Y4 Pharmacology Flashcards
What is pharmacodynamics?
Pharmacodynamics is the study of the actions of medicinal substances on living organisms. It determines the biochemical and physiological effects of drugs and the mechanisms of drug action on the surface and within cells. The substances exert their therapeutic action by interacting with specific macromolecules.
The target macromolecules may be regulatory receptors, enzymes or structural proteins.
Intercellular= located or occurring between cells.
Intracellular= located or occurring within a cell or cells.
The features of intercellular signalling relevant to drug treatment are as follows:
- secretion of a chemical molecule by the transmitting cell
- many chemical signalling molecules, including proteins, e.g. insulin; amino acid derivatives, e.g. noradrenaline, serotonin, thyroxine; steroids, e.g. cortisol, testosterone; fatty acid derivatives, e.g. the prostaglandins; and nitric oxide
- the signalling molecule, aka. the ligand, may travel far from its secreting cell, e.g. hormones (endocrine signals), may act only locally, e.g. the chemical signals controlling inflammation (paracrine signals), or may act only on a single cell across a nerve synapse, e.g. most neurotransmitters
- the ‘receiving’ cell recognises only the signals, or ligands, that are relevant to it: embedded in the cell membrane are a variety of proteins, some of which are receptors, with different receptors for different chemical signals
- a receptor recognises its ligand and binds it with a reversible chemical bond
the process of chemical binding causes conformational change in the receptor protein. This change in structure activates it and leads to further signalling within the cell; the signalling in turn causes the appropriate alteration in cell function
What is Transmembrane signalling?
While a lipophilic molecule such as a steroid can readily pass through a cell membrane, the hydrophobic nature of the membrane precludes many water-soluble messenger molecules from entering cells.
Transmembrane signaling mechanisms.
A. Ligand binds to the extracellular domain of a ligand-gated channel.
B. Ligand binds to a domain of a receptor, which is coupled to a G protein.
C. Ligand binds to the extracellular domain of a receptor that activates a kinase enzyme.
D. Lipid-soluble ligand diffuses across the membrane to interact with its intracellular receptor.
What are receptors?
A receptor can be defined as a protein molecule that receives chemical signals from outside a cell. When the chemical signal binds to a receptor, they cause some form of intracellular response.
Receptors can be classified in terms of the chemicals which interact with them, their localisation or their functions. On the other hand, substances which bind to receptors (ligands) are described in terms of their affinity, efficacy (intrinsic activity) and selectivity.
What is affinity?
The strength of binding of a substance to a receptor depends on how well it fits, and the sum of those bonds. Most ligands bind reversibly to their receptors, and at any given time, equilibrium will exist between a proportion that is bound to receptors and a proportion that is free. The relative amounts of bound and free molecules can be described by the affinity constant, K(A) of the ligand, so that a substance with a high affinity constant will spend longer in association with a receptor, and vice versa for a low constant.
The higher the affinity of a ligand for a protein, the lower the concentration is necessary to occupy a given proportion of the receptors. The extent of ligand-receptor association is the primary determinant of the ultimate cellular or tissue response and depends upon 3 major parameters:
- Affinity between drug and receptor
- Receptor density
- Concentration of drug
What is Intrinsic activity (efficacy)?
Molecule’s ability to change the conformation (3-dimensional shape) of the receptor protein. This is referred to as intrinsic activity or efficacy.
molecule binds to a receptor without inducing a change = intrinsic activity, and can only occupy/block the receptor.
intrinsic activity = either be a full agonist or a partial agonist, depending on the maximum degree of stimulation.
Stimulation of a receptor by an agonist has been likened to a key fitting a lock and unlocking a door.
What is the difference between agonists and antagonists?
Drug occupation of a receptor either activates (agonist action) or inactivates (antagonist action) that receptor.
What are agonists?
Agonists are drugs that have the ability to activate a receptor by binding to it. They interact with receptors to alter the proportion of activated receptors, thus modifying cellular activity. They bind to and activate receptors in a dose-dependent manner until all receptors are occupied.
