Clin Pharm Flashcards
1
Q
What is the difference between pharmacodynamics and pharmacokinetics
A
PD - the biological and physiological effects of the drugs, their modes of action and relationship with concentration
PK - study of characteristics of the time course and extent of drug exposure
2
Q
What are the 5 main cellular receptors that drugs interact with?
A
- Ion channels
- Nuclear receptors
- Enzymes
- GPCRs
- Receptor kinases
3
Q
What are the 3 main cellular consequences of receptor activation?
A
- Ion channel opening or closing
- Biochemical messengers activated and initiate signalling pathways
- A normal cellular function is physically inhibited
4
Q
Define a drug antagonist
A
It binds to the receptor, produces no cellular effect but inhibits access of agonists and prevents their effects
5
Q
Define a partial agonist
A
A drug which fails to produce a maximal response even when all the receptors are occupied
(this is compared to a full agonist, in some cases you don’t need all the receptors to be filled to have the maximal effect)
6
Q
What are the 5 types of antagonism?
A
- Competitive antagonism
- Non-competetive antagonism (binds to a site other than the receptor domain to cause a conformational change)
- Irreversible antagonism
- Physiological anatagonims (the action of the two agonists cancels each other out)
- Antagonism by neutralisation (the drugs bind to eachother and become inactive)
Important because drugs are safer if they can be removed from the receptor (hence are reversible)
7
Q
What is drug tolerance?
A
This is where you require more drug to have the same effect
This can occur due to desensitiation (which can link to receptor down/up regulation)
8
Q
Define drug potency
A
The amount of drug required to produce 50% of its maximal effects
(in practice it is generally the amount of drug needed to have an effect)
9
Q
Define:
- EC50
- LD50
- Therapeutic index
- Margin of safety
A
- Effective concentration - concentration of drug that induces a clinical effect in 50% of patients
- Lethal dose - concentration of drug that induces death in 50% of patients
- Therapeutic index - a measure of drug safety (LD/EC)
- Margin of safety is the margin between the therapeutic and lethal doses of a drug - the larger it is generally the safer the drug
10
Q
What are the 3 main methods of metabolism/excretion of drugs by the body?
A
- Liver metabolism and then extretion in the biliary system
- Excretion (+/- metabolism) by the kidney
- Excretion by the lungs (exhalation is volatile)
But remember drugs can also accumulate in other compartments such as the ECF, ICF, CSF, bone and skin
(and in milk in lactating animals for some drugs)
11
Q
What are the 5 mechanisms by which drugs can cross membranes
A
- Passive diffusion (rapid for lipophilic, non ionic and small molecules)
- Facilitated diffusion
- Aqueous channels for small hydrophilic drugs down a gradient (don’t exist in BBB)
- Active transport
- Pinocytosis for very large molecules
12
Q
Why is the ionisation state of a drug important?
A
Because the body pH will influence it - basic drugs are ionised and retained in acidic fluids and ionised drugs cannot diffuse across membranes
13
Q
What are ATP binding cassette transporters and where are they found
A
The are responsible for outwards transport of endogenous and exogenous compounds - found in the GI tract and CNS
They prevent the absorption of toxins, xenobiotics or other drugs
14
Q
Define bioavailability and how can you calculate it
A
The proportion of the administered dose that reaches the central compartment (i.e. the circulation)
Plot of plasma concentration vs time and calculate area under curve - compared for normal administration (oral etc.) vs i.v
Generally the more complex the drug formulation the lower the bioavailability
Even of the same drug, liquid preparations tend to have more consistent bioavailability than solid
15
Q
What are the main pros and cons of oral drug formulations
A
- Unionised drugs can cross the gut wall - depending on drug pH it will be absorbed at different GI sites (also influenced by GI surface area)
- Convenient, cheap and non need for sterility - and can even get the dose back if you act fast enough
- But can have massive variability due to physiology, feeding, disease etc.
