Pharmacology Flashcards
Define the term “drug”.
A drug can be defined as a chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect.
What is a medicine?
A medicine is a chemical preparation which usually, but not necessarily, contains one or more drugs and is administered with the intention of producing a therapeutic effect.
Define pharmacology.
Pharmacology can be defined as the study of the effects of drugs on the function of living systems.
What is pharmacodynamics?
Pharmacodynamics is the branch of pharmacology that describes how the drug affects the body.
What is pharmacokinetics?
Pharmacokinetics is the branch of pharmacology that describes the disposition of a compound within an organism. It describes the absorption, distribution, metabolism and excretion of the drug in the body (ADME).
What are the four main kinds of regulatory proteins that are commonly involved as primary drug targets?
Receptors
Enzymes
Ion channels
Carrier molecules
What is a receptor?
A receptor is a component of a cell that interacts with a specific ligand and initiates a change in biochemical events leading to the ligand’s observed effects.
What are the different types of ligands?
Endogenous:
- hormones (testosterone, hydrocortisone)
- neurotransmitter (ACh, serotonin)
- autacoids (cytokines, histamine)
Exogenous: drugs
What is an agonist?
An agonist is a ligand that binds to and activates a receptor.
What is an antagonist?
An antagonist is a ligand that binds to but does not activate a receptor and by doing so, prevents an agonist from binding.
What is an inverse agonist?
An inverse agonist is a ligand that binds to and activates a receptor but induces an effect opposite to that of an agonist.
Define potency.
Potency is a measure of drug activity expressed in terms of amount required to produce an effect of given intensity.
What is drug affinity?
Occupation of receptors is governed by affinity which is the tendency of a drug to bind to the receptor.
What is drug efficacy?
Efficacy is the tendency of the drug, once bound, to activate the receptor. Thus, antagonists have zero efficacy.
What is the difference in the response induced by partial and full agonists?
Partial agonists have intermediate efficacy and therefore induce a submaximal response even at 100% concentration where as full agonists elicit a maximal tissue response.
Why can’t concentration-effect curves be used to measure agonist affinity?
This is because the response produced is not directly proportional to receptor occupancy as full agonists produce a maximal response even though they are bound to less than 100% of the receptors hence tissues are said to possess spare receptors.
What is competitive antagonism?
It is when the agonist occupancy at a given agonist concentration is reduced due to the presence of a antagonist because the receptor can accommodate only one molecule at a time.
What is reversible competitive antagonism?
It is when the antagonism is surmountable as raising agonist concentration can restore agonist occupancy and hence tissue response.
What are the two main characteristics of reversible competitive antagonism?
- In the presence of the antagonist, the agonist log concentration-effect curve is shifted to the right without change in slope or maximum. The extent of the shift is a measure of dose ratio which increases linearly with antagonist concentration.
- Antagonist affinity, so measured, is used as a basis for receptor classification.
What is dose ratio?
The ratio by which the agonist concentration needs to the increased in the presence of the antagonist in order to restore a given level of response.
What is irreversible competitive antagonism?
It occurs when the antagonist binds to the same site on the receptor as the agonist but dissociates very slowly, or not at all, from the receptors. This results in no change in the antagonist occupancy when the agonist is applied.
What type of bonds do irreversible antagonists form with the receptor?
Covalent
What are the uses of drugs in therapeutics? Give examples.
- Cure disease
- chemotherapy in cancer/leukaemia
- antibiotics in specific bacterial infections - alleviate symptoms
- antacids in dyspepsia
- NSAIDs in rheutmatoid arthritis - Replace deficiencies
- thyroxine in hypothyroidism
- insulin in diabetes mellitus
Give examples of drugs that inhibit enzyme action.
- Digoxin- Na/K ATPase
- Aspirin- platelet COX
- Captopril- ACE
- Selegiline- monoamine oxidase B
- Carbidopa- decarboxylase
- Allopurinol- xanthine oxidase
Give an example of a reversible antagonist.
Atenolol is a competitive beta-adrenoceptor antagonist. Used in hypertension and angina. Effects last for hours. Can be overcome by administering beta receptor agonist like isoprenaline.
Give an example of an irreversible antagonist.
Vigabatrin is an irreversible inhibitor of GABA (gamma aminobutyric acid) amino-transferase. Used in epilepsy. Effects persist for days due to irreversible binding.
Give an example of a selective agonist.
Salbutamol is a selective beta-2-adrenoceptor agonist.
Acts on medium and large airways in the lungs. Used for COPD and asthma.
Give an example of a non-selective agonist.
