Y4 Pharmacology Flashcards
(140 cards)
1
Q
What is pharmacodynamics?
A
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.
2
Q
The features of intercellular signalling relevant to drug treatment are as follows:
A
- 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
3
Q
What is Transmembrane signalling?
A
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.
4
Q
What are receptors?
A
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.
5
Q
What is affinity?
A
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
6
Q
What is Intrinsic activity (efficacy)?
A
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.
7
Q
What is the difference between agonists and antagonists?
A
Drug occupation of a receptor either activates (agonist action) or inactivates (antagonist action) that receptor.
8
Q
What are agonists?
A
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.
9
Q
What are partial agonists?
A
- 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.
10
Q
What are inverse agonists?
A
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.
11
Q
What are antagonists?
A
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.
12
Q
Give two examples of antagonists
A
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.
13
Q
What are the 5 types of antagonists?
A
Competitive
Irreversible
Non-competitive
Chemical
Physiological
14
Q
What are competitive antagonists?
A
Bind reversibly with receptors, and tissue response can be returned to normal by increasing dose of agonist.
15
Q
What are irreversible antagonists?
A
Effect cannot be reversed by increasing concentration of agonist. eg. phenoxybenzamine (alpha blocker)
16
Q
What are non-competitive antagonists?
A
Don’t bind to receptor site but act downstream to prevent the response to an agonist eg. calcium channel blockers
17
Q
What are chemical antagonists?
A
Bind to active drug and inactivate it. eg. protamine abolishes anticoagulant effect of heparin
18
Q
What are physiological antagonists?
A
Two agents with opposite effects that cancel each other out ie. prostacyclin and thromboxane A2 on platelet aggregation
19
Q
What is a bioassay?
A
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
20
Q
What is Tachyphylaxis?
A
When a drug is given repeatedly, its effects often decrease. If effects occur quickly, it is called tachyphylaxis or desensitization.
21
Q
What causes Desensitisation?
A
Caused by changes in receptors, downregulation of receptor number.
22
Q
What is drug tolerance?
A
Slower decrease in response (days or weeks). May be increased metabolism of drug
23
Q
What is drug resistance?
A
Loss of the effect of chemotherapeutic drugs ie. antimalarials
24
Q
What is physiological dependence?
A
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.
25
What is addiction?
Addiction is a less precise term used for states of physiological or psychological dependence.
26
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
27
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.
28
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.
29
What is acetylcholine?
Acetylcholine (ACh) is a neurotransmitter which plays a key role in motor activity in the peripheral nervous system.
30
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
31
Acetylcholine receptors (cholinoceptors) are divided into what 2 subtypes?
nicotinic and muscarinic
32
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
33
What are the actions of muscarinic receptors?
Muscarinic effects are mostly parasympathetic
Effects are blocked by atropine
34
What are nicotinic receptors?
Nicotinic receptors occur in autonomic ganglia and the adrenal medulla.
35
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.
36
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.
37
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.
38
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.
39
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
40
Name herbs which interact with acetylcholine receptors
Nicotiana tabacum (nicotinic receptor)
Atropa belladonna, Hyoscymus niger (muscarinic receptor)
Evodia rutaecarpa (anti-acetylcholinesterase)
41
Name herbs which interact with dopamine receptors
Mucuna pruriens (natural source of l-dopa)
Polygala tenuifolia
Corydalis yanhusuo (tetrahydrocolumbamine inhibits dopamine receptors)
42
Name herbs which interact with opioid receptors?
Papaver somniferum, Escholtzia californica
43
Name herbs which interact with GABA/Benzodiazepine receptors:
Passiflora incarnata
Piper methisticum
Valeriana officinalis
44
What are enzymes?
Enzymes are catalytic proteins that increase the rate of chemical reactions in the body. Drugs can act by inhibiting enzymes.
45
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.
46
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
47
What is acetylcholinesterase?
This enzyme hydrolyses ACh to choline and acetate, and thereby terminates its action as a neurotransmitter. Inhibitors will therefore potentiate ACh.
48
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.)
