Pharmacology Flashcards
What are the 4 drug targets?
Enzymes
Receptors
Transporters
Ion channels
Give an example of drugs which target enzymes
Statins e.g. atorvotstatin (HMG-CoA reductase inhibitors, blocking the rate limiting step in cholesterol pathway)
ACE-inhibitors e.g. ramipril (prevent angiotensin II production, so lowers water/salt retention and blood pressure)
What receptors are used as drug targets?
- Ligand-gated ion channels (pore-forming membrane proteins, interaction with ligand opens pore, allows ion transfer)
- G-protein coupled receptors (7 membrane spanning regions, interaction with ligand causes incorporation of G-protein due to GDP->GTP, molecular variation gives selectivity and causes different effects, can be Gs-stimulatory, Gi-inhibitory, Gq-both)
- Kinase-linked receptors (transmembrane, stimulation by ligand phosphorylates tyrosine, allows intracellular protein binding leading to effect)
- Nuclear receptors (located within nucleus/cytosol, modify gene transcription through ‘zinc fingers’)
Give an example of a transporter as a drug target
Proton pump inhibitors (e.g. omeprazole, lansoprazole) target K+/H+ATPase pumps in the parietal cells of the stomach
They prevent the exchange of K+ from the lumen for H+ in the cell, to reduce acid secretion in the treatment of heartburn/acid reflux and the prevention and treatment of stomach ulcers
Give an example of an ion channel drug target
Loop diuretics (e.g. furosemide) target Na+/K+/Cl- symporters
They inhibit these ion channels in the thick ascending loop of Henle to increase the excretion of sodium, potassium, and chloride ions, so decreases water retention to lower blood pressure and oedema
Define pharmacokinetics
The action of the body on the drug
What does ADME in pharmacokinetics stand for?
Absorption
Distribution
Metabolism
Excretion
What properties of a drug affect its absorption?
- Lipid soluble drugs will pass through the membrane directly, so absorbed and has an effect quickly
- Water soluble drugs will need passive diffusion to pass through the membrane
- Larger drugs will need facilitated diffusion, active transport, or endocytosis to be absorbed into the cell
- Unless given IV, not all of the drug will make to the circulation as it is broken down in the gut and liver first (first pass metabolism)
Define bioavailability
The rate and extent to which a drug reaches the systemic circulation (IV=100%)
What does the distribution of a drug depend on?
- Blood flow to the area (gets to well perfused areas like the brain fastest)
- Permeability of the capillaries (using slit junctions, lots in the liver)
- Protein-binding (must be free from proteins to pass through membranes and have an effect)
- Lipophilicity (lipophilic drugs will easily pass through membranes, increasing the spread of distribution)
What happens in the 2 phases of drug metabolism?
- Phase 1 = makes drugs hydrophilic (using CYPs e.g. cytochrome P450 )
- Phase 2 = if still too lipophilic, add something else to make it polar so that it can’t be absorbed (acetylation)
How do CYPs effect drug metabolism?
CYPs are a large group of enzymes, most deactivate drugs for excretion, some activate drugs to their active forms
Some drugs act on CYPs to increase (inducers) or reduce (inhibitors) the metabolism of other drugs
How are drugs excreted?
Most drugs are excreted by the kidneys in the urine
Some are excreted by the liver in the bile and faeces
Define pharmacodynamics
The action of the drug on the body
What is an agonist?
Something which binds to a receptor to activate it by mimicking the endogenous substrate
What is an antagonist?
Something which inhibitors the activity of a receptor by binding to the active site to block the substrate (competitive), or by binding allosterically elsewhere to change its binding ability with the substrate (non-competitive)
Define affinity and efficacy, in relation to agonists and antagonists
Affinity - how well the substrate/drug binds to the receptor (same as potency)
Efficacy - how well the substrate/drug activates the receptor
Agonists have affinity and efficacy
Antagonists have affinity but no efficacy
Define cholinergic and adrenergic pharmacology
Cholinergic = referring to acetylcholine and its receptors (nicotinic and muscarinic)
Adrenergic = referring to noradrenaline and its receptors (alpha/beta)
What receptors and neurotransmitters are used in the somatic nervous system?
