Drug Action Flashcards
What is the difference between agonists and antagonists?
Agonist- Possess affinity and efficacy
Bind to a receptor and produce a response
Antagonist- possess affinity but not efficacy
Binds to a receptor but does not produce a response
Atropine blocks acetylcholine but not histamine
Mepyramine blocks histamine but not acetylcholine
List some drugs that work by their physiochemical properties
Antacids- NaHCO3- basic Bulk laxatives- methylcellulose- large and indigestible Osmotic laxatives- magnesium sulphate Osmotic diuretics- mannitol General anaesthetics- halothane Alcohol
What is the Emax and EC50?
Emax is the saturation dose
EC50 is halfway to Emax- 50% response
What is the response equation?
P=bound receptors/total receptors= [drug]/(Kd+[drug]
Name some potential drug receptors
Enzymes- COX- aspirin
Ion channels- Ca channels blocked by nifedipine
Transporters- noradrenaline transporters blocked by cocaine
(Not meant to be bound to- no real agonists or antagonists)
Physiological receptors
Name the receptor superfamilies
Integral ion channels- ligand gated Nicotinic or glycine receptors Integral tyrosine kinases- enzymes Insulin receptors Steroid receptors- inside the cell Oestrogen receptor G protein coupled receptors- has no direct action- actives a G protein Muscarinic or adrenoreceptors Cytokines receptors- enzyme free in the cytosol Prolactin and growth hormone receptor
What is the difference between the concept of spare receptors and partial agonists?
Spare receptors- highly efficacious agonists can produce a max response without binding to all the receptors
Partial agonists- low efficacy agonists cannot produce the max response even when bound to all the available receptors
Give an example for the allosteric effects on receptors
The GABA-A receptor a ligand gated Cl channel
Benzodiazepines increases the affinity for GABA on the channel
Antagonist- flumazenil- no effect
Inverse agonists- betacarbolines- less likely
Give some examples of competitive antagonists
Atropine at muscarinic receptors
Propranolol at beta-adrenoreceptors
Nalixone used in opiate overdose
Give some examples of irreversible antagonists
Phenoxybenzamine at alpha-adrenoreceptors and decreases max response
Give examples of allosteric antagonists
Gallamine at the muscarinic receptor
Betacarbolines at the GABA-A receptor
Bind reversibly and decrease agonist affinity
Name a channel blocker
Phencyclidine at the NMDA receptor
Binds inside the channel to block ions
What is an example of a ‘physiological antagonist’?
Acetylcholine and adrenaline
Both agonists at their own receptors but produce opposite effects
Describe the phenomenon of desensitisation
Prolonged and repeated exposure to an agonist reduces the response to that drug
Eg tolerance to heroin- ⬆️adenyl cyclase activity in the brain in response to the decrease cAMP
Inactivation of nicotinic receptors
What is the importance of ion trapping in drug delivery?
For weak acids and bases the degree of dissociation depends on the pH
Only the unionised form is sufficiently lipid soluble to diffuse through cell membranes
Drugs will tend to accumulate in area where ionisation is favoured
Name the advantages and disadvantages of drug administration routes
Oral- common, easy but strong acids and bases (>10 and <3 pKa)
Rectal- useful if patient is vomiting and cannot swallow but absorption is unreliable
Injections- fastest and most reliable, rate of absorption depends on the site of injection and local blood flow
Inhalation- high absorption SA that raises the chances of attentive side effects
Sublingual- absorbed directly into circulation also useful if the drug is too unstable to get to the intestine, helpful if the drug tastes nice
Topical/transdermal- local effects but most drugs are poorly absorbed through unbroken skin
What are the factors that influence absorption?
Route of administration
Blood flow
Drug conc.
Drug solubility in lipids and aqueous body fluids
How do you calculate apparent volume of distribution?
Dose/plasma conc.
What is the basic structure of a local anaesthetic?