49
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
50
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.
51
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.
52
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.
53
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).
54
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.
55
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.
56
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.
57
What types of drugs inhibit carbonic anhydrase?
Some allopathic diuretics act by inhibiting the enzyme carbonic anhydrase. These agents inhibit the release of hydrogen ions and bicarbonate ions, leading to a reduction in hydrogen ion secretion. This causes a reduction in sodium reabsorption in exchange for hydrogen ions, and so, more sodium, potassium and water are excreted in the urine.
Eventually, metabolic acidosis and hypokalaemia (low blood potassium levels) result, the latter requiring compensation by potassium supplements. An example is acetazolamide, which is used to treat glaucoma by reducing intraocular pressure.
58
What is COMT?
Nonspecific enzyme which deactivates adrenaline, noradrenaline and dopamine. Inhibition of this enzyme results in elevated neurotransmitter levels.
COMT inhibitors, such as entacapone, protect levodopa from COMT and prolong its action. This drug is a widely-used adjunct drug of levodopa therapy in Parkinson’s disease.
59
Describe the action and use of selegiline
Selectively inhibits Monoamine Oxidase-b (MOA-b), for which dopamine is a substrate. Reduces metabolism of dopamine and potentiates levodopa. It can delay the need for levodopa in Parkinson’s patients.
60
Three cyclo-oxygenase isozymes are currently known:
COX-1, COX-2 and COX-3.
61
What is COX-1?
Catalyses the synthesis of prostaglandins that protect the lining of the gastrointestinal tract and stomach by inhibiting gastric acid secretion, and increasing mucosal blood flow and mucus production. It is also involved in kidney and platelet function. *Inhibition responsible for GIT damage*
62
What is COX-2?
Converts arachidonic acid into prostaglandins G2 and H2 (PGG2 and PGH2). PGH2 is then metabolised to series 2 prostaglandins, including pro-inflammatory prostacyclin (PGI2), and thromboxane A2 (TxA2). *Inhibition: Responsible for anti-inflammatory action*
63
What is the action of NSAIDs?
Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-2, and thereby interfere with the production of inflammatory mediators. They are widely prescribed for controlling certain types of pain, such as headache, dental and musculoskeletal pain. Commonly-used examples include aspirin (acetylsalicylic acid), paracetamol and ibuprofen.
However, the classical NSAIDs lack selectivity and also inhibit COX-1. This explains why they can cause gastritis, peptic ulceration and dyspepsia.
Note that PGI2 decreases platelet aggregation and consequently prolongs bleeding time and can promote GI blood loss.
64
Plant-derived COX inhibitors include:
salicylates (in Salix, Populus, Betula spp., etc.), coumarins (e.g., scopoletin and umbelliferone), cepaenes (in Allium cepa), and unknown constituent(s) of Urtica dioica leaf. Alkamides in Echinacea spp. are reported to be potent inhibitors of cyclo-oxygenase.
65
What are the types of NSAIDs?
NSAIDs all have the ability to inhibit cyclo-oxygenase (COX), resulting in inhibition of prostaglandin synthesis.
Salicylic Acid derivatives: Aspirin (acetylsalicylic acid)
4h duration. Longest standing NSAID. Weak acidity increases absorption in stomach, but also absorbed in small intestine. Hydrolysed by esterases in blood and converted to salicylate (active) and acetic acid.
50% people can’t tolerate due to GIT upset because of high doses needed for anti-inflammatory effect.
Propionic Acid derivatives:
Ibuprofen, naproxen. Associated with fewer GIT side effects than aspirin. Lowest side effects.
Selective COX-2 inhibitors
celecoxib, etoricoxib and lumiracoxib. Lowest GIT toxicity, but concerns around cardiovascular safety (do not inhibit platelet aggregation) makes them contraindicated in cardiovascular disease.
Others:
Diclofenac, indometacin, nabumetone
Analgesic only:
Paracetamol
66
What are the actions of NSAIDs?
Analgesic action:
Exerted peripherally and centrally, but peripheral actions predominate. Analgesic action associated with anti-inflammatory action, as result of inhibition of prostaglandin synthesis.