Acetylcholine, acting on nicotinic 1 receptors
What receptors and neurotransmitters are used in the parasympathetic nervous system?
Pre-synaptic ganglions use acetylcholine, acting on nicotinic 2 receptors
Post-synaptic ganglions use acetylcholine, acting on muscarinic receptors
What receptors and neurotransmitters are used in the sympathetic nervous system?
Pre-synaptic ganglions use acetylcholine, acting on nicotinic 2 receptors
Post-synaptic ganglions use noradrenaline, acting on alpha/beta adrenergic receptors
Where are the different types of muscarinic receptors found?
M1 = brain
M2 = heart
M3 = organs with parasympathetic innervation
M4/5 = CNS
What does the activation of M2 receptors do?
At the SA node… decrease heart rate
At the AV node… decreased conduction velocity, induces AV node block (increase PR interval)
THINK parasympathetic = rest + digest, so slows heart
What do M3 receptors do in the respiratory, GI, urinary systems, skin, and eyes?
Respiratory = produces mucous, induces smooth muscle contraction
GI = increases saliva production, increases gut motility, stimulates bile secretion
Urinary = contracts detrusor muscle, relaxes internal urethral sphincter
Skin = causes sweating (only sympathetic effect)
Eye = causes myosis (pupil constriction), increased drainage of aqueous humour, secretion of tears
Name a muscarinic agonist
Pilocarpine is used to treat acute glaucoma, elevated intraocular pressure, and dry mouth
Activates M3 receptors
Name a muscarinic antagonist
Atropine is an antagonist to all muscarinic receptors, causing pupil dilation and increased heart rate
Used to treat muscarine poisoning
Name an inhaled antimuscarinic
Ipratropium is used in an inhaler to treat COPD, by blocking M3 receptors to cause bronchodilation
Side effect caused by blocking M3 receptors = dry mouth, worsening glaucoma
How is ACh used in the CNS, and how dose this contribute to the side effects of antimuscarinics?
ACh is used in CNS receptors involved in memory, so antimuscarinics can cause memory problems
How is ACh used in the somatic nervous system, and how can this be targeted in pharmacology?
ACh is used in neuromuscular junctions of skeletal muscle
Botulinum toxin (botox) prevents ACh release, so induces paralysis, treats muscle spasms, and is used cosmetically
Nicotine receptor blockers (e.g. atracurium) inhibit ACh activity, so act as muscle relaxants used in anaesthetics
What are catecholamines and where are they released?
The neurotransmitters noradrenaline (released from sympathetic nerve endings) and adrenaline (released from adrenal glands)
Describe the pathway of catecholamines production
Phenylalanine
Tyrosine
DOPA
Dopamine
Noradrenaline
Adrenaline
What type of receptor are the alpha and beta adrenergic receptors, and how do they work?
Alpha 1 = Gq, increase intracellular calcium
Alpha 2 = Gi, inhibits cAMP generation
Beta 1/2 = Gs, increases cAMP generation
What do alpha-1 receptors do?
Constriction of smooth muscle: blood vessels (mainly in the skin and splanchnic beds - structures not needed for fight/flight), and pupils
Constriction of sphincters: pyloric, urinary, and prostate
Name an alpha-1 agonist
Noradrenaline is given to treat shock, as it activates alpha-1 receptors to vasoconstrict and increase peripheral resistance to increase systemic blood pressure
Name an alpha-1 antagonist
Doxazosin is used to lower blood pressure by reducing vasoconstriction
Where are alpha-2 receptors located and what do they do?
They are located in the periphery and brain, and have mixed effects on smooth muscle
Name an alpha-2 agonist
Clonidine is used to reduce vascular tone and blood pressure to treat hypertension, and to improve concentration in ADHD
Where are beta-1 agonists located and what do they do?