Isoprenaline is a non-selective beta-adrenoceptor agonist. Used for bradycardia, heart block and rarely asthma.
Give examples of drugs acting at receptors.
Beta 1 adrenoceptor blockers Beta 2 adrenoceptor agonists Opioids Benzodiazipines Inahled steroids Inhaled anti-muscarinics H1 antihistamines H2 antagonists
How would you administer diazepam to a fitting child who had no visible veins and jaws clenched tight?
Rectal diazepam
How would you administer X-ray dye for looking at coronary blood vessels?
Intra-arterial
How would you administer Ondansetron to a patient having chemo who can’t stop vomiting?
IV
How would you administer GTN to a patient having an angina attack at home?
Sublingual
How would you administer insulin to a diabetic adult?
Subcutaneous injection
Give examples of non-adherence.
- Not taking prescribed medication
- Taking bigger/smaller doses than prescribed
- Taking medication more/less often than prescribed
- Stopping the medicine without finishing the course
- Modifying treatment to accommodate other activities (work, social)
- Continuing behaviours against medical advice (diet, alcohol, smoking)
What are the reasons for unintentional non-adherence?
Practical barriers regd capacity and resources:
- difficulty understanding instructions
- problems using treatment
- inability to pay
- forgetting
What are the reasons for intentional non-adherence?
Motivational barriers that are perceptual in nature:
- patients’ beliefs about their health/condition
- beliefs about treatment
- personal preferences
What is the necessity-concerns framework?
Necessity- perception of personal need for treatment
Concerns about range of potential adverse consequences
What is meant by patient-centred care?
Patient-centred care is a philosophy of care that encourages:
- Consultation focus is on the patient as a whole person who has individual preferences situated in a social context
- shared control of the consultation, decisions about interventions or management of health problems with the patient
What are the impacts of good doctor-patient communication?
- better health outcomes
- higher adherence to therapeutic regimens in patients
- higher patient and clinician satisfaction
- decrease in malpractice risk
What steps can be taken to ensure shared decision making with patients?
- Define the problem and take pt and pr views.
- Convey that professionals may not have a set opinion about the best treatment, even when patient priorities are taken into account
- Outline the options and, if relevant, the consequences of no treatment
- Provide information in preferred format
- Check the patient’s understanding of the options
- Explore the patient’s concerns & expectations about the condition, treatment options & outcomes
- Check the pt accepts the decision sharing process
- Involve the patient in the decision making process to the extent the patient wishes
- Review the needs & preferences after the patient has had time for further consideration
- Review treatment decisions over time
What are the patient barriers to concordance?
- may not want to engage in discussion
- can cause pt more worry
- patients may just want to be told what to do
What are the clinical barriers to concordance?
- relevant communication skills
- time/resources/organisational constraints
- challenging when pt choice is different to evidence
What is adherence?
Adherence is the extent to which the patient’s actions match agreed recommendations
What are the four kinds of drugs that act on membrane ionic channels?
- antiarrhythmic drugs
- calcium slow channel antagonists
- general and local anesthetics
- anticonvulsants
What is bioavailability?
Bioavailability describes the fraction of the dose that is absorbed into the systemic circulation and is usually designated F.
What is first-pass metabolism?
It refers to metabolism of a drug that occurs en route from the gut lumen to the systemic circulation.
Define desensitisation.
AKA tachyphylaxis, it is the gradual diminution (in minutes) in the effect of a drug when it is given continuously or repeatedly.
Define tolerance.
A gradual decrease in responsiveness to a drug over the course of hours, days or weeks.
What is refractoriness?
Loss of therapeutic efficacy
What is drug resistance?
A term used to describe the loss of effectiveness of antimicrobial or antitumour drugs.
What factors give rise to desensitisation and tolerance to drugs?
- change in receptors
- exhaustion of mediators
- physiological adaptation
- translocation of receptors
- increased metabolic degradation of the drug
- active extrusion of drug from cells
What changes in receptors can lead to desensitisation or tolerance?
Ion channel desensitisation can occur in two ways.
- Conformational change- tight binding of agonist without opening ion channel
- phosphorylation of intracellular regions of receptor protein (slower mechanism)
GPCR phosphorylation interferes with ability to activate second messenger cascade.
How does translocation of receptors lead to desensitisation/tolerance?
Prolonged exposure to agonist leads to gradual decrease in number of receptors expressed on cell surface as a result of internalisation by endocytosis.
Common for hormone receptors.
How does exhaustion of receptors lead to desensitisation? Give an example.
It is associated with depletion of an essential intermediate substance.
