentration of antagonist which at equilibrium would occupy 50% of the receptors in absence of agonist
~In a experiment in which a single concentration of antagonist has caused a parallel shift of the agonist concentration response curve, the pKB value can be calculated using the Gaddum equation
Gaddum equation:
Gaddum equation: pKB= log (concentration ratio- 1) - log (agonist concentration)
For a competitive antagonist (one where the slope of the schild plot =1) the pKB is theoretically = pA2 value. In practice there may be some discrepancy. pKB value should also= pKi value for compound determined in a binding assay although there may again be a discrepancy caused by the use of different media etc.
Schild plot:
The slope of a Schild plot should equal 1 for a competitive antagonist.
* A slope which is significantly greater than 1 may indicate nonspecific binding (e.g. to glassware or partitioning into lipid), or lack of antagonist equilibrium,
* A slope which is significantly less than 1 may indicate removal of agonist by a saturable uptake process, or it may arise because the agonist is acting at a second receptor type (this can also cause curved Schild plots).
* If the slope of a Schild plot is greater than 1, the calculated pA2 value will be an underestimate of the pK value (i.e. the antagonist is less potent than expected).
Conversely, if the slope is less than 1, the calculated pA2 value will overestimate the pKB value.
Non competitive antagonism:
in this antagonism no amount of agonist can completely overcome the inhibition once it has been established
~non competitive antagonist may bind:
1. Covalently to the agonist binding site
2. To site adjacent to agonist receptor and modify conformation of the receptor preventing the agonist binding (allosteric)
3. To a site involved in mediating the cellular responses, e.g blocking ca2+ of binding to contractile protein= cell can not respond to an agonist
Antagonist affinity use:
To classify receptors
To investigate agonist specificity
Example of competitive antagonism:
A good example of competitive
antagonism is the effect of tubocurarine on the responses to acetylcholine at motor end plates in skeletal muscle.
* Kg values for Tubocurarine vs Ach:
* Intestine
Heart
Skeletal muscle
* 10-4 М
10-4M
10-8 M
* Kg values for Atropine vs Ach:
* Intestine
Heart
Skeletal muscle
* 10-8M
10-8M
10-4
Characteristics of non competitive antagonism:
Reduction in slope of agonist D-R curve
How is the effects of a signal (action potential) produced?
To produce these effects the signal (action potential) received by the receptor on the postsynaptic membrane, must be communicated to appropriate sites in the cell by a process known as= signal transduction .
Type 1- Receptors which are part of ligand-gated ion channels (ionotrophic receptors):
-receptors on which fast neurotransmitters act e.g. nicotine, acetylcholine, receptor, GABA receptor, glutamate receptors
Typical iontropic receptor:
The nicotinic receptor has a central ‘pore’ which carries negative charge
-only two ions (Na and K+ ) can get through when the pore is opened
Examples of ionotropic receptor:
E.g. acetylcholine- transmitter at skeletal neuromuscular junction
-binds to nicotinic receptors (nAchR)
-opens channel for 1-2 sec (mean open time) and causes an increase Na+ and K+ (cation)
-net inward current carried mainly by Na+ depolarises the cell membrane- release the ca2+ from SR- ca2+binding to troponin C- activation of myosin ATPase contraction of skeletal muscle
Nicotinic acetylcholine receptor:
(a typical ligand-gated ion channel) in side view (left) and plan view (right). The five receptor subunits (a2, B, y, 0) forn cluster surrounding a central transmembrane pore, the lining of which is formed by the M2 helical segments of each subunit. These contain a preponderance of negatively charged amino acids, which makes the pore cation selective. There are two acetylcholine binding sites in the extracellu portion of the receptor, at the interface between the a and the adjoining subunits. When acetylcholine binds, the kinked a helices either straighten or swing out of the way, thus opening the channel pore.
Ion flow through the ionotropic receptors :
- Both Na+ and K+ can flow through the ion channel but move in opposite directions through the channel.