Benzene ring- linkage (amide or ester)-amine
List some examples of local anaesthetics, their linkage and duration
Procaine/cocaine-ester-short
Lidocaine-amide-medium
Prilocaine-amide-medium
Bupivacaine-amide-long
Describe the equilibrium of a local anaesthetic in solution
What does use dependent block mean in the context of local anaesthetics?
LA only block open voltage gated Na channels
⬆️nociceptors activity ⬆️block
How does inflammation effect local anaesthetic?
Low pH ⬇️ the neutral form of the drug leading to poor anaesthesia
What are the different methods of administering local anaesthetic?
1 topically 2 infiltration (surrounding the wound) 3 nerve block 4 epidural 5 spinal
What are the possible unwanted effects of local anaesthetics ?
Hypersensitivity to other components of the solution Tremor, convulsions, respiratory failure Decreased cardiac contractility Vasodilation ⬇️blood pressure
What other drugs are administered with local anaesthetics?
Vasoconstrictors eg adrenaline
Describe the action of botulinum toxin
Has a heavy and light chain
To get into the cell and have it’s action once inside the cell
1 binds to presynaptic membrane and mediates endocytosis
2 peptidases cleave proteins involved in exocytosis (SNAP-25)
SNARE complex doesn’t work
Describe the action and name examples of non-depolarising neuromuscular blockers
Curare, pancuronim, vecuronium
Competitive antagonists at nicotinic acetylcholine receptors to decrease the end plate potential
Used as an adjunct to general anaesthetic as a muscle relaxant
Side effects include decreased blood pressure and histamine release
Describe the action and name an example of a depolarising neuromuscular blockers
Agonist at nicotinic acetylcholine receptors
Suxamethonium
1 causes end plate depolarisation
- action potential
- uncoordinated fine contractions
2 not broken down by acetylcholinesterase
- prolonged depolarisation
Type1 paralysis due to inactivation of voltage gated Na channels
Type2 desensitisation- longer action
Name the unwanted effects of depolarising blockers
Bradycardia K release - cardiac arrest Increased intraocular pressure Prolonged paralysis if there is a deficiency of plasma cholinesterase
Describe the action of cholinesterase inhibitors
List some examples
Interacts with AChE and plasma cholinesterase to prevent the breakdown of ACh
Enhances synaptic function
Affects other synapses where ACh is released
Edrophonium- ionic (minutes)
Neostigmine- covalent (hours)
Organophosphate- phosphorylation (irreversible) war gases and pesticides, reactive red by pralidoxmine
What are the uses of anti cholinesterase?
Reverses the effects of non depolarising NMJ blockers
Used at the end of an operation
⬆️ACh to compete with antagonist
Effects of depolarising blocker are made worse
️ACh acquires suxamethonium-like action
Used in the treatment of Myasthenia gravis
Edrophonium
Neostigmine
Pyridostigmine
Where are drugs metabolised and excreted?
Liver- first pass metabolism Kidney- some enzymes but mostly excretory Lungs Skin Plasma Gut
What is the difference between active and toxic metabolites?
Active- Pro-drugs eg cortisone, choral hydrate
Diazepam is metabolised to nordiazepam which is also active
Toxic- eg paracetamol, carcinogens- activated by metabolism to more active carcinogens
Describe liver metabolism
Phase 1
Oxidation, reduction
Often introduces reactive groups- products may be more toxic
Phase 2
Conjugation- using the modification from phase 1
Products tend to be soluble and inactive
Secreted into bile and/or urine
What is the importance of cytochrome P450?
Oxidise a range of drugs
Haem containing enzymes
>1 drug at a time can create competition for the active site
Substrate inhibition- phenytoin
Non-substrate inhibition- quinidine
Induction- barbiturates, rifampicin, brassica, tars
What are the three processes of renal excretion that eliminate drugs?