E.g. Amphetamine - acts by releasing amines from nerve terminals. It shows marked tachyphylaxis as amine stores get depleted.
Give two examples of how altered drug metabolism leads to tolerance.
- Repeated administration of barbiturates or ethanol can lead to the same dose producing lower plasma concentration due to increased metabolic degradation.
- Nitrovasodilators- decreased metabolism leads to reduced release of NO.
How does physiological adaptation lead to desensitisation/tolerance?
It is the diminution of a drug’s effect as it is nullified by homeostatic response. The action of thiazide diuretics is limited because of gradual activation of RAAS.
What are the different types of drug antagonism? Give examples.
- Chemical (interaction in solution leading to loss of effect of active drug). Dimercaprol is a chelating drug that binds to heavy metals and reduces their toxicity.
- Pharmacokinetic (one drug affects ADME of another). Phenytoin increases the rate of hepatic metabolism of warfarin.
- Competitive (both drugs bind to same receptor)
- Interruption of receptor-response linkage (antagonist blocks downstream from binding site)
Ketamine blocks ion channel pore of NMDA receptor. Verapamil prevents influx of calcium ions through cell membrane. - Physiological (two agents producing opposing effects)
Histamine acts on parietal cells of gastric mucosa to stimulate acid secretion. Omeprazole blocks this effect by inhibiting the proton pump.
What are ion channels?
Ion channels are gateways in cell membranes that selectively allow the passage of particular ions and that are induced to open or close by a variety of mechanisms.
What are the two types of ion channels?
Ligand-gated open when agonist molecule is bound.
Voltage-gated channels are controlled by changes in transmembrane potential.
Give examples of allosteric binding to channel proteins.
- Benzodiazepine tranquilisers- GABA
- Dihydropyridine-type vasodilators inhibit opening of L-type calcium ion channels.
- Sulfonylureas used to treat diabetes increase insulin by acting on ATP-gated K+ channels of beta-islet cells.
Give an example of a false substrate acting on an enzyme.
Fluorouracil replaces uracil in purine biosynthesis so there is no conversion to thymidylate. This blocks DNA synthesis so there is no cell division.
Give an example of a prodrug acting on an enzyme.
Enalapril is converted to enalaprilat (ACEi) by esterases.
What are the four types of receptors?
- Ligand-gated ion channels/ionotropic receptors
- GPCR/metabotropic/7-TDM
- Kinase-linked receptors
- Nuclear receptors
Describe ligand-gated ion channels.
- ligand binding and channel opening occur on millisecond timescale
- involved in fast synaptic transmission
- directly linked to ion channels
- nicotinic ACh receptor, GABA type-A
Describe GPCRs.
- involved in relatively fast transduction
- most interact with phospholipase C or adenylyl cyclase
- muscarinic ACh, adrenergic, dopamine, serotonin, opiate receptors
Describe kinase-linked receptors.
- receptor tyrosine kinases for growth factors, TLRs and insulin receptors.
- receptor serine kinase- transforming growth factors
- cytokine receptors for interferons and colony-stimulating factors; slow response time (minutes)
Describe nuclear receptors.
They initiate changes in gene transcription. e.g. corticosteroids, thyroid hormone, retinoic acid, vitamin D.
Class I- present in cytoplasm and migrate to nucleus, respond to endocrine ligands (hormones)
Class II- present in nucleus and respond to lipid ligands (fatty acids).
What is an enzyme inhibitor?
An enzyme inhibitor is a molecule that binds to an enzyme and changes (normally decreases) its activity. It prevents substrate binding to active site and prevents catalysis of reaction.
How do statins work as enzyme inhibitors?
Statins are HMG-CoA reductase inhibitors. They block the rate limiting step in the cholesterol pathway. They are a type of lipid-lowering medication and decrease CVD and mortality in those at high risk.
How do ACE-inhibitors work?
RAAS regulates blood pressure. It increases BP by increasing salt and water retention in the body. The inhibitor acts on ACE and decreases levels of angiotensin II and hence decreases BP.
Briefly describe the various enzyme inhibitors used to treat Parkinson’s Disease.
PD is caused by early degeneration of dopamine in the nigrostriatial pathway leading to autonomic dysfunction and dementia. The substrate is L-DOPA .
- peripheral ddc inhibitor (carbidopa) blocks ddc in periphery to make more L-dopa available to CNS
- peripheral COMT inhibitor prevents breakdown of L-dopa
- central COMT inhibitor
- MAO-B inhibitor prevents dopamine breakdown and increases availability
- central dopamine receptor agonists
What are the three main types of protein ports in cell membranes?