Heart… chronotropic (increased heart rate) and inotropic (increased force)
Kidney… stimulate renin release
Adipose cells… cause lipolysis
Name a beta-1 agonist
Adrenaline is given to treat anaphylaxis by increasing heart rate and stroke volume
Name a beta-1 antagonist
Bisoprolol is a beta blocker, so will reduce heart rate and stroke volume as treatment after heart failure (to allow myocardial recovery)
Where are beta-2 receptors located and what do they do?
Lungs… bronchodilation
Bladder… inhibits micturition
Skeletal muscle… increases contraction speed
Pancreas… insulin/glucagon secretion
Uterus… inhibits labour
Name a beta-2 agonist
Salbutamol is used in inhalers to treat asthma and COPD, by causing bronchodilation
Name a beta-2 antagonist
Propranolol (non-selective beta blocker, so antagonist to beta 1 and 2 receptors) treats hypertension by causing vasoconstriction
How have drugs been developed to target DNA?
- Preventing DNA synthesis
- Blocking the incorporation of certain factor to cause chain termination and cytotoxicity
- Preventing replication by causing irreversible crosslinks
How do protein kinase inhibitors work?
Protein kinase inhibitors (e.g. imatinib) block the phosphorylation that is needed in transcription, and have been developed to target specific mutations
Name the naturally occurring opioids
Morphine
Codeine
Name the opioids which are simple chemical modifications
Diamorphine
Oxycodone
Name two synthetic opioids
Pethidine
Fentanyl
What routes of administration are available for opioids?
Oral (low bioavailability, so slowest option)
Parenteral (subcutaneous, intramuscular, intravenous)
Epidural (drugs are given into the CSF)
Transdermal (used for lipid-soluble drugs like fentanyl)
IV patient controlled analgesia (patient has more when needed)
What is the bioavailability of oral morphine, and how does this effect the dose needed compared to IV?
The bioavailability or oral morphine is 50%, so the dose will need to be twice as much as an IV dose to have the same effect
How do opioids induce analgesia?
Opioids act on the existing pain modulation system, by increasing the activity of the descending pain inhibition pathway, which prevents the transmission of pain signals to the ascending spinothalamic neurons
What are the names of the 4 opioid receptors, and what type of receptor are they?
MOP (the target of all current opioids), KOP, DOP, NOP
G-protein coupled receptors, acting through secondary messangers
What is tolerance?
Tolerance is the downregulation of receptors caused by prolonged use, meaning that a higher dose is needed to have the same effect
What affects the potency of a drug, and how will this change doses needed of diamorphine, morphine, and pethidine?
Potency relates to how well the drug binds to the receptor (affinity), meaning different drugs will need different doses to achieve the same potency/effect:
Diamorphine = 5mg, Morphine = 10mg, Pethidine = 100mg
What is dependency?
Dependency is when drug-taking becomes impulsive due to physical or psychological impairment, which can lead to withdraw symptoms of not taken
What are the side effects of opioids?
Respiratory depression
Sedation
Constipation
Nausea and vomiting
Addiction
Immune suppression
Itching
Endocrine effects
Why do the side effects of opioids occur?
Because there are opioid receptors outside of the CNS (also in the GI tract and respiratory control centres in the brain)
What is the antidote to opioids?
Naloxone is a competitive antagonist to opioid receptors, so is used to treat opioid overdoses and respiratory depression (as a side effect to opioids)
What is pharmacogenetics?
Genetic factors which change the metabolism of a drug
Codeine and tramadol require CYP206 to metabolise them to morphine to have an effect
10-15% of the population have decreased CYP206 activity
10% have an absence of CYP206
5 % have an over reactive CPY206 (increased risk of respiratory depression)
Define adverse drug reaction
An unwanted or harmful reaction following the administration of a drug under normal conditions of use, suspected to be related to the drug
Define side effect
An unintended effect of a drug related to its pharmacological properties, including unexpected benefits of treatment
Why are ADRs significant?