- Since the concentration gradient for Na+ is greater than for K+, entry of Na+ into the postsynaptic cell, predominates, Sodium entry causes the post-synaptic membrane to depolarise
Type 1:
Y -Aminobutyric Acid receptors (GABAA receptors):
* An inhibitory neurotransmitter in the CNS.
* Activation of the receptor on Cl channel protein by agonist opens the channel and Cl- ions enter the cell causing hyperpolarisation (inhibits depolarisation).
In addition to the GABA binding site, the GABA receptor complex appears to have distinct binding sites for benzodiazepines, barbiturates (anxiolytic/hypnotic/anticonvulsants agents), ethanol, inhaled anaesthetics, etc.
What is type 1:
Notes that various agonist drugs induce similar conductance with different mean open time. Due to a difference in closing rate constant- so agonists with low efficacy exhibit faster closing rate constants
Type 2-G protein coupled receptors or metabotrophic receptors or 7 transmembrane receptors
~receptors coupled to G protein leads to a response
~largest family including receptors for many hormones and slow transmitters
~response takes seconds,minutes,hours
~G protein coupled receptors are largest class of membrane proteins in human genome. 7tm receptor which was used interchangeably with GPCR but some receptors 7 TM domains that do not signal through G proteins
Examples of metabotrophic receptors:
-GPCRs have common architecture, consisting of:
-Single polypeptide with an extracellular N-terminal
-An intracellular C-terminal
-7 hydrophobic TM domains (TM1-TM7) linked by 3 intracellular loops (ECL-1-ECEL3) and 3 intracellular loops (ICL1-ICL3)
-About 800 GPCRs- 50% sensory function
-mediating olfaction (400), taste(33), light perception (10), pheromone signalling (5)
Typical metabotrophic receptor:
7 alpha helices in the protein structure create a large transmembrane protein.
This is a neuropeptide
Y receptor, but the classical example (a ß[beta] adrenoceptor
for NAdr) has the same structure.
The receptor is coupled to G-proteins
Type 2:
Coupling of the ‘a’ subunit to an agonist- occupied receptor causes the bound GDP to exchange with intracellular GTP
What is a second messenger?
- The ‘first messenger’ is the neurotransmitter.
- The ‘second messenger’ is located in the cell and can alter cell function.
- When the neurotransmitter binds to the cell via a metabotropic receptor it initiates a ‘signal’ which diffuses through the cell and creates a change eg it can activate an enzyme, phosphorylate a protein, change the calcium concentration etc
- In effect this signal carries an intracellular message or second message which alters the functioning of the
: The system is based on cyale nucteotides such as cydic
AMP (cAMP) and the other on inositol triphosphate (IP3) and diacyl glycerol (DAG).
Targets for a G-protein examples,
Adenylcyclase, phospholipase C, ion channels, RHOA/ Rhokinase
What is adenylate cyclase/ CAMP:
-Catalyses formation of the intracellular messenger CAMP
-CAMP activates various protein kinases that control cell function in many different ways by causing phosphorylation of various enzymes, carriers and other proteins
What is Phospholipase C/ inositol triphosphate (IP3)/ Diacylglycerol:
-catalyses the formation of two intracellular messengers, IP3 and DAG, from membrane phospholipid.
-IP3 acts to increase free cytosolic ca2+by releasing ca2+ from intracellular compartments.
-Increased free ca2+ initiates many events, contraction secretion, enzyme activation and membrane hyper-polarisation.
-DAG activates protein kinetic, which controls many cellular functions by phosphorylating a variety of proteins
The neurone:
Human nervous system contains more than 10 billion neurons
Basic structure includes:
cell body (perikaryon). -Nucleus. -Schwann cell/oliogodendrocyte
-terminal (synaptic). -axon hillock. -dendrite. -axon. node of ranvier
How is a chemical transmitter is produced?