- uniporters- use energy from ATP to pull molecules in
- symporters- use inward movement of one molecule to pull in another molecule against conc gradient (same direction)
- antiporters- one substance moves against its conc gradient using energy from another molecule moving down its conc grad (Na,K,H)
Symp and anti tend to be cotransporters.
Give an example of a drug that inhibits a symporter.
Furosemide- loop diuretic for hypertension and oedema acts by inhibiting the luminal NKCC in the ascending loop of Henle causing the loss of ions in the urine, thereby preventing re-uptake and increasing urine volume.
Symporter- Na-K-Cl cortransporter
Give examples of drugs that block epithelial sodium channels.
ENaCs cause reabsorption of Na+ at collecting ducts in nephrons, colons, lungs and sweat glands.
anti-hypertensives:
Blocked by high affinity diuretic amiloride.
Used with thiazide which targets Na-Cl cotransporter that reabsorbs Na and Cl from tubular fluid.
Give an example of a drug that inhibits voltage-gated calcium channels.
Found in the membranes of excitable cells like muscle, neurones, glial.
Amlodipine is an angioselective CCB that inhibits the movement of Ca into and hence contraction of vascular smooth muscle cells and cardiac muscle cells.
Causes vasodilation and a drop in peripheral vascular resistance = decrease in BP.
Give an example of a drug that inhibits voltage/ligand-gated sodium channels.
Lidocaine is an anaesthetic which blocks transmission of action potential by prolonging inactivation of voltage-gated sodium channels. It also alters signalling in the heart and hence is used to treat ventricular arrhythmias.
Define an action potential.
It is a momentary change is electrical potential on the surface of a cell, especially of a nerve or muscle cell, that occurs when it is stimulated, resulting in the transmission of an electrical impulse.
Give examples of drugs that block voltage-gated potassium channels.
Repaglinide, nateglinide, sulfoylurea reduce blood glucose levels by blocking K+ channels in the beta-islets of Langerhans to stimulate insulin secretion and are used in the treatment of type II diabetes mellitus.
Increased levels of glucose block the ATP-dependent K+ channels. Repeated firing of APs causes Ca2+ influx which triggers insulin secretion via exocytosis.
Give an example of a ligand-gated chloride channel and drugs that act on it.
GABA-A receptor activated by endogenous ligand GABA (inhibitory nt). Post-synaptic, opens chloride channel and induces hyperpolarisation. Barbiturates like phenobarbitone increase permeability of channel to chloride hence causing greater inhibition.
What is the sodium pump? Where is it found? Give an example of a drug that inhibits it.
Na/K ATPase antiporter pumps 3 NA out for every 2 K into cell using energy from ATP. It is found in excitable membranes. It is inhibited by Digoxin mainly in the myocardium and is used to treat atrial flutter, atrial fibrillation and heart failure.
What is the proton pump? Where is it found? Give an example of a drug that inhibits it.
K/H ATPase pump found in the stomach. Exchanges K+ from lumen with cytoplasmic hydronium. Is responsible for acidification of stomach and activation of pepsin. Ideal target for inhibiting secretion because terminal stage in gastric acid secretion. Example of PPI- omeprazole (irreversible).
Histamine H2 receptor antagonists are more commonly used.
Which enzyme are organophosphates irreversible inhibitors of? Where are they found?
Cholinesterase
found in insecticides (diazinon) and nerve gases (sarin)
What are the muscarinic symptoms of pesticide poisoning?
DUMBELS
Diarrhoea. diaphoresis, urination, miosis, bronchospasm, bronchorrhoea, bradycardia, emesis, lacrimation, salivation.
What are the nicotinic symptoms of pesticide poisoning?
twitching, severe weakness, paralysis, diaphragmatic failure
What are the general CNS symptoms of pesticide poisoning?
convulsions, loss of reflexes, confusion, coma
Give examples of irreversible enzyme inhibitors.
Omeprazole- PPI Simvastatin- statin Ramipril- ACEi Aspirin- COXi Paracetamol- COXi Diazinon and sarin- cholinesterase inhibitor
What are the four main components of pharmacokinetics?
Absorption from site of administration
Distribution within the body
Metabolism
Excretion
What does the rate of diffusion depend on?
molecular size/weight
What are the four main ways by which molecules cross cell membranes?