Anti-inflammatory action:
Inhibits prostaglandin synthesis, which reduces vasodilation and vascular permeability and therefore reduces oedema.
Antipyretic action:
During fever, endogenous pyrogen (interleukin-1) is released, acting on thermoregulatory centre of hypothalamus, increasing body temperature. NSAIDs (aspirin) inhibit interleukin-1. Does not reduce normal body temperature or reduce elevated temperature in heat stroke (hypothalamic malfunction).
Action on COX-1 and COX-2:
Non-selective COX inhibitors block channels of both COX-1 and COX-2, reversibly inhibiting enzymes access to arachidonic acid. Aspirin is different because it acetylates the enzymes, which is irreversible. Selective COX-2 inhibitors (celecoxib, etoricoxib and lumiracoxib) are too bulky to block smaller COX-1 channel, but can block COX-2 channels.
Paracetamol:
Effective analgesic, especially when leukocyte infiltration is low, but not effective anti-inflammatory. Overdose likely to cause hepatotoxicity.
67
What is HMG CoA reductase?
HMG CoA reductase is responsible for synthesising cholesterol in the liver. Inhibitors (statins) such as pravastatin and simvastatin efficiently lower cholesterol production, but are associated with adverse effects including muscle and nerve damage.
These drugs are similar to lovastatin produced by red rice yeast (Monascus purpureus).
68
What are MAOIs?
Monoamine oxidases are nonspecific enzymes which deactivate a number of amine neurotransmitters, including noradrenaline, dopamine and serotonin.
Monoamine oxidase inhibitors (MAOIs) such as tranylcypromine artificially raise brain neurotransmitter levels, and are used for treating depression. The older drugs such as phenelzine, are also useful for treating depression, but are no longer widely used because of interactions with other drugs and some foods.
69
Which herbs contain inhibitors of MAO enzymes?
Coumarin (e.g., Asperula odorata, Dipteryx odorata [Tonka bean], Cinnamomum cassia)
Myristicin (e.g., Myristica fragrans)
Harmine (e.g.,Tribulus terrestris, Passiflora spp., etc.). Harmine is a potent MAO inhibitor which can be used for treating the tremors in Parkinson's disease by elevating dopamine levels.
70
What are monoamine oxidases?
These nonspecific enzymes deactivate a number of amine neurotransmitters, including noradrenaline, dopamine and serotonin.
71
Describe the adverse effects of MAOIs
Phenelzine
Older, irreversible non-selective MAOI. Rarely used because of adverse side effects such as postural hypotension, dizziness, anticholinergic effects, liver damage. Interaction with sympathomimetic amines ie. ephedrine, and with foods containing tyramine (cheese, game, alcohol) resulting in severe hypertension.
Moclobemine
Reversible selective MAOI (inhibits monoamine oxidase A), ie. selegiline. Interacts with same drugs as other MAOIs but interaction is diminished when drug discontinued. Side effects: dizziness, nausea, insomnia. Second-line drug after SSRIs and Tricyclics.
Lithium
Prophylaxis for bi-polar disorder and treatment for acute mania, but antipsychotic drug may be preferred for more immediate effect. Therapeutic/toxic doses are similar and serum lithium must be measured regularly. Adverse effects: nausea, vomiting, anorexia, diarrhoea, tremor, polydipsia, polyurea and some patients develop nephrogenic diabetes insipidus. Signs of toxicity: drowsiness, ataxia, confusion. Serum levels above 2-3mM can result in life threatening seizures and coma.
72
What is phosphodiesterase (PDE)?
Phosphodiesterase (PDE) enzymes catalyse the hydrolysis of phospho-diester bonds in cAMP and cGMP. Inhibition of these enzymes therefore increases levels of these messengers.
73
What is Sildenafil?