Glomerular filtration- <20% passive filtration
Tubular secretion- active transport of substances into urine- unaffected by plasma binding
Two transporters- acids eg penicillin, probenicid, uric acid
Organic base eg pethidine, quinine
Reabsorption- water reabsorbed forced alkaline diuresis speeds elimination of acidic drugs- ion trapping
Describe the process of adrenaline
Tyrosine➡️DOPA➡️dopamine➡️noradrenaline➡️adrenaline
- Tyrosine hydroxylase- rate limiting step, feed back inhibition by NAd
- DOPA decarboxylase
- Dopamine-beta-hydroxylase- inhibited by disulfiram
- PNMT- in A cells in the medulla
List some drugs that affect noradrenalin synthesis
Alpha-methyl tyrosine- inhibits tyrosine hydroxylase
Carbidopa- inhibits DOPA decarboxylase, works in the periphery, used in Parkinson’s disease
Methyldopa- taken up in sympathetic neurons, converted into alpha-methylnoradrenaline, acts as a ‘False transmitter’
6-OH dopamine- neurotoxin
How is adrenaline and noradrenaline stored?
Sub cellular membrane-limited particles
Chromaffin granules
Name the transporters involved in noradrenaline storage in vesicles
H ATPase
VMAT (vesicular mono amine transporter) antiporter- H/dopamine
(Vesicle contains dopamine-beta-hydroxylase)
VNUT (vesicular nucleotide uptake transporter)- ATP in
Describe the autoregulation of noradrenaline release
Alpha-2 adrenoceptors in the presynaptic membrane which are negatively coupled to adenyl cyclase are involved
Name some mediators of noradrenaline release
Morphine
Acetylcholine- inhibits via muscarinic receptors
Adenosine- inhibits via (A1 receptors)
Opioids- inhibits via u-receptors
Angiotensin- facilitates release via AT1 receptor
Describe the neuronal uptake of catecholines
Secondary active transporter NET (norepinephrine transporter)
Relatively selective for noradrenaline (NAd>Ad>isoprenaline)
Co-transports Na, Cl (uses electrochemical gradient
Inhibitors- phenoxybenzamine
Desipramine- tachycardia and dysthymia
Cocaine- tachycardia, increased BP
Describe the non-neuronal uptake of catecholamines
Low affinity for noradrenaline
Ad>NAd>isoprenaline
Inhibited by normetabephrine, steroid hormones, phenoxybenzamine
Name some enzymes involved in the degradation of catecholamines
Monoamine oxidase (MAO)- bound to the surface of mitochondria converts catecholamines to aldehydes which are metabolised by aldehyde dehydrogenase (PNS) or aldehyde reductase (CNS)
Some antidepressants block MAO irreversibly to increase levels of NAd, dopamine and 5-HT eg phenelzine, tranylcypromine, iproniazid
Catechol-O-methyl transferase (COMP)
Converts catecholamines to methoxy derivatives
What is VMA?
3-methoxy,4-hydroxylase mandelic acid
Final metabolite of adrenaline and noradrenaline excreted in urine
List the agonist potency order of adrenergic receptors
Alpha1- noradrenaline>=adrenaline»_space;isoprenaline
Alpha2- adrenaline>noradrenaline»isoprenaline
Beta1- isoprenaline >noradrenaline>adrenaline
Beta2- isoprenaline>adrenaline>noradrenaline
Beta3- isoprenaline >noradrenaline=adrenaline
Describe the intracellular cascade from the alpha1 adrenoceptors
Coupled to a Gq protein that activates phospholipase C➡️IP3+DAG
IP3➡️IP3 receptor, Ca channel in the ER (➡️contraction in smooth muscle)
DAG➡️protein kinase C
Describe the intracellular cascade from alpha2 adrenoceptor
Couple to Gi protein which inhibits adenyl cyclase➡️ decreased cAMP➡️ decreased PKA activity➡️ decreased phosphorylation of certain intracellular proteins➡️ effect
Describe the intracellular cascade from beta adrenoceptors
(All beta receptors stimulate AC)
Coupled to Ga protein➡️activates Adenyl cyclase➡️ increased cAMP➡️ increased PKA➡️ increased phosphorylation of certain intracellular proteins➡️ effect
What are the functions of beta1 adrenoceptors?
They are important cardiac adrenoceptors SA node- increased heart rate AV node- increased conduction velocity Atria- increased contractility Ventricles- increased contractility - enhanced automaticity
What are the functions of beta2 adrenoceptors?