Common cause of death
2% of admissions
60% are preventable
Adversely affects quality of life
Increases cost of patient care
Occurs in 10-20% of inpatients
When do the following contribute to ADRs?
- Toxic effects
- Collateral effects
- Hyper-susceptibility
- Toxic effects happen when the dose is above the therapeutic range, or if renal/hepatic function impairs excretion (e.g. nephrotoxicity or ototoxicity with high doses of aminoglycosides like gentamicin)
- Collateral effects occur when the dose is within the therapeutic range (e.g. beta blockers cause bronchoconstriction, dangerous is asthma/COPD)
- Hyper-susceptibility happens with sub-therapeutic doses (e.g. anaphylaxis with penicillin)
What are the risk factors for ADRs?
Age (elderly or neonates)
Genetic predisposition
Polypharmacy (drug-drug interactions)
Hepatic/renal impairment
Adherence problems
Prescriber’s error
Low therapeutic range
Steep dose-response curve
What is a type A ADR?
Type A = augmented pharmacology
An extension of the primary effect, or a secondary effect
e.g. hypotension caused by hypertensives
What is a type B ADR?
Type B = bizarre or idiosyncratic
Includes allergy or hypersensitivity
e.g. anaphylaxis caused by penicillin
What is a type C ADR?
Type C = chronic/continuous
Related to time and cumulative doses
e.g. steroids causing osteoporosis
What is a type D ADR?
Type D = delayed
Seen some time after the use of the drug
e.g. thalidomide taken in pregnancy, effects aren’t seen until baby is born
What is a type E ADR?
Type E = end of use
Occurs soon after the withdrawal of the drug
e.g. opiate withdrawal
What is a type F ADR?
Type F = failure
Often caused by drug interactions
e.g. oral contraceptives and enzyme inducers
How should you respond to an ADR?
When any symptoms are expected to be an ADR after the drug is started, stopped, or dose increased…
- asses for need of urgent care, review history, review adverse effect profile of suspected drug, modify dose/stop/swap
- report all suspected and serious reactions using the yellow card system (important for patient safety)
What does the ABCDE stand for in the treatment of anaphylaxis?
A = airways (check for compromised)
B = breathing (check resp rate)
C = circulation (check heart rate and blood pressure)
D = disability (level of consciousness)
E = exposure (check for rash, and allergens)
What are the side effects of these common drugs:
- NSAIDs
- Antihistamines
- ACEi
- PPIs
- Diuretics
- NSAIDs = GI upset and bleeding, renal impairment
- Antihistamines = some can cross the blood-brain barrier and cause sedation
- ACEi = dry cough due to bradykinin
- PPIs = prolonged use in elderly can increase risk of fracture
- Diuretics = increased frequency and dehydration
How do NSAIDs work?
NSAIDs (e.g. ibuprofen, aspirin) are cyclooxygenase (COX) inhibitors, so prevent the production of prostaglandins
The inhibition of COX2 is useful (anti-inflammatory action)
The inhibition of COX1 causes the adverse effects (gastric damage)
How do antihistamines work?
Antihistamines (e.g. cetirizine) are H1 receptor antagonists
They prevent the release of histamine from storage granules in mast cells, so stop them causing an allergic reaction
What are the two categories of antibleeding drugs?
Anticoagulants
Antiplatelets
Name two examples of anticoagulants and how they work
Warfarin (oral) - prevent the activation of clotting factors II, VII, IX, X
Heparin (injectable) - activates antithrombin III, so inhibits thrombin
Give an example of an antiplatelet drug, and how it works
Aspirin - irreversible COX1 inhibitor, preventing aggregation of platelets
Give an example of an antiplatelet drug, and how it works
Aspirin - irreversible COX1 inhibitor, preventing aggregation of platelets