- direct diffusion through lipid
- combine with solute carrier or membrane transporter
- diffusion through aquaporins
- by pinocytosis
What factors determine the number of molecules crossing the membrane per unit area in unit time?
permeability coefficient P
concentration difference across the membrane
Which two physiochemical factors contribute to the permeability coefficient P?
solubility in the membrane (partition coefficient)
diffusivity (diffusion coefficient)
What types of drugs promote and retard the absorption of weak acids like Aspirin?
promoted by drugs that accelerate gastric emptying (metoclopramide)
retarded by drugs that slow gastric emptying (propantheline or antimuscarinics like oxybutinin)
How does urinary acidification affect the excretion of weak acids and bases?
Accelerates the excretion of weak acids and retards that of weak bases.
How would you increase plasma pH? What effect would that have on acidic drugs?
Administer sodium bicarb
will extract weakly acidic drugs from cns into plasma
How would you decrease plasma pH? What effect would that have on acidic drugs?
Administer carbonic anhydrase inhibitor like acetazolamide
Causes weakly acidic drugs to become concentrated in the cns and increases their neurotoxicity.
What must you keep in mind while deciding how to alkalinise urine when treating aspirin overdose?
bicarb and acetazolamide will increase urine pH but bicarb reduces (and acetazolamide increases) distribution of salicylate to the CNS.
What are the main sites where solute carriers are expressed?
BBB GI tract renal tubule biliary tract placenta
What are the main sites where P-gp (Permeability- glycoprotein) transporters are present?
renal tubule brush border membranes
bile canaliculi
astrocyte foot processes in brain microvessels
GI tract
What drugs does albumin bind to?
acidic drugs like warfarin, NSAIDs, sulphonamides
basic drugs like tricyclic antidepressants and chlorpromazine
What does drug-plasma protein binding depend on?
- concentration of free drug
- affinity for binding site
- concentration of protein
Name two plasma proteins apart from albumin that bind to drugs.
beta-globulin and acid glycoprotein (bind to basic drugs)
What does partition into body fat depend on?
fat:water partition coefficient
blood supply
Give an example of a drug that does not get stored in fat.
Morphine (fat:water ratio of 0.4) which makes it soluble enough to cross BBB but not accumulate in fat.
Give an example of a drug that accumulates in body fat.
Thiopental (10)
Where in the body does chloroquine tend to accumulate?
retina due to high affinity for melanin, can lead to ocular toxicity
Where in the body do tetracyclines accumulate?
bone and teeth (high affinity for calcium)
Give an example of a drug that accumulates in the liver and lung.
Amiodarone (anti-dysrhythmic) - can cause hepatitis, interstitial pulmonary fibrosis
Give an example of a solute carrier (SLC).
OAT 1- found in kidney and secretes penicillin and uric acid. Probenicid blocks it leading to excretion of uric acid.
What is pinocytosis?
It is a mode of endocytosis in which small particles suspended in ECF are brought into the cell through an invagination of the cell membrane, resulting in a suspension of the particles within a small vesicle inside the cell.
Give an example of a drug that is taken up via pinocytosis.
Amphotericin
What does the extent of ionisation of a drug depend on?
the strength of the ionisable group and the pH of the solution
What is the pKa of a drug?
It is the dissociation or ionisation constant which determines the pH at which half of the substance is ionised and half is unionised.
Where are weak acids best absorbed?
stomach
Where are weak bases best absorbed?
intestine
What does intestinal drug absorption depend on? Any exceptions?
Passive diffusion, the rate of which is determined by the ionisation and the lipid solubility of the drug molecule
Exceptions:
1. levodopa- taken up by phenylalanine transporter
2. fluorouracil- pyrimidine carriers
3. iron absorbed by specific carriers in epithelial cell membrane of jejunal mucosa
4. calcium is absorbed by vit D-dependent carrier
How long does it take a drug to come into effect after it has been administered by the following routes?
- IV/ intraosseous
- Endotracheal/inhalation
- Sublingual
- Intramuscular
- Subcutaneous
- Rectal
- Ingestion
- Transdermal/topical
IV/IO- 30 to 60 s ET/inhal- 2 to 3 min Subling- 3 to 5 min IM- 10 to 20 min SC- 15 to 30 min rectal- 5 to 30 min oral- 30 to 90 min topical- variable (mins to hrs)
What factors affect absorption when a drug has been administered orally?
- drug structure
- drug formulation
- gastric emptying
- first pass metabolism
How does drug structure impact absorption?
needs to be soluble to be absorbed from gut
drugs unstable at low pH (benzyl penicillin) or in presence of digestive enzymes (insulin)
What is first-pass metabolism?
The phenomenon by which concentration of an orally-administered drug is greatly reduced by intestinal and hepatic degradation after absorption which removes some of the active substance from the blood before it enters the systemic circulation.