Important in smooth muscle
Blood vessel dilation (alpha1+2 for constriction)
Bronchi dilation
GI tract relax (alpha1+2 contraction of sphincters)
Uterus relax (alpha1 contract)
Name a use of beta 3 adrenoceptors?
Adipose tissue- lipolysis and thermogenesis
Skeletal muscle- thermogenesis
Name the selective agonists and antagonists of alpha1 receptors
Agonists- phenylephrine
Antagonists- prazosin and doxazosin
Name the selective agonists and antagonists of alpha2 receptors
Agonist- clonidine
Antagonist- yohimbine and idazoxan
Name the selective agonists and antagonists of beta1 receptors
Agonists- dobutamine
Antagonists- atenolol and metoprolol
Name the selective agonists and antagonists of beta2 receptors
Agonists- salbutamol, terbutaline and salmeterol
Antagonists- butoxamine
Name a non selective agonist and antagonist of beta adrenoceptors
Agonist- isoprenaline
Antagonist- propranolol
Name some uses for adrenoceptors agonists
Adrenaline- (alpha + beta) help restore cardiac rhythm & acute anaphylaxis and asthma & adjunct to local anaesthetics
Dobutamine- (beta1) cardiogenic shock
Salbutamol & Terbutaline- (beta2) asthma & delay of premature labour
Salmeterol- (beta2) asthma
Mirabegron- (beta3) prodrug for overactive bladder syndrome
Phenylephrine- (alpha1) nasal decongestion
Clonidine- (alpha2) hypertension and migraine
Name some uses for alpha adrenoceptor antagonists
Hypertension- prazosin (short acting) doxazosin (long acting)
Benign prostatic hypertrophy- tamsolusin
Phaeochromacytoma- phenoxybenzamine
Name some uses for beta adrenoceptor antagonists
Cardiovascular- metoprolol and atenolol Glaucoma- timolol Thyrotoxicosis- pre-operatively Anxiety States- propranolol Migraine prophylaxis Benign essential tremor
How is the supply of choline kept at a sufficient level?
Choline is taken from the diet and the liver to nerve endings via high affinity carrier, Na dependent process
How is acetylcholine synthesised?
Choline + acetylCoA➡️acetylcholine + CoA
Catalyses by choline acetyltransferase
How is acetylcholine stored?
Energy dependent vesicular ACh transporter
Uptake mechanism is not very specific
Acetyltriethylcholine can be stored and released as a false transmitter
Describe some of the feedback systems for cholinergic nerves
Muscarinic ACh receptors in the enteric nervous system inhibit ACh release
ATP is converted to adenosine which inhibits release via A1 receptors
Morphine- inhibits release via u receptor
Noradrenaline- inhibits release alpha2 adrenoceptors
List the relative potency series of agonists for skeletal muscle and autonomic ganglia
Skeletal muscle
Nicotine>carbachol»DMPP»>methylcholine muscarine
Autonomic ganglia
Nicotine, DMPP>carbachol»>methacholine muscarine
Autonomic ganglia are selectively antagonised by what?
Hexamethonium
What is the mechanism of action of hexamethonium?
Blocks the ion channel
Use dependent block
Which are the three most important subclasses of muscarinic receptor?
M1- found in stomach and salivary glands antagonist- pirenzepine
M2- found in cardiac muscle, antagonist- gall amine
M3- found in smooth muscle
What are some clinical uses of muscarinic antagonists?