Many hormones and neurotransmitters (e.g. acetylcholine, histamine, noradrenaline) and many drugs (e.g. morphine, phenylephrine [nasal decongestant]) act as agonists.
What are partial agonists?
- Bind to same receptors as full agonists
- Have less intrinsic activity than the endogenous ligands
- At low doses they have a similar dose-dependent activity profile.
Because partial agonists bind to the same limited number of receptors but activate them less, partial agonists reach maximal activation at a much lower level than full agonists. Partial agonists are required to interact with a large proportion of receptors to produce a maximum cellular response.
What are inverse agonists?
Inverse Agonists bind to a receptor and produce an effect that is opposite to that of the endogenous ligand.
If an inverse agonist is used to control blood pressure, the drug will actually cause a direct decrease in the blood pressure rather than just block intrinsic mechanisms that cause a rise in blood pressure.
What are antagonists?
Antagonists are drugs that have affinity for the same receptor sites as an agonist or partial agonist. They interact selectively with receptors but do not lead to an observed effect.
By binding to the receptor, they block the binding of full or partial agonists, and therefore block receptor activation.
Antagonists can be reversible or irreversible.
Give two examples of antagonists
Antihistamines - bind to histamine receptors (H1) and prevent them being stimulated by the histamine released in allergic response.
Naloxone is an opioid antagonist which reverses symptoms of opioid overdose by blocking the opioid receptors in the central nervous system.
What are the 5 types of antagonists?
Competitive
Irreversible
Non-competitive
Chemical
Physiological
What are competitive antagonists?
Bind reversibly with receptors, and tissue response can be returned to normal by increasing dose of agonist.
What are irreversible antagonists?
Effect cannot be reversed by increasing concentration of agonist. eg. phenoxybenzamine (alpha blocker)
What are non-competitive antagonists?
Don’t bind to receptor site but act downstream to prevent the response to an agonist eg. calcium channel blockers
What are chemical antagonists?
Bind to active drug and inactivate it. eg. protamine abolishes anticoagulant effect of heparin
What are physiological antagonists?
Two agents with opposite effects that cancel each other out ie. prostacyclin and thromboxane A2 on platelet aggregation
What is a bioassay?
What is a bioassay?
Bioassays involve use of biological tissue to relate drug concentration to a physiological response. Usually isolated tissues are used b/c its easier to control drug concentration around tissue and reflex responses don’t occur. Sometimes bioassays involve whole animals.
Bioassays estimate:
concentration of drug
binding constants
potency relative to another drug
What is Tachyphylaxis?
When a drug is given repeatedly, its effects often decrease. If effects occur quickly, it is called tachyphylaxis or desensitization.
What causes Desensitisation?
Caused by changes in receptors, downregulation of receptor number.
What is drug tolerance?
Slower decrease in response (days or weeks). May be increased metabolism of drug
What is drug resistance?
Loss of the effect of chemotherapeutic drugs ie. antimalarials
What is physiological dependence?
symptoms and signs which are opposite to those sought, when a drug is withdrawn.
This can be explained by the body adjusting to a new homeostatic state during drug use, and reacting in the opposite direction when the new equilibrium is disturbed.
Alcohol and coffee are two examples. Psychological dependence is linked to a form of satisfaction derived from the use of a drug.
What is addiction?
Addiction is a less precise term used for states of physiological or psychological dependence.
What is the sequence of hormone/neurotransmitter action?
Biosynthesis
Storage
Release
Interaction with a target receptor
Subsequent coupling mechanisms
Enzymatic degradation
Reuptake into storage sites
How can drugs decrease response?
Decreased stimulation can result from:
- interfering with the biosynthesis of endogenous stimulants
- encouraging their reuptake and degradation, depleting storage vesicles
- preventing access to or blocking actions on the target organ
- The commonest way that drugs decrease a response is to antagonise the actions of endogenous substances at their target tissues.
What are some of the first drugs to be isolated?
morphine from Papaver somniferum
emetine from Cephaelis ipecacuanha
quinine from Cinchona officinalis
cocaine from Erythroxylum coca.