Sildenafil (viagra) was the first of a new series of drugs for treating erectile dysfunction in men. It acts by relaxing smooth muscle in the penis during arousal, allowing blood engorgement of erectile tissue. The underlying mechanism is inhibition of PDE5 which prevents the breakdown of cGMP. It is effective in both organic and psychogenic problems, but is contraindicated in patients taking nitrate vasodilators, and those who have suffered recent strokes or myocardial infarcts. Adverse effects include hypotension, headache and dizziness.
74
What are some herbal phosphodiesterase (PDE) inhibitors?
Plant-derived inhibitors include caffeine (Caffea arabica) and theophylline (Theobroma cacao), which are competitive but nonspecific PDE inhibitors. Papaverine (an alkaloid from Papaver somniferum) is a vasodilator and an antispasmodic which acts, at least partially, by inhibiting phosphodiesterases and increasing intracellular concentrations of cyclic AMP. It was widely used as vasodilator but it is now replaced by more suitable drugs
75
What is 5-α-Reductase?
This enzyme converts testosterone to its more potent derivative, 5α-dihydrotestosterone (5α-DHT). The drugs dutasteride and finasteride are specific inhibitors of 5 α-reductase. They reduce the production of 5αDHT and the size of an enlarged prostate.
76
What are possible herbal 5-a-reductase inhibitors?
Putative plant inhibitors include constituent(s) of Serenoa repens (possibly phytosterols such as β-sitosterol), and unknown constituent(s) of Urtica dioica.
Serenoa is used for the treatment of benign prostatic hypertrophy (BPH). It may also inhibit the binding of androgens to their receptors in the prostate gland, and/or stimulate the synthesis of (sex hormone binding globulin) SHBG, which binds (and therefore inactivates) androgens.
77
What are antacids?
These are simply weak inorganic bases that raise the luminal pH of the stomach by neutralising gastric acid. They are used in dyspepsia, and provide symptomatic relief in peptic ulcer and oesophageal reflux. Active ingredients usually include sodium bicarbonate, magnesium hydroxide or aluminium hydroxide.
78
What are anthelmintics?
Anthelmintics are drugs used to treat infections with parasitic worms, including tapeworms (cestodes), roundworms (nematodes) and liver flukes (Fasciola spp.).
All these drugs paralyse the parasites, but use a variety of mechanisms. Piperazine acts as a weak partial agonist for GABA-gated chloride channels. It causes a flaccid, reversible paralysis of body wall muscle.
79
What are examples of anthelmintics?
Levamisole, pyrantel and morantel are nicotinic receptor agonists which cause spastic muscle paralysis by prolonged activation of excitatory nicotinic acetylcholine receptors on body wall muscle
80
Which herbs have anthelmintic properties?
Artemisia absinthium, Cinchona succirubra and Thymus vulgaris. Active constituents include bitter alkaloids (e.g. absinthin and quinine) and volatile constituents (e.g. thujone and thymol).
81
How do anti-cancer drugs work?
Drugs used to treat cancer inhibit cell proliferation, but suffer from the disadvantage that they also attack healthy cells. However, because the cells of malignant tumours divide more rapidly, they are affected more than normal cells.
82
How do alkylating agents work?
- Form covalent bonds with DNA bases, preventing the two strands to the double helix from cross-linking.
- Drugs such as cyclophosphamide and cisplatin.
- Side-effects are prominent, can result in sterility in males, and acute lymphocytic leukaemia.
83
What is the mechanism of cytotoxic antibodies?
Stimulate the immune system to encourage T-cell activity.
Eg. Interferon alpha,
Cytokines also interfere with the way cancer multiplies therefore reducing growth.
Eg. interleukin 2, proleukin
84
What is the action of Vinca alkaloids and taxanes?
Tubulin is required to form the microtubules that give shape and structure to a cell. Binds to tubulin blocking the ability of the cell to divide and cause apoptosis.
Eg vinblastine sulphate, vincristine sulphate, vinorelbine
85
What is the action of antimetabolites (form of anti-cancer drug)?
As antimetabolites structurally resemble essential molecules, enzymes mistake them for essential molecules and combine with them resulting in an exclusion of the essential molecules in their normal role.
Eg methotrexate, pentostatin, fludarabine phosphate
86
What are monoclonal antibodies?