Asthma- iota tropism
Bradycardia- atropine
Decrease gut motility and secretions- pirenzepine
Summarise the 3 main acetylcholine receptors
Skeletal nicotinic- ligand gated, alpha1 Nicotine vs. decamethonium Neuronal nicotinic- ligand gated, alpha2-7 DMPP vs. hexamethonium Muscarinic- G protein coupled, M1-5 Carbacol vs. atropine
Name some weak base used as antacids
Sodium bicarbonate
Magnesium hydroxide
Aluminium hydroxide
Calcium carbonate
Name two H2 antagonists and their action
Cimetidine and ranitidine
Inhibits resting and stimulated acid acid secretion
Used in peptic ulcer
Cimetidine inhibits P450
Describe the muscarinic antagonists
Pirenzepine
Inhibits acid secretion at cons that do not produce marked anti-muscarinic side effects
Selective for M1 receptors
Describe the action of omeprazole
Irreversibly inhibits H/K ATPase
Weak base, accumulates in the stomach, reduces acidity and increases its own absorption
Side effects- headache, diarrhoea, rashes, stomach stones and an increase in gastrin secreting cells
Name and describe a prostaglandin analogue
Misoprostol
Inhibits acid (and mucous) secretion
Can be used to prevent ulcers
Side effects- diarrhoea and abortion
Name and briefly describe the action of mucosal protectants
Carbenoxoline- increase secretion and salt/water retention
Sucralfate- forms a gel in acid and binds to ulcer craters and protects it
Bismuth chelate- antibacterial
Name the H. Pylori antibacterial drugs
Amoxicillin
Clarithromycin or metronidazole
What is the action of domperidone and metoclopramide?
Increased ACh release this increases tone of oesophageal sphincter, speed of gastric emptying and transit through the small intestine
Used in reflux oesophagitis, nausea, delayed gastric emptying
What are the types, and name some examples of drugs used to treat constipation?
Bulk laxatives- methylcellulose
Saline purgatives- magnesium sulphate, lactulose (also decreases ammonia production by bacteria)
Irritant purgatives- Senna, bisacodyl
Faecal softeners- liquid paraffin, docusate sodium
What are the types of drugs used in diarrhoea?
Oral rehydration therapy
Absorbents- kaolin, methylcellulose
Opiates
Antispasmodics- antimuscarinics, peppermint oil, mebeverine
Anti-inflammatory- steroids, mesalazine
Drugs which inhibit secretion- enkephalinase inhibitor
What is the clinical significance of ️glucose-6-phosphate deficiency?
Is an X linked characteristic, more common in some races that confers protection against malaria
Causes haemolytic reactions to primaquine (malaria drugs)
Oxidative stress causes lysis
of RBCs
Describe two polymorphisms in the cytochrome P450
CYP2D6 metabolised 25% of prescription drugs
5-10% of Caucasians have polymorphisms
-CYP2D65, entire gene deleted
-CYP2D62, multiple copies of gene
CYP3A5 75% of Caucasians and 50% blacks do not express functional enzyme with virtually no clinical significance as other enzymes are unregulated to compensate
What are the relevant pharmacogenomics for Thiopurine S-methyl transferase?
Inactivates mercaptopurine and azothiaprine
Slow, intermediate and fast metabolisers
2 common SNPs associated with decreased enzyme levels that could be tested for before prescription
What is the clinical significance of Her2?
Epidermal growth factor- increased cell growth
Over expressed in some forms of breadth cancer
Trastuzumab is a monoclonal antibody against Her2
What is the clinical significance of Bcr-abl?
It’s an active tyrosine kinase
Keeps signalling to cells to grow in chronic myeloid leukaemia
Selectively inhibited by imatinib
What is the clinical significance of B-raf?
A kinase involved in cell growth
V600E mutation leaves it permanently activated
Vemurafenib is a specific inhibitor, licensed for use in melanoma
What is the clinical significance of hERG?
Encodes a cardiac K channel
Mutations with ‘long QT syndrome’
Many drugs bind to hERG and induce long QT EG. Erythromycin and terfenadine
Drugs that bind to hERG are not developed
What is the triad of general anaesthetic?
Need for unconsciousness
Need for analgesia
Need for muscle relaxation
Describe the protein theory of general anaesthetics
Proteins are the targets of action and lipid solubility is needed to access the binding domain
There is a cut off phenomenon; increased chain length and therefore lipid solubility only increases anaesthetic potency only up to a certain point
Plus there appears to be stereoselectivity
What are the proposed molecular targets of general anaesthetics?