What is acetylcholine?
Acetylcholine (ACh) is a neurotransmitter which plays a key role in motor activity in the peripheral nervous system.
Acetylcholine is the transmitter substance released at the following:
All preganglionic autonomic nerves (ie both sympathetic and parasympathetic)
Postganglionic parasympathetic nerves
Nerve to the adrenal medulla
Somatic motor nerves to skeletal muscle endplates
Some neurons in the central nervous system
Acetylcholine receptors (cholinoceptors) are divided into what 2 subtypes?
nicotinic and muscarinic
What are muscarinic receptors?
Acetylcholine released at the nerve terminals of postganglionic parasympathetic fibres acts on muscarinic receptors.
M1 receptors occur in brain and gastric parietal cells
M2 occur in the heart
M3 occur in smooth muscle and glands
What are the actions of muscarinic receptors?
Muscarinic effects are mostly parasympathetic
Effects are blocked by atropine
What are nicotinic receptors?
Nicotinic receptors occur in autonomic ganglia and the adrenal medulla.
What are the actions of nicotinic receptors?
Stimulates the autonomic ganglia, which is relatively weak compared to acetylcholine’s muscarinic effects.
Nicotinic effects are sympathetic ie. elevated BP and dilated pupils.
What is dopamine?
Dopamine is the most abundant amine neurotransmitter in the CNS and is found at high levels in the midbrain. It is believed to be involved in complex movements and emotional responses.
What are the 2 dopamine receptors?
D1-like:
Linked to adenylyl cyclase stimulation
D2-like:
Predominant subtype in the brain and is involved in known functions of dopamine. Occur in limbic system, associated with mood and emotional stability, and in the basal ganglia where they are responsible for control of movement and coordination.
What are opioids?
Opioids are defined as compounds with effects that are antagonised by naloxone. There are three families of opioid peptides: endorphins, enkephalins and dynorphins. They all have inhibitory actions at synapses in the CNS and gut where they inhibit pain impulses and GI motility respectively.
What are the 3 main types of opioid receptors?
u-receptors: most highly concentrated in the brain, involved in nociception and is where most opioid analgesics interact to produce analgesia. Nociception is the neural processes of encoding and processing noxious stimuli
d-receptors: selective for enkephalins
k-receptors: selective for dynorphins
They are all blocked by naloxone
Name herbs which interact with acetylcholine receptors
Nicotiana tabacum (nicotinic receptor)
Atropa belladonna, Hyoscymus niger (muscarinic receptor)
Evodia rutaecarpa (anti-acetylcholinesterase)
Name herbs which interact with dopamine receptors
Mucuna pruriens (natural source of l-dopa)
Polygala tenuifolia
Corydalis yanhusuo (tetrahydrocolumbamine inhibits dopamine receptors)
Name herbs which interact with opioid receptors?
Papaver somniferum, Escholtzia californica
Name herbs which interact with GABA/Benzodiazepine receptors:
Passiflora incarnata
Piper methisticum
Valeriana officinalis
What are enzymes?
Enzymes are catalytic proteins that increase the rate of chemical reactions in the body. Drugs can act by inhibiting enzymes.
What are inhibitors?
act by inhibiting enzymes. Enzyme inhibitors are classified as either reversible or irreversible depending on whether they can be displaced from the enzyme by high concentrations of substrate.
What are the 3 types of enzyme inhibition?
Competitive inhibition: A competitive drug can compete with the substrate for the active site of the enzyme. If the drug binds to the enzyme site it prevents binding of the normal substrate. The drug will just occupy the active site and then leaves it unchanged. Another drug or a substrate will then take its place. The action of the enzyme is slowed down by the number of times it gets occupied by a competitive substance.
Non-competitive inhibition: Some drugs will compete for the active site but then stick there, just like the wrong key in a lock, and inactivate the enzyme. This inactivation is usually irreversible.