Manufactured antibodies that act by targeting specific proteins so that the immune system can destroy those abnormal proteins, essentially allowing the immune system to respond and attack the cancer.
Eg. Trasruzumab, rituximab
87
How are some antibiotics used in cancer therapy?
Some antibiotics are cytotoxic, and are used in cancer therapy, e.g., doxorubicin. These act by intercalating between bases in RNA.
88
How do glucocorticoids treat cancer?
Glucocorticoids inhibit cell division by interfering with DNA synthesis. Used in leukemias, lymphomas and breast cancer.
ie. prednisolone
89
How do hormone receptor antagonists treat cancer?
Hormone receptor antagonists are used in hormone dependent cancers ie. some breast and prostate cancers. ie. tamoxifen (oestrogen antagonist) or aromatase inhibitors (ie. anastrozole or letrozole which block conversion of androgen to oestrogen)
90
How do gonadorelin analogues treat prostate cancer?
In prostate cancer, gonadorelin analogues (synthetic GnRH) ie. buserelin are used. They initially stimulate, then inhibit luteinizing hormone (LH) secretion, thereby suppressing testosterone release. The “flare” in LH can be controled by flutamide (antiandrogen) however the non-hormone dependent cells eventually proliferate.
91
Give examples of topical antifungals
clotrimazole, ketoconazole, fluconazole.
They are widely used topically to treat Candida infections, and act by inhibiting ergosterol synthesis in the fungal cell membrane.
92
Give examples of internal antifungals
Amphotericin is a wide-spectrum antifungal used for serious systemic infections such as Aspergillus and Candida. It is usually given intravenously. Side-effects are common, and include fevers, chills and nausea. Renal damage may result from long-term use.
93
Name some herbal antifungals and their constituents
Thymus vulgaris - thymol, carvacrol
Berberis vulgaris - Berberine
Hydrastis canadensis - berberine
Hypericum perforatum - quercetin, flavonoids
94
Name some antimalarial drugs
Chloroquine and quinine are well-known examples of antimalarial drugs which are toxic to parasites in the liver. They are used to treat malarial attacks, while other drugs such as proguanil are used prophylactically. Side-effects include nausea and vomiting, diarrhea, rashes and hypersensitivity reactions.
95
What does Metronidazole treat?
amoebic dysentery, giardiasis and trichomoniasis.
96
What is the action of antimicrobials (antibiotics)?
Most of the well-known antimicrobial drugs, including the penicillins, cephalosporins and vancomycin, act on cell wall synthesis.
97
What is benzylpenicillin?
benzylpenicillin, a 'narrow spectrum' antibiotic given mainly by injection
98
Give exampls of 'broad spectrum' antibiotics
amoxycillin and ampicillin
99
What are Cephalosporins?
Cephalosporins are mainly used to treat meningitis, pneumonia and septicaemia. They are broad spectrum antibiotics, but have a tendency to cause allergic reactions, and cross-react with penicillin. Commonly-prescribed examples include cefadroxil and cefuroxime.
100
What is metronidazole used for?
active against most anaerobic bacteria, and is the drug most commonly prescribed for protozoal infections.
101
How do aminoglycosides, tetracyclines, macrolides and chloramphenicol work?
inhibit bacterial protein synthesis by binding to different subunits of t-RNA
102
What are tetracyclines?
Tetracycline and its analogues are broad spectrum antibiotics, and may be given orally or by injection. They are favoured for specific organisms such as Chlamydia. Side-effects include discoloration of the teeth, and should be avoided in children up to 8 years old, and in pregnant and lactating women.
103
Describe the mechanisms responsible for resistance to antimicrobial drugs.
A bacterial species may have innate resistance before the drug is introduced to it; an example of this is Pseudomonas aeruginosa and its resistance to flucloxacillin (Neal, 2020). Acquired resistance can also occur; bacteria develop a mechanism to render the antibiotic inactive, such as impermeability to the drug, increased efflux of the drug, alternative metabolic pathways that bypass the drug, modification of the drug’s target cells, or producing enzymes that destroy or alter the drug (Neal, 2020). An example of a bacteria with acquired resistance is those of the Enterobacteriaceae family which have evolved to produce extended-spectrum betalactamases enzyme that neutralise and kill beta-lactam antibiotics (CDC, 2019).