K channel activation ⬇️membrane excitability
Ligand gated channels excitatory
Glutamate, 5-HT, ACh inhibitory GABA-A, glycine
What are the four stages of anaesthesia?
- Analgesia- drowsiness, reflexes intact, still conscious
- Delerium- excitement, deletion, loss of consciousness, unresponsive to painful stimuli, muscle rigidity, spasms, cardiac arrhythmias, vomiting, choking
- Surgical anaesthesia- unresponsive to pain, regular breathing, no reflexes, muscle relaxation, synchronised EEG
- Medullary paralysis- pupillary dilation, respiration/circulation ceases, EEG wanes➡️death
What is the minimal alveolar concentration?
The concentration of anaesthetic in the alveoli required to produce immobility in 50% of patients when exposed to a noxious stimulus
How is the MAC is related to lipid solubility?
The more lipid soluble the lower the MAC, the lower concentration needed to produce the anaesthetic effect
What factors increase the speed of induction of general anaesthetic to the alveoli?
⬆️[anaesthetic]
⬆️rate and depth of breathing
What are the factors involved in the transfer of general anaesthetics from the lungs to the blood?
Solubility in blood
(High solubility➡️blood has a large capacity ➡️more molecules needed to saturate blood and the blood needs to be saturated before it can get into the brain)
Rate of pulmonary blood flow
(High cardiac output=faster transfer)
What are the factors that affect the transfer of general anaesthetic from blood to tissue?
Solubility in tissue (tissue:blood coefficient 1 in lean tissue much more than 1 in adipose-high capacity; accumulation
Tissue blood flow- high in lean tissue, low in adipose tissue
What are the advantages and disadvantages of some general anaesthetics?
Halothane- potent, fairly fast; possible liver toxicity
Enflurane- less liver damage; potential seizures
Isoflurane- rapid acting, muscle relaxation; bad smell
Sevoflurane- pleasant odour, rapid recovery; metabolites could cause renal damage
Nitrous oxide- very rapid, good analgesic; low potency- normally combined with other agents
What a possible adjuncts to general anaesthesia?
Premedication to decrease anxiety, pain and to induce amnesia- benzodiazepines, opioids, antimuscarinics
Muscle relaxants- benzodiazepines and neuromuscular blockers
Anti-emetics- metoclopramide
Briefly name some corticosteriods
Hydrocortisone, aldosterone Prednisolone- anti-inflammatory Dexamethasone- anti-inflammatory Beclometasone- nasal spray Triamcinolone- injection into a joint
What is the action of glucocorticoids?
Acts at nuclear receptors and effects the expression of genes involved in inflammatory and immune response with a delayed action
What are the metabolic effects of steroids?
⬆️conversion of protein into glycogen ⬆️blood glucose ⬇️protein synthesis ⬆️breakdown Fat redistribution ⬆️bone reabsorption
What are the anti-inflammatory effects of steroids?
Suppress all phases of the inflammatory response
Decreases the production of inflammatory mediators
Describe the production of inflammatory mediators
Membrane phospholipids➡️(via PLA2) arachidonic acid➡️(via COX) prostaglandins- increased expression of anti-inflammatory proteins
➡️(via LOX) leukotrienes- decreased expression of pro-inflammatory proteins
What inhibits PLA2 in the production of inflammatory mediators ?
Annexin-1
What are the immunosuppressant effects of steroids?
Decreased expression of genes for IL-2, TNF-alpha, TNF-gamma etc
Via inhibition of transcription factors such as AP1 and NFkappaB
What are the uses of anti-inflammatory steroids?
Replacement therapy in Addison’s disease
Inflammatory disease- eczema, asthma, arthritis
Immunosuppression in organ transplantation or ⬇️lymphopoesis in some leukaemias
What are the side effects of using steroids?
Hyperglycaemia and diabetes Muscle weakness and wasting Central obesity Osteoporosis Thin skin and bruising Increased appetite and weight gain Mood changes Infections Glaucoma and cateracts Peptic ulcers (inhibiting prostaglandin production) Adrenal suppression and atrophy
Where is the site of action of non-steroidal anti-inflammatory drugs?