Uncompetitive inhibitors: This is rare and often occurs when one or more substrates are involved in a reaction. These inhibitors bind to the enzyme-substrate complex
What is acetylcholinesterase?
This enzyme hydrolyses ACh to choline and acetate, and thereby terminates its action as a neurotransmitter. Inhibitors will therefore potentiate ACh.
What are drug and herbal examples of AchE inhibitors?
neostigmine - used for treating postoperative atonia of the bowel and bladder, and for overcoming Ach deficiency in myasthenia gravis.
Herb examples: physostigmine (in the calabar bean, Physostigma venenosum) and berberine (in Berberis spp.)
Describe the mechanism of action of anticholinesterases and their effects
Action
Acetylcholine binds to esterase and becomes choline and acetylated enzyme
Inhibited by edrophonium (reversible anticholinesterase) or neostigmine, pyridostigmine which are broken down by esterase in the same way but take much longer (30 min-6hr)
Effects
similar to muscarinic agonists but transmission at neuromuscular junction is also potentiated.
produce less vasodilation than directly acting agonists
large doses marked by bradycardia and hypotension
What is angiotensin converting enzyme (ACE)?
This enzyme is present in blood and in organs including the lungs, kidneys and heart. It forms part of the renin-angiotensin-aldosterone system which controls cardiovascular parameters including cardiac output, arterial blood pressure and venous return.
It converts the biologically-inactive angiotensin I into angiotensin II, which is a vasoconstrictor. ACE also inactivates various kinins including bradykinin.
Name some ACE inhibitors?
Ramipril, captopril and a metabolite of enalapril, a prodrug.
These compounds are false substrates for the enzyme, being accepted into and binding to the active site. They are used for treating hypertension and cardiac failure.
Side-effects of these drugs include a dry cough, and more rarely, angioedema, proteinuria and neutropenia. The newer drug, losartan, an angiotensin receptor antagonist, does not cause a cough.
What is aromatase?
Aromatase is a cytochrome P450 enzyme that converts androstenedione to oestrone. This is the last step in the biosynthesis of oestrogens. Inhibitors decrease oestrogen levels in post-menopausal women who have hormone-receptor-positive breast cancer.
What are drug and herbal examples of aromatase inhibitors?
drugs: anastrozole and letrozole.
Plant-derived inhibitors: flavonoids quercetin (Curcuma longa, Glycerrhyza glabra, Foeniculum vulgare) kaempferol (Brassicaceae, Anethum graveolens), and apigenin (Matricaria recutita).
What is H+/K+ ATPase?
H+/K+ ATPase, also known as the proton pump, is responsible for secreting H+ ions from the parietal cell into the lumen of the stomach, and represents the final stage in the secretion of gastric acid. Drugs which inhibit this enzyme have become popular for controlling gastric acid secretion. They are often effective in patients who are resistant to H2 antagonist therapy, and are also useful in Zollinger-Ellison syndrome where there is severe hypersecretion of gastric acid. Omeprazole is the most-prescribed example.
What is Na+/K+ ATPase?
These enzymes occur on the extracellular side of the cell membrane of heart myocytes, where they pump out sodium that has leaked into the cell in exchange for potassium that has leaked out of the cell, thus maintaining transmembrane Na+ and K+ gradients, the negative resting membrane potential and normal excitability of the cell membrane.
What does digoxin inhibit?
The cardioactive steroidal glycoside, digoxin in Digitalis purpurea and D. lanata inhibits Na+/K+ ATPase, and is the main inotropic drug used in chronic congestive heart failure, especially when associated with atrial fibrillation.
It depolarises the cell membrane and causes a rapid rise in cytosolic calcium concentration. This leads to increased cardiac output and efficiency. The resulting increase in renal blood flow also leads to a beneficial increase in diuresis.
However, its therapeutic ratio is low, and toxicity, in the form of nausea and vomiting, arrhythmias and bradycardia may be seen. Moreover, if too many sites are occupied, arrhythmias can occur. These drugs also act on Na+/K+ ATPases in the CNS, where they decrease heart rate via increasing vagal nerve activity.