104
What are the mechanisms of some antivirals?
A number of mechanisms are available for exploitation in orthodox antiviral therapy.
- Aciclovir: a selective antiviral which becomes activated when phosphorylated by viral enzymes.
- Amantadine: inhibits viruses from entering host cells, but has been largely superseded as a prophylactic for influenza A infections by vaccines.
- Zidovudine: used to treat HIV infections, but they are hampered by toxicity and tolerance.
- Interferon: a natural antiviral protein produced by leucocytes. It is given by intramuscular injection, and used in the treatment of hepatitis B and C.
105
What are the actions and use of immunoglobins?
Human immunoglobulins contains specific antibodies against superficial antigens of viruses and can interfere with their entry into host cells, inhibiting entry of the virus into the host cell. Normal immunoglobulin injections are used to give temporary protection against hepatitis A, measles, and rubella.
Eg Enfuvirtide prevents HIV-1 virus from entering host cells
Eg Palivizumab
106
What are the actions and use of Neuraminidase inhibitors?
Neuraminidase are spikes found on the influenza virus and are required to help the virus exit the host cell. Neuraminidase inhibitors reduce the symptoms of influenza by one day and are most effective if taken within a few hours on the onset of symptoms.
Eg. zanamivir, oseltamivir
107
What are the actions and use of Viral DNA polymerase inhibitors?
Selectively antiviral as inactive until phosphorylated by enzymes that are preferentially synthesised by the virus
E.g. aciclovir used in herpes zoster viruses.
E.g. valaciclovir a prodrug that after oral administration releases aciclovir. Higher bioavailability than aciclovir.. Used to treating herpes simplex & herpes zoster infections of skin & muscous membranes
E.g. ganciclovir (intravenous) only used in severe cytomegalovirus in immunocompromised
108
What are the actions and use of Viral Reverse transcriptase inhibitors?
Nucleoside reverse transcriptase inhibitors (NRTI)
E.g. Zidovudine, abacavir, tenofovir - inhibits reverse transcriptase of HIV
109
What are the actions and use of protease inhibitors?
A virus-specific protease helps to convert the inert polyproteins that are formed from HIV mRNA into essential mature proteins.
Inhibition of the virus-specific protease prevents maturation of the virions resulting in the production of non-infectious particles.
Protease inihibitors are used in combination with other drugs. They can act as both inhibitors and inducers of the cytochrome P450 system.
Eg Darunavir, ritonavir, saquinavir
110
What are the actions and use of interferons?
Interferons are drugs that modulate the host immune system.
Eg Lamivudine – Hepatitis B
Eg Pegylated IFN-α, ribavirin - Hepatitis C
111
What is the action of diuretic drugs?
Diuretic drugs act by reducing sodium chloride reabsorption at different sites in the nephron, thereby increasing urinary sodium chloride and water excretion.
112
What is the action of thiazide diuretics?
The thiazide diuretics, such as bendrofluazide, act in the distal tubule and ascending loop of Henle by binding to the sodium transporter, thereby inhibiting sodium reabsorption. They reduce extracellular fluid (including blood) volume and reverse autoregulation, leading to a decrease in peripheral vascular resistance. These and other diuretics are used for treating heart failure and hypertension.
113
What are the side effects of thiazide diuretics?
- metabolic alkalosis
- hyperglycaemia,
- hyperuricemia
- hypokalemia
- hypotension
114
What are loop diuretics?
- The most effective diuretics
- Inhibit the reabsorption of sodium at the ascending loop
- Have a rapid onset of action, but are relatively short acting.
- Serious imbalances and dehydration can result from their use.
Furosemide is used to reduce peripheral and pulmonary oedema in moderate and severe heart failure.
115
What are potassium sparing diuretics?