What are the four major metabolic barriers in the body?
intestinal lumen, wall, liver, lungs
How can hepatic first pass metabolism be avoided?
give drug to region of gut not drained by splanchnic vessels like mouth or rectum
What factors affect GI absorption?
- gut content (feeding vs fasted)
- splanchnic blood flow
- gastrointestinal motility
- particle size and formulation
- drug interactions
Name two conditions that cause gastric stasis.
diabetic neuropathy and migraine
Give an example of a drug that decreases GI motility.
antimuscarinic
Give an example of a drug that increases GI motility.
metoclopramide (antiemetic used to increase absorption of analgesic in migraine)
Name two factors that affect splanchnic blood flow.
food increases blood flow hence increased plasma concentration of propranolol after meal
hypovolaemia or heart failure causes reduced blood flow
Give examples of drugs taken orally so they are NOT absorbed.
- vancomycin- to treat C.diff in pts with pseudomembranous colitis
- mesalazine- pH-dependent acrylic coat that degrades in terminal ileum and proximal colon to treat IBD
- Osalazine- prodrug cleaved by colonic bacteria in distal bowel so to treat distal colitis.
When is sublingual administration useful?
- rapid response
- drugs unstable at gastric pH
- drugs metabolised by liver
Give examples of drugs that are administered sublingually.
glyceryl trinitrate
buprenorphine
When is rectal administration used in children?
Used to administer diazepam in children who are status epilepticus with difficulty establishing IV access
Give two examples of when transdermal dosage via stick-on patches is used.
testosterone/oestrogen in HRT
Fentanyl (72h) for pain management in cancer
What are the advantages and disadvantages of transdermal patches?
- produces a steady rate of drug delivery
- avoids pre-systemic metabolism
- suitable only for lipid-soluble drugs
- relatively expensive
What are the advantages of intranasal administration?
- good surface area
- low levels of proteases and drug-metabolising enzymes
Give examples of drugs administered as nasal sprays.
usually peptide hormone analogues:
ADH
GRH
Calcitonin
What is the advantage of administering dorzolamide as an eye drop?
Carbonic anhydrase inhibitor used to reduce ocular pressure in patients with glaucoma. Local effect without systemic side effects of acidosis in kidney.
What are the advantages and disadvantages of administering drugs via inhalation?
+ good surface area
+ good blood flow
+ minimises systemic effects
- possible toxicity to alveoli
- cannot to be used to deliver non-volatile drugs
Give examples of drugs that are inhaled.
glucocorticoids (beclomethasone dipropionate)
bronchodilators (salbutamol)
ipratropium - muscarinic-receptor antagonist (modified atropine) for bronchodilation. Inhaled to reduce adverse systemic effects.
Which is the fastest and most certain route of drug administration?
IV
What factors affect absorption from the site of injection?
a) diffusion through tissue
b) removal by local blood flow
How can drug diffusion through tissue be improved when giving an injection?
Hyaluronidase- enzyme that breaks down intercellular matrix
What are the advantages and disadvantages of intradermal and subcutaneous injections?
+ avoids barrier of stratum corneum
+ small volume can be given
+ used for local effect or to deliberately limit rate of absorption
- mainly limited by blood flow
What is a depot injection?
A depot injection is an injection (usually SC, ID or IM) that deposits a drug n a localised mass, called a depot, from which it is gradually absorbed by surrounding tissue.
Name four methods used to delay drug absorption.
- addition of adrenaline to local anaesthetic
- formulation of insulin with protamine and zinc
- poorly soluble salt of penicillin (procaine penicillin) injected as aqueous solution
- esterification of steroid hormones and antipsychotic drugs so injected in oily solution
Give examples of drugs administered intrathecally.
- methotrexate to prevent relapse of childhood leukaemia in CNS
- local anaesthetic- bupivacaine
- Baclofen- GABA analogue to treat muscle spasms
- Antibiotics that slowly cross BBB- aminoglycosides
Give an example of a drug administered as an intravitreal injection.
Ranibizumab to treat wet age-related macular degeneration
Define distribution.
The process by which the drug is transferred reversibly from the general circulation to the tissues as the blood concentration increases and then returns from the tissues to the blood when the blood concentration falls.
What are the major body fluid compartments? And what percentage of body weight do they form?
intracellular fluid- 35% fat- 20% interstitial fluid- 16% plasma- 5% transcellular fluid- 2%
What factors affect the equilibrium pattern of distribution between various fluid compartments in the body?
- permeability across tissue barriers
- binding with compartments
- pH partition
- fat:water partition
What is the blood-brain barrier?