By a presynaptic neurone and is released by action potential. This action potential first depolarises the axon terminal allowing the transmitter to be released into the synaptic cleft
Comparison between electrical and chemical synapses
-Action potentials reaching an electrical synapse will always be transmitted to the next cell
-An action potential reaching at a chemical synapse may not release enough transmitters to allow the postsynaptic cell to fire an action potential
-The transmitter can be depleted when there is intense stimulation of the synapse when there is intense stimulation of the synapse. Excitability will be restored if time is allowed to replenish the transmitter
-The post synaptic cell may have reduced sensitivity to excitation which would reduce its probability of firing an action potential
-The same transmitter may be excitatory at some synapses and inhibitory at others, depending on the type of receptors located on the post synaptic membrane.
-Chemical transmission occurs in only one direction, from the pre to the post-synaptic membrane.
Where is acetylcholine produced?
Choline + acetyl co enzyme A ——-> Acetylcholine
Choline acetyltransferase
What happens to released acetylcholine?
When Ach diffuses to the post-synaptic membrane it binds to the nicotinic receptor for an instant . In order to allow the cell to recover and respond to a new stimulus, the Ach must be rapidly removed from the junction
Modification of cholinesterase activity:
some nerve gases, such as sarin, used in warfare to position and incapacitate individuals, act by inhibiting acetylcholinesterase.
-in addition to the acetylcholinesterase at the N-M junction there is a less selective, pseudocholinesterase, widely distributed in tissues and body fluids.
-AchE is located on and around the post-synaptic membrane, and has its active site facing into the synaptic cleft. Hydrolysis of ach takes approximately 1msec.
-the choline produced is actively transported back into the axon terminal to be re-used to synthesis new ach: this process is called reuptake.
-only ONE Action potential reaching the N-M junction is needed to release enough ach to stimulate the muscle
-in some other types of cholinergic synapse multiple action potentials are required to stimulated to post-synaptic cell.
Modifying transmission at the neuromuscular junction:
various substances both natural and synthetic are able to block the actions of ach or prevent its release ,or inhibit its degradation.
-agents which block the nicotinic cholinergic receptors on the motor end plate induce muscular paralysis
-neuromuscular transmission can be promoted by agents which inhibit the actions of cholinesterase at the junction. However if the dosage of cholinesterase is too great it allows the transmitter acetylcholine to accumulate in excessive quantities.
-prolonged depolarisation of the post-junctional membrane can then occur making the junction inexcitable
Diseases of neuromuscular transmission :
Myasthenia gravis:
-produce antibodies to nicotninic receptors, antibodies bind to the nicotinic receptor to produce a complex. No of nicotinic receptors at the N-M junction decrease up to 90%
-motor neurones release normal amounts of A ch but few receptors so little contraction even when the movement is quite small eg raising the eyelids. Most common patients are 20-40 years female.
Treatment of myasthenia gravis:
Alternatively a proportion of the antibodies can be removed from blood by plasmapheresis. This process involves taking a blood sample which is centrifuge to remove the plasma. The plasma is discarded, and the patient’s blood cells are suspended in fresh plasma to be returned to the circulation.
Muscle relaxants- non-depolarising neuromuscular blockers
Receptor activation and ion channel opening are therefore inhibited. Eg tubocurarine.
Blockade by non-depolarising agents can be reversed by allowing high concentrations of Ach to accumulate at the synaptic cleft.
This can be achieved by using acetylcholinesterase inhibitors.
Muscle relaxants- depolarising neuromuscular blockers
Suxamethonium chloride (also known as succinylcholine, scoline, or colloquially as sux) is a medication widely used in emergency medicine and anaesthesia to induce muscle relaxation, usually to make endotracheal intubation possible.
What is chemical transmission?
In order to coordinate the diverse actions of the
body, communications between cells is necessary,
and major mechanism for mediating this involves
discrete chemical substances
1.)Neurotransmitters
They mediate rapid, specific and short-lived actions.
Confined to the nervous system and are released from nerve terminals at specialized junctions called synapse.
Typically, nerve action potential causes depolarisation of the pre-synaptic nerve terminal leading to an enhancement of the Ca2+ permeability of the membrane.