- Antagonising aldosterone (which stimulates sodium reabsorption in the distal tubules)
OR
- By blocking sodium channels (thereby reducing potassium secretion).
Eg. Spironolactone - use is now limited due to potential carcinogenicity.
Amiloride represents the sodium channel blockers. Both of these drugs may cause severe hyperkalemia.
116
What are osmotic diuretics?
Osmotic diuretics such as mannitol are filtered in the glomerulus, but, because of their polarity, cannot be reabsorbed. This leads to an increase in the osmolarity of the filtrate, and to maintain osmotic balance, water is retained in the urine. They are sometimes used to maintain diuresis during surgery.
117
Which herbs have osmotic diuretic effects?
Osmotic diuretic plants include Zea mays, Agropyron repens and Taraxacum officinale.
118
What is the action of caffeine?
Coffea spp. contain the alkaloid caffeine, which is a glomerular vasodilator.
119
What are expectorants?
Expectorants loosen and clear mucus and phlegm from the respiratory tract.
Guaifenesin is an ingredient in many over-the-counter cough and cold remedies.
120
Give examples of herbs and constituents with expectorant action
EO: Cineole rich – Eucalyptus globulus
Relaxing expectorant – demulcent (polysaccharides) / anti inflam / antispasmodic - Glycyrhhiza glabra, Lobelia inflata, Pimpinella anisum, Tussilago farfara
Stimulating expectorant – alkaloid / saponin / volatile oil - Inula helenium, Marrubium vulgare, Viola odorata
121
What are mucosal protectors?
Promote ulcer healing by binding to the ulcer base, providing physical protection.
After oral administration, sucralfate polymerizes in the acid environment of the stomach to give a viscous gel. Bismuth chelate may act in a similar way.
Both compounds must be taken on an empty stomach.
122
What are the actions of tannins?
Astringent action: bind locally to structural proteins. Their styptic and haemostatic actions are due to vasoconstriction.
Tannins can bind to digestive and other enzymes and inhibit them non-specifically. They can also bind iron (as can other polyphenols) and thiamine in the diet and prevent their absorption. The former action is useful in the treatment of haemochromatosis.
Tannins are also hypocholesterolemic and anti-uraemic. Tannins have anti-secretary actions, e.g. ellagic acid suppresses gastric acid secretion. Polyphenolic compounds usually act as reducing agents, and behave as biological antioxidants. It is fortunate that tannins bind to proteins because they can be hepatotoxic if they enter the bloodstream.
Notably astringent plants:
Potentilla erecta
Hamamelis virginiana and
Agrimonia eupatoria
123
What is the action of bitters?
Stimulation of bitter taste receptors at the back of the tongue leads to an improvement in appetite (aperient action) and promotion of gastrointestinal secretory and motor activity via the gustatory and vagus nerves. One of the most important uses of bitters is as remedies for the liver, stimulating bile flow, and supporting its metabolic functions. Many bitter herbs are classified as either cholagogues, which promote the release of bile, or choleretics, which increase the production of bile. Putative bitter receptors also exist in the stomach.
124
What are the indications of bitters?
Bitters are indicated in all atonic digestive conditions, including constipation, dyspepsia, and gastroesophageal reflux (in small amounts), and are best taken 30-60 minutes before meals.
They are also indicated in conditions where elimination of toxic or irritant substances via the gut is to be promoted, for example, in skin conditions such as eczema, in arthropathies, hyperlipidaemia and allergic conditions.
125
What are the bitter constituents?
alkaloids, flavonoids, terpenes (especially mono- and seco-iridoids), anthraquinones and some saponins.
Herbal: amarogentin from Gentiana lutea and absinthin from Artemisia absinthium.
126
What are demulcents?
Demulcents consist of polysaccharides which, when mixed with water, form thick, protective layers. This action is useful for treating inflamed or irritated tissues, both internally and externally. Demulcents are also cooling for hot conditions. Typical examples are Althaea officinalis, Plantago major and Symphytum officinale.
127
What are the indirect actions of demulcents?