- Have to consider feeding or starvation
- V/D can affect treatment
16
Q
What are the main pros and cons of IM drugs
A
Pro - More consistent absorption that oral or s/c (although rate is dependent on local blood flow) - More rapid onset also - Sustained effects possible - Can be administered in unconscious, vomiting or fractious patients - Certainty of administration Cons - Pain - Muscle damage - Dose cannot be removed once given
17
Q
Describe water and lipid soluble boluses and their pros and cons
A
Bolus injection
When water soluble the drug is already dissolved in water and so mixes with tissue fluid rapidly for absorption - rate will be dependent on local blood flow
Lipid soluble ones have to wait for the drug to dissolve in the tissue fluid first
Cons - risk of pain, muscle damage haematoma, abscessation, inadvertent iv
18
Q
Why is inhalation used so commonly for anaesthetic drugs?
A
Because the lung has such a huge surface area for absorption directly into the bloodstream
Also avoids the first pass effect
However it does require very small drug particle size
19
Q
What are the main influences on drug distribution
A
- Membrane permeability of a drug
- Plasma/tissue protein binding (inactivates the protein and they get caught in equilibrium)
- Blood flow
- Depot (fat) storage
20
Q
Discuss drug binding to plasma proteins
A
- Acidic drugs bind to albumin whereas basic drugs bind to alpha glycoprotein
- ALso some binding to lipoprotein and potentially erythrocytes
- Once bound the drug is inactive but also cannot be metabolised or excreted
- Forms an equilibrium
- So not a good thing if the drug has high toxicity
- Degree of binding varies between drugs
- Remember if you use two drugs that bind to the same protein site, then competition will lead to higher free concentrations for both drugs
21
Q
Discuss fat storage of drugs
A
Lipophylic drugs can accumulate in fat which leads to slow and gradual release and can increase half life of the drug
(e.g. thiopentone sedation)
22
Q
How does inflammation affect drugs in the body
A
Inflammation increases membrane permeability and increases blood flow to tissues
Tissues also become acidic so alkaline drugs may not be taken up as easily (so become less effective)
23
Q
How does the BBB prevent drug entry and what drugs can cross it?
A
Polar molecules do not pass through and there are ABC cassette pumps to remove drugs
Small, moderately lipophilic drugs that aren’t a strong ligand of efflux pumps can generally get through
24
Q
Why are drugs metabolised?
A
To make them more polar and water soluble for excretion
In some cases the metabolites are the active form
25
Describe the two phases of drug metabolism
Phase 1 - drugs are oxidised/reduced to a more polar form (involves P450 enzymes)
Phase 2 - a polar group such as glutathione is conjugated t the drug to make it more water soluble - this stage is reduced in carnivores (e.g. cats and paracetamol)
26
What is the enterohepatic circulation
This begins with the biliary excretion of drugs, which is complicated by reabsorption of bile salts, fats, toxins and hence drugs, in the SI and LI - leads to drug recirculation without significant excretionn
(for example cardiac glycosides in dogs)
27
Give some specific examples of drugs metabolised differently/to note in different species
- Paracetamol in cats
- Propofol anaesthetic is not metabolised as effectively in cats
- Dogs have deficits in N-acetylated derivated such as sulphonamides - so are more susceptible to methaemaglobinaemia
28
Give 3 examples of conditions that can impact the first pass effect
- Diarrhoea
- Severe fasciola hepatica infection in sheep
- Severe brain damage - may affect control of circulation in the gut and liver
- Feline LUT disease - production of some renal metabolites like urea that can change the way that drugs are metabolised
29
What are the 4 main factors that affect renal excretion of drugs
- GFR - because drugs only pass through by diffusion (unless protein bound)
- Tubular secretion - as some drugs are actively secreted
- Tubular reabsorption (less likely as metabolites are ionic
- Altered urinary pH
30
What is total body clearance?