It is a continuous layer of endothelial cells joined by tight junctions and surrounded by pericytes.
What are the various routes of drug administration?
- Oral
- Sublingual
- Rectal
- Topical/epithelial surface:
- skin
- nasal mucosa
- cornea
- vaginal - Inhalation
- Injection
- subcutaneous
- intradermal
- intramuscular
- intravitreal
- intravenous
- intra-arterial
- intrathecal
What type of drugs can easily cross the placenta?
lipid-soluble
What is the apparent volume of distribution?
The apparent volume of distribution (Vd) is defined as the volume that would contain the total body content of the drug (Q) at a concentration equal to that present in the plasma (Cp). So Vd= Q/Cp
What is the clinical importance of Vd?
Determines the dose that has to be administered to produce a particular plasma concentration. It also tells us where in the body the drug is.
What are the consequences for a charged drug in terms of Vd?
low Vd so confined to circulatory volume due to solubility and protein binding. E.g. heparin
What are the consequences for a lipophilic drug in terms of Vd?
high Vd so distributed in total body water i.e. binding of drugs outside plasma compartment or partitioning into body fat. E.g. phenytoin and ethanol.
Gives two examples of drug interactions where there is an increase in plasma concentration and a decrease in renal excretion.
- salicylates displace methotrexate from albumin and compete with OAT to reduce renal excretion.
- antidysrhythmic drugs like quinidine, verapamil and amiodarone displace digoxin from tissue binding sites and reduce its renal excretion leading to digoxin toxicity which can cause severe dysrhythmias.
Gives examples of types of special drug delivery systems that improve delivery and localise the drug to the target tissue.
- prodrug
- biologically erodible nanoparticles
- antibody-drug conjugate
- packaging in liposomes
- coated implantable devices
What are prodrugs?
Prodrugs are inactive precursors that are metabolised to active metabolites.
Give examples of prodrugs.
- Levodopa converted to active dopamine by nerve terminals in basal ganglia
- Zidovudine phosphorylated to active triphosphate metabolite only in cells containing the appropriate reverse transcriptase making it HIV-selective.
- Cyclophosphoamide is cytotoxic and activated by hepatic metabolism.
- Heroin to morphine and 6-monoacetyl morphine
What is drug elimination?
It is the irreversible loss of drug from the body and is comprised of drug metabolism and excretion.
What is drug metabolism?
It is the build-up or break down of substances by enzymatic conversion of one chemical entity to another within the body.
What are the main excretory routes in the body?
kidneys
hepatobiliary system
lungs
Which enzyme system is responsible for hepatic metabolism?
cytochrome P450 pathway
What do extrahepatic P450 enzymes do?
biosynthesis of steroid hormones and eicosanoids
What do phase 1 and 2 metabolic reactions do?
They reduce lipid solubility of the drug compound to increase its renal clearance.
What are phase 1 reactions?
oxidation, reduction, hydrolysis
Where do phase 1 reactions take place?
liver
Are phase 1 reactions catabolic or anabolic?
catabolic
Which CYP proteins are involved in drug metabolism?
CYP 1, 2 and 3
What is functionalisation?
It is the addition of a functional reactive group like -OH, -NH2, -SH
What does oxidation by P450 system require?
- substrate (drug)
- oxygen
- P450 enzyme
- NADPH
- NADPH- P450 reductase (flavoprotein)
Give examples of inducers of P450.
smoking
alcohol
Brussel sprouts
Give examples of inhibitors of P450.
grapefruit
What is the phase 2 metabolic reaction?
Conjugation
What does the conjugation reaction involve?
Involves the formation of a covalent bond between the drug (or its phase 1 metabolite) and an endogenous substrate.
Are phase 2 reactions anabolic or catabolic?
anabolic
Where do phase 2 reactions take place?
liver
What does the phase 2 reaction involve?
Conjugation of phase 1 metabolite with glucuronic acid, sulphate, methyl or acetyl groups.
Give examples of drugs that undergo substantial first-pass metabolism?
- Analgesics:
- aspirin
- morphine
- paracetamol
- pentazocine
- pethidine - Oral contraceptives
- Respiratory drugs: salbutamol and terbutaline
- CV drugs:
- GTN
- isoprenaline
- isosorbide dinitrate
- lidocaine
- metoprolol
- propranolol
- verapamil - CNS drugs:
- levodopa
- clomethiazole
- imipramine
- nortriptyline
In what ways are low molecular weight polar drugs excreted from the body?
fluid- urine, bile, sweat, tears, breast milk
what is the eneterohepatic circulation? give examples of drugs that undergo it.