Demulcents also have actions on remote tissues. For example, they are used in respiratory disorders as relaxing expectorants, and as urinary tract demulcents. These actions have been explained in terms of reflex actions from the digestive system, involving the nervous system.
128
What are the types of pharmacodynamic interactions?
Additive or synergistic interactions
Antagonistic interactions
Interactions due to altered transport mechanisms
Interactions due to altered fluid and electrolyte balance
Indirect pharmacodynamic interactions
129
What are examples of additive or synergistic interactions?
e.g., when a CNS depressant such as Gelsemium sempervirens is administered to a patient taking hypotensive drugs. This might result in hypotension and drowsiness.
Ginkgo biloba contains a constituent that is a PAF antagonist, and if given together with an anticoagulant such as warfarin, might result in impaired blood clotting and haemorrhaging.
Mild serotonin syndrome has been reported to occur when Hypericum perforatum is combined with an orthodox selective serotonin reuptake inhibitors (SSRIs).
130
What is combined toxicity?
When two or more drugs which have toxic effects on the same organ are given concurrently, damage to that organ is often more severe. For example, when two nephrotoxic drugs are co-administered, kidney toxicity may be found even though neither drug may cause toxicity at the same dose.
131
When is herb/drug interaction most dangerous?
Narrow therapeutic range (ie. warfarin, digoxin, anticonvulsant)
Pharmacokinetic:
Altered absorption
Pharmacodynamic:
Additive/antagonist effects
132
What are antagonistic herb/drug interactions?
- Opposing effects at the same receptor. ie. if a β receptor agonist were to be given alongside a β receptor antagonist, or Hyoscyamus niger (containing the muscarinic antagonist (−)-hyoscyamine) were given with the muscarinic agonist, carbachol.
133
Describe toxicity of essential oils
- Monoterpenes, sesquiterpenes & phenylpropanoids can cause irritation when undiluted.
- Can cause allergic response for some – Melaleuca alternifolia
- High doses of thujone (terpene) can be hallucinogenic, cause convulsions and cause lesions on the brain cortex - Artemesia absinthium, Alchillea millefolium
- Abortifacient – Tanacetum vulgare
- Can cause kidney irritation in nephrotic conditions - Juniperus communis
Can cause oesophageal sphincter relaxation exacerbating symptoms in GORD – mentha pepperita, foeniculum vulgare
134
What is the toxicity of flavonoids?
Quercetin can be ‘genotoxic’ or ‘carcinogenic’ when taken in isolation and at large doses (GA)
135
What is the toxicity of Tannins and oligomeric Procyanidins?
- reduction of absorption of proteins and other nutrients
- inhibitory effect on many enzymes and they precipitate proteins into insoluble complexes (PE)
Combined with other herbal medicines there is a tendency to cause precipitates in some cases (PE)
In high doses has excessive astringent effect on gut and can lead to irritation – ie. Quercus robur, Hamamelis virginiana
Ellagic acid suppresses gastric acid secretion
136
What is the toxicity concerns of pungent constituents?
Piperine inhibits hepatic processes and has the potential to induce drug herb interactions – Piper longum, Piper nigrum,
137
What are the toxicity concerns of saponins?
Due to detergent effects can increase permeability of membranes and can cause haemolysis (PE)
In large doses can be mucous membrane irritants and can cause vomiting (PE)
138
What are the toxicity concerns of anthraquinones?
At high doses is a GIT irritant causing symptoms such as nausea, vomiting, diarrhoea, dizziness, abdominal pain, and in severe cases kidney damage (HO)
139
What are the toxicity concerns of coumarins?
Furanocoumarin may cause phytotoxic reactions in people with normal skin (PE) eg giant hogweed (HE) producing photodermatitis on contact (HE)
The derivative of coumarin, dicoumarol which is formed after being contaminated with certain molds, has potent anticoagulant effects (HO)
140
What are the toxicity concerns of phytoestrogens?
Should be avoided in HER2+ cancers as can cause cancer cells to grow more quickly – Trifollium pratense, Foeniculum vulgare, Cimicifuga racemosa