Inhibit COX and therefore prostaglandin production
What are the side effects of NSAIDs?
Gastric irritation and ulceration due to loss of the protective prostaglandins
“Hypersensitivity” increased leukotrienes production
Decreased renal function- trivial without an underlying problem
Prolonged gestation
Describe aspirin
Irreversible COX inhibitor
Anti-platelet action
Side effects- high incidence of GI side effects
Salicylism- tinnitus, dizziness, deafness, acid-base disturbance,
Reyes disease
Describe ibuprofen
Reversible COX inhibitor
Low incidence of side effects
5-15% experience GI side effects
Describe paracetamol
Analgesic and anti-pyretic but not anti-inflammatory
Prevents peroxide a binding to COX competitively so under inflamed conditions the [peroxide] overwhelms the effect if paracetamol so it doesn’t work
No effect on the GI tract, acid-base balance, bleeding time or uric acid secretion
Describe paracetamol toxicity
Paracetamol➡️(via conjugation) harmless
➡️(via P450) toxic
➡️via cells- cell death
➡️via glutathione- harmless
What is the importance of COX2 inhibitors?
COX2 more associated with inflammation
Celecoxib
They have fewer side effects
What is the action of osmotic diuretics?
Eg. Mannitol
Filtered by the glomerulus but not readily absorbed
⬆️osmolarity of tubular fluid
⬇️water reuptake
Used in acute glaucoma/eye surgery, cerebral oedema, oliguria produced by renal failure
Not on heart failure
What is the action of loop diuretics?
Eg. Furosemide and ethacrynic acid
Stops the action of salt transporters in the ascending limb, reducing the salt concentration in the medulla and reducing water reabsorption
Side effects- dehydration and increased ion excretion, alkalosis and hypokalaemia
Used in heart and renal failure, hypercalcaemia/kalaemia and hypertension
Describe the action of thiazides
Eg. Bendroflumethiazide
Acts in the DCT stops salt transporters
Side effects- ⬆️Mg, H, K excretion
⬇️Ca excretion
Disrupted electrical activity, kidney stones, erectile dysfunction
Used in hypertension, heart failure and oedema not used in kidney failure
What is the action of spironolactone?
Potassium-sparing diuretics
Mineralocorticoid receptor anatagonist
Used in hypertension due to elevated aldosterone
Side effects- action at other steroid receptors- gynaecomastia and sexual dysfunction
Hyperkalaemia
What is the action of amiloride/triamterene?
Potassium sparing diuretics
Blocks sodium channels in the collecting duct
Side effect- hyperkalaemia
Often used to counter the hypokalaemia from using thiazides
What are the different ways of targeting viruses?
1 target viruses outside the cell
2 inhibition of genetic replication and integration
3 protease inhibitors
How would you target a virus outside the host cell?
Vaccine
Neuraminidase- oseltamivir- Tamiflu
Breaks the sialic acid bond between the virus and the cell it was released from
How do DNA polymerase inhibitors work to treat viruses?
Eg. Acyclovir used in the herpes viruses
-prodrug, an guanosine derivative with an altered ribose domain
Phosphorylated by viral thymidine kinase more than host TK➡️acyclo GTP- active form 40-100x higher in infected cells
Inhibits viral DNA polymerase and terminates viral DNA chain extension
How do reverse transcriptase inhibitors work against viruses?
Used in AIDS Nucleoside analogues- lamivudine Cytosine analogue Phosphorylates to a triphosphate Inhibits RT and terminates viral DNA chain Non-nucleosides- efavirenz Denatures active site of enzyme
How does integrase inhibition work against viruses?
For HIV
Raltegravir
Used in combination with nucleoside RT inhibitors
Viral DNA is incorporated into host DNA using viral integrase
Side effects- GI upset, rash and maybe hepatitis
Describe the action of protease inhibitors
Used in AIDS
Eg. Saquinavir
Inhibits aspartate proteases- post translational modification of poly proteins into functional proteins by viral proteases
What are the main forms of malaria?