It is the closed circulation a drug goes thrugh after passing phase II metabolism. The glucoronide concentrated in bile goes to the intestine where it is hydrolysed to regneate the active drug. The free drug is reabsorbed and the cycle repeats. morphine, ethinyl oestradiol, vecuronium and rifampicin
define renal clearance.
renal clearance is defined as the volume of plasma containing the amount of substance that is removed from the body by the kidneys in unit time.
what is the formula used to calculate renal clearance?
CLren = [Cu x Vu]/Cp i.e. the product of urinary conc and rate of urine flow divided by plasma conc
what proceses directly affect renal drug excretion? how are they interlinked?
glomeular filtration
active tubular secretion
passive reabsoption
total excretion = glomerular filtration + tubular secretion - reabsorption
What type of drugs do OCT transfer in tubular secretion? give examples.
organic bases in their protonated cation forms
dopamine, histamine, morphone, pethidine, quinine, serotonin
What type of drugs do OAT transfer in tubular secretion? give examples.
acidic drugs in their negatively charged anionic forms
furosemide, glucoronic acid conjugates, methotrexate, penicillin, probenicid, sulphate conjugates, thiazide diuretics, uric acid
Define pharmacokinetics.
Pharmacokinetics can be defined as the measurement and formal interpretation of changes with time of drug concentrations in one or more different regions of the body in relation to dosing.
What is total drug clearance?
CLtot is defined as the volume of plasma which contains the total amount of drug that is removed from the body in unit time. ml/min or l/h
How do you calculate rate of drug elimination?
rate of drug elimination = plasma drug conc x total drug clearance
What is first-order kinetics?
the rate of elimination is directly proportional to drug concentration i.e. a constant fraction of the drug is eliminated per unit time. dependent on plasma conc so the conc of the drug is the rate limiting factor. when plasma conc is plotted against time, the decrease is exponential
what is the half-life of a drug defined as?
it is the time taken for the drug plasma concentration to decrease by half
what is zero-order kinetics?
Zero-order kinetics describes a decrease in drug levels in the body that is independent of the plasma conc and the rate is held constant by a limiting factor such as enzyme co-factor availability. when the plasma conc is plotted against time, the decrease is a straight line.
give an example of a drug that exhibits zero-order kinetics.
ethanol once alcohol dehydrogenase has been saturated
What is bioavailability?
Bioavailability is a term used t indicate the fraction F of an orally administered dose that reaches the systemic circulation as intact drug, taking into account both absorption and local metabolic degradation. F is 1 for IV drugs as 100% reaches circulation
how can bioavailability of a drug be estimated from a plasma conc-time graph?
area under curve
if a drug has an oral bioavailability of 0.1 then how does its oral dose compare to its IV dose?
oral dose = 10 x IV dose
what factors affect the bioavailability of a drug?
drug preparation, variation in enzyme activity of gut wall or liver, gastric pH, intestinal motility
what does the rate of distribution of water-soluble drugs depend on?
rate of passage across membranes
what does the rate of distribution of lipid-soluble drugs depend on?
blood flow to tissues that accumulate the drug
what is an opioid?
An opioid is any substance, whether endogenous or synthetic, that produces a morphine-like effect and can be blocked by antagonists like Naloxone.
what is an opiate?
compounds like morphine and codeine that are found in the opium poppy
what are the main groups of synthetic opioid analogues?
piperidines (pethidine and fentanyl)
methadone-like drugs
benzomophans (pentazocine)
thebaine derivatives (buprenorphine)
what are the different routes of administration for opioid analgesics?
oral parenteral (SC, IV, IM) IV PCA- patient controlled analgesia Epidural/CSF/intrathecal transderal patch for lipid soluble drugs (fentanyl)
name two naturally-occurring opioids
morphine, codeine
give examples of simple chemically modified opioids.
diamorphine, oxycodone, dihydrocodeine
what is the half life of morphine?
3 to 4 hours
give examples of synthetic opioids.
pethidine, fentanyl, alfentanil, ramifentanil
how does the bioavailability of morphine affect how it is administered?
50% of oral morphine undergoes first pass metabolism therefore halve the dose when administering parenterally.
which opioid receptor is responsible for most of the analgesic effects of opioids?
myu (u) receptors
what are some of the unwanted side effects of u-opioid receptor agonsists?
respiratory depression, constipation, euphoria, sedation and dependance
what does sigma-opioid receptor activation lead to?
analgesia but can be proconvulsant
What are the effects of kappa receptor agonists?
sedation, dysphoria, hallucinations as they contribute to analgesia at the spinal level