The resulting Ca2+ influx facilitates the release of neurotransmitter by exocytosis.
The released neurotransmitter then diffuses a short distance across the synaptic cleft and elicit its effects through the activation of postsynaptic receptors.
The neurotransmitter is then inactivated either by enzymatic degradation or by uptake into the presynaptic terminal, or in many cases a combination of both.
Pharmacologically, many agents commonly affect neurotransmission by modulating any one of these processes.
How are neurotransmitters classified?
However, some transmitters are excitatory at one synapse and inhibitory at another: eg Acetylcholine is excitatory at the neuromuscular junction but inhibitory on the heart.
Classification of transmitters by chemical structure
TYPE I: Amino acids eg GABA (gamma amino butyric acid), glutamate and glycine
TYPE II: Ach, monoamines eg serotonin, adrenaline and purines (eg ATP). Sometimes called the ‘classical’ transmitters
TYPE III: Neuropeptides - opioids eg endorphin and non-opioids eg oxytocin, arg-vasopressin.
Peripheral Neurotransmission
Acetylcholine (Ach) and Noradrenaline (NA) are important peripheral neurotransmitters.
Ach & NA are the two important neurotransmitters in the autonomic nervous system (ANS).
Acetylcholine and noradrenaline as transmitters in the peripheral nervous system. The main two types of ACh receptor, nicotinic (nic) and muscarinic (mus), are indicated. NA, noradrenaline (norepinephrine).
How is acetylcholine released?
Is released from all preganglionic autonomic nerves, postganglionic parasympathetic nerves and from nerves innervating the adrenal medulla.
Acetylcholine as a transmitter:
Also found in the CNS.
ACh is made in the terminal, from acetyl-CoA and choline
Stored in vesicles, ready for release
Degraded in synapse by enzyme acetylcholinesterase (AChE)
Presynaptic terminal recycles the choline (active reuptake)
Cholinergic nerve transmission:
In nerve terminal mitochondria
pyruvate——->AcCoA—->citrate
Citrate diffuses out into cytoplasm, where it is converted (by citrate lysase enzyme) into oxaloacetate and AcCoA
AcCoA then undergoes conversion shown in diagram (CholineAcetylTransferase ChAT enzyme makes ACh)
ACh goes into vesicles, and is released, binds to receptors, is broken down by AChE, and reuptake occurs for recycling
In the autonomic nervous system, Ach acts at both nicotinic and muscarinic ach receptors
Drugs can influence cholinergic transmission
either by acting on postsynaptic ACh receptors as agonists or antagonists, or by affecting the release or destruction of endogenous Ach:
muscarinic agonists (parasympathomimetic)
muscarinic antagonists
ganglion-stimulating drugs
ganglion-blocking drugs
neuromuscular-blocking drugs
anticholinesterases and other drugs that enhance cholinergic transmission.
Muscarinic receptors:
Muscarinic receptors (mAChRs) are those membrane-bound acetylcholine receptors that are more sensitive to muscarine than to nicotine.Those for which the contrary is true are known as nicotinic acetylcholine receptors (nAChRs).