Pre-erythrocytic Plasmodium falciparum- malignant malaria P. malariae- benign Exo-erythrocytic stage P. vivax, P. ovale - benign
List some anti-malarial drugs
Chloroguins- concentrated in parasite lysosomes- site of Hb metabolism
Prevents haem polymerisation
Used in chemoprophylaxis and in the acute phase of gametogenesis in erythrocytes
Quinine- same as chloroquine
Also used in the acute phase- used for P. falciparum
Artemisinin- activated by haem to form free radicals that bond to and modify proteins damaging the membrane- used in the acute phase
Primaquine- disrupts mitochondria and decreases pyrimidine synthesis
Used in liver for Exo-erythrocytic P. vivax and ovale
And used to prevent transmission
What is the action of two drugs in bacteria folate metabolism and utilisation?
Bacteriostatic
Sulphonamides- competitive inhibit dihydrofolate synthase turns PABA➡️folate
Trimethoprim- inhibits dihydrofolate reductase turns folate into tetrahydrofolate which is necessary for DNA synthesis
List antibiotics that inhibit peptidoglycan synthesis
Penicillins Cephalosporins Cyclase run Vancomycin Bacitracin
List antibiotics that increase the permeability of the cytoplasmic membrane
Polymixin B
Gramicidin
List antibiotics that inhibit protein synthesis
Tetracyclins; competitive with tRNA for the A site in ribosomes- selective uptake into prokaryotes
Aminoglycosides- (streptomycin) anticodon recognition- misreading the message
Erythromycin- inhibition of translation
Give examples of antibiotics that inhibit nucleic acid synthesis
Inhibiting DNA or RNA polymerase Rifampicin- TB
Inhibiting DNA gyrase
Quinolones- gram -ve infections
What is the action of metronidazole?
Interferes with energy metabolism
Effective against anaerobic bacteria and Protozoa
Cytotoxic products destroy the cell
What are the common side effects of anticancer drugs?
bone marrow suppression Impaired wound healing GI tract damage Sterility Hair loss
Describe the action of cyclophosphamide
Alkylating agents
Binds irreversibly to both strands of DNA and prevents replication
Prodrug activated by P450
Side effects- nausea, vomiting, bone marrow suppression, harmorrhagic cystitis due to acrolein (mesna inactivates this)
Describe the action of bleomycin
Cytotoxic antibiotics
Breaks up the DNA chains
Most effective in G2, will also work in non-dividing cells
Side effects- little bone marrow suppression
Pulmonary fibrosis
Allergies
Hyperpyrexia
Describe vincristine and vinblastine
Inhibits tubulin polymerisation
Arrests cell division in metaphase
Also affects other cell functions
Side effects- relatively non-toxic
Vincristine- little myelosuppression but neurotoxicity is common
Vinblastine- less neurotoxicity but causes leukopenia
Describe the action of methotrexate
Antimetabolites- inhibits mammalian dihydrofolate reductase
Decreases tetrahydrofolate production and thymidylate synthesis for DNA production
Side effects- bone marrow suppression
High doses- nephrotoxicity
Rescue with folinic acid to help with recovery
How can you control the side effects of anticancer drugs?
Drug combinations given intermittently Anti emetics- ondansetron Chilled skull caps Harvesting bone marrow- haemopoetic factors Management of infections
Briefly describe anticancer drug resistance
P-glycoprotein- membrane transporter
Hydrophobic ‘Hoover’- drugs at often hydrophobic
List some anti-fungal drugs
Nystatin- binds to ergosterole and creates holes in the cell membrane- cation leakage
Amphotericin- similar method as nystatin -anion influx
Ketoconazole- inhibits fungal cytochrome P450- lagosterole to ergosterole
What are the different mechanisms of drug resistance?
Develop a method of drug resistance- beta-lactamase production
Expression of drug transporters- MDR family
Alter target- PBP polymorphism in MRSA
Alter metabolic pathway- PABA in folate metabolism
Decreased drug permeability- spore formation in fungi