Muscarinic Ach Receptors:
7 transmembrane
- M1 -autonomic ganglia, CNS
- M2 -heart
- M3 -smooth muscle, glands
- M4, M5—– possibly in the CNS
- M135 act as excitatory ↑ PLC through PI-IP3-DAG pathway
M24 acts inhibitory ↓AC- cAMP pathway
- All G-protein coupled receptors
Muscarinic effects on organ systems
- Heart (M2)
- ↓ HR, ↓ contractility, ↓conduction velocity
- vasodilation: (M3) thro release of nitric oxide (NO)
- Other smooth muscle (M3)
- Eye: pinpoint pupil (miosis), focus for near vision
- GI-tract: ↑tone to intestine, bladder, ↓ tone to sphincters
- Lung: contract bronchial SM. → ↑resistance, ↑ secretions
- Exocrine glands:
↑ sweating (M3), ↑ salivation (M3), ↑ gastric acid secretion (M1)
- Exocrine glands:
Muscarinic receptor agonists:
Choline esters
- ACH (muscarinic & nicotinic action)
- *bethanechol (muscarinic action, oral or sc, never iv or im → urinary retension)
- methacholine (not common)
- carbachol (muscarinic & nicotinic)
* Alkaloids:
- muscarine (mushrooms)
- *pilocarpine (used in glaucoma)
- oxotremorine (synthetic) CNS action (basal ganglia)
* Uses:
- ophthalmic (Ach, brief miosis)
- diagnostic for bronchial hyperactivity (methacholine)
- urinary retention (bethanechol)
- reverse GIT depression by causing contraction (bethanechol)
*Only bethanechol and pilocarpine are now used clinically.
Adverse Reactions - Cholinergics
Adverse reactions: (SLUDE)
- Salivation
- Lacrimation
- Urination
- Diarrhoea
- Emesis (vomiting)
Non-selective muscarinic Ach receptor antagonists
used in the treatment of:
Parkinson’s disease (eg. Benzhexol, benztropine or orphenadrine)
Asthma (eg ipratropium, oxitropium)
Cardiac arrhythmias (eg, atropine)
Adverse effects (anticholinergic effects):
Dry mouth, urinary retention, constipation & sedation
Nicotinic Ach receptors:
3 main classes:
Muscle type—skeletal NMJ
Ganglionic type—involved in transmission at symp & parasym ganglia
CNS type—widespread in the brain
Nicotinic Ach receptor subs-types: Muscle type
Membrane response: Excitatory Increased cation permeability (mainly Na+, K+)
Nicotinic Ach receptor subs-types: Ganglion type
Main synaptic location: Autonomic ganglia: mainly postsynaptic
Nicotinic Ach receptor subs-types: CNS type
Membrane response: Pre- and postsynaptic excitationIncreased cation permeability(mainly Na+, K+)
Nicotine and lobeline:
Nicotine and lobeline are tertiary amines found in the leaves of tobacco and lobelia plants
nicotine = is used clinically to help people to stop smoking.
Nicotinic receptors are stimulated by nicotine absorbed from cigarette smoke, which is highly addictive. Supplying nicotine via a skin patch or gum helps to moderate the urge to smoke another cigarette and so aids the ‘quitter’.
In the past Lobeline was used for smoking as a deterrent agent which acts similar to nicotine but at high dose induces emesis/nausea.
Drugs that act presynaptically:
Drugs that inhibit Ach synthesis :
In the synthesis of Ach, the rate-limiting process appears to be the transport of choline into the nerve terminal.
Hemicholinium blocks this transport and thereby inhibits ACh synthesis.
It is useful as an experimental tool but has no clinical applications.
Its blocking effect on transmission develops slowly, as the existing stores of ACh become depleted.
Drugs that inhibit Ach release:
Agents that inhibit Ca2+ entry include Mg2+ and various aminoglycoside antibiotics (e.g. streptomycin and neomycin), which occasionally produce muscle paralysis as an unwanted side effect when used clinically.
Two potent neurotoxins, namely botulinum toxin and β-bungarotoxin, act specifically to inhibit ACh release.
Drugs that enhance cholinergic transmission
(Indirectly-Acting Parasympathomimetics)
Drugs that enhance cholinergic transmission act either by inhibiting cholinesterase or by increasing ACh release, pseudocholinesterase
Nonadrenaline receptors:
All belong to G-protein-coupled receptors.
There are two main groups of adrenergic receptors:
α and β, with several subtypes.
α receptors:
α1 receptors are coupled to PLC activation causing breakdown of membrane phosphoinositides to inisitol phosphates leading to mobilisation of Ca2+.
Activation of α1 receptors causes contraction of smooth muscle cells.
Locations of α1 receptors : For example, blood vessels of gut and skin, sphincters of bladder and gut.