This is the plasma volume that is cleared per minute - linked to organ flow and function as well as intrinsic clearance
It is closely tied liver and kidney functions - and you need to decrease the dose if these organs are diseases:
- Kidney failure - 75% of normal dose
- Hepatic failure - 50% of normal dose
31
Describe the single compartment model
The drug is confined to a single compartment - e.g. delivered into a restricted to the plasma and then removed solely by glomerular filtration
This means removal of the drug from the body occurs as a proportional rate to the amount remaining at any one time (decline is exponential
32
What assumptions does the single compartment model rely on
- Drug in the blood is in rapid equilibrium with drug in the extravascular tissues
- Drug concentration is proprtional to the concentration of drug in the blood at all times
- Drug is mixed instantaneously in blood or plasma
- Drug elimination follows first order kinetics
33
What is first order kinetics in terms of drug excretion
This is here the drug is removed unchanged by renal filtration by a non-saturated process
(fits with the one compartment model or the second, linear phase of the two compartment model
Essentially as the plasma concentration falls the rate of excretion will also fall
34
What are zero order kinetics in terms of drug excretion
Here drug excretion rate is constant irrespective of concentration - these drugs are more difficult to use reliably or safely
(also become a problem if you reach saturation point - for example using several drugs at once)
35
What is the equation for clearance rate?
| How is the graph of it important?
CL = rate of elimination/arterial plasma concentration
It is useful for calculating dose rates when continuous or repeat dosing is used
The area under the graph relates to dose and clearance - important for evaluating the availability of drugs when administered by routes other than iv
36
What is apparent volume of distribution?
It allows you to work out where in the body the drug is going (the volume can correspond to compartments)
37
What are the volume of distribution/volumes for:
- Total body water
- ECF
- ICF
- Circulating blood volume
- Plasma volume
- Total body water = 600-650ml/kg
- ECF = 200-250ml/kg
- ICF = 300-350ml/kg
- Circulating blood volume - 85-90ml/kg
- Plasma volume - 45-50ml/kg
38
WHat is a loading dose and how do you calculate it
It is used to get the drug to steady state (therapeutic) more rapidly, and is then followed by maintenance doses
Calculated:
D = V'd x BW x (required plasma conc)
39
What are the multicompartment models?
These allow for uptake of drug differently by different tissues and takes into account the different blood flows to these tissues
Tissues that share the same pharmacokinetic propertie become one compartment
40
Describe the two compartment model
The decline in drug conc has 2 components, with the distribution phase representing mixing between these compartments - once the different compartments are in equilibrium the elimination becomes a single, first order process
41
What factors affect neonatal pharmakokinetics particularly
(Wide species differences in terms of time - generally 10-12wks for dogs)
- See increased GI drug absorption
-Lower binding to plasma proteins
- A lower ratio of body fat:fluid
- Large ECF volume
- Increased permeability of BBB
- Slower biotransformation and elimination (longer half life)
Also need to consider liver and kidney function (take 7 weeks and 2-3 days respectively to reach adult function)
42
What are the 6 main types of drug interaction?
- Altered absorption
- Altered metabolism
- Plasma protein binding
- Altered excretion
- Receptor interactions
- Physiochemical
43
How might drug interaction alter absorption?
- Inhibiting absorption across membranes -e.g. anti ulcer drug block absorption across the gut wall
- Change in pH
- Change in gut motility (e.g. metaclop)
- Altering bacterial flora -some are used to activate or inactivate drugs (e.g. activation of sulfasalazine or inactivation of digoxin)
44
Give 3 examples of drugs that inhibit P450 enzymes
Fluconazole, fluoroquinolones and omeprazole
45
Give 3 examples of drugs that compete for plasma protein binding
Bute, warfarin, phenytoin
46
What are the main drug interactions that can alter drug excretion?
- Drugs that alter renal function and hence excretion (e.g. aminoglycosides will decrease digoxin excretion)
- Changing urine pH (although this can be used to your advantage to control excretion of acidic and basic drugs)
47
Give an example of drug interactions that can occur in the syringe/giving set
Penicillin with phenytoin,B cmplex vitamins or carbenicillin or gentamicin
48
What are the 5 major effects of drug interactions
- Additive
- Synergistic
- Potentiated (a drug with no effect enhances the second drug)
- Antagonistic
- Neutral
49
What are the 7 potential mechanisms of food interactions with drugs
- Gastric emptying rate
- Dissolution of drugs - due to changes in gastric pH linked to food
- Bile acid activity - a high fat meal to stimulate bile acid production will enhance the absorption of lipid soluble drugs
- Pancreatic and intestinal mucosal enzyme activity
- Splanchnic blood flow
- Barriers to absorption
- Pharmacalogically active food substances (uncommon in pet food)
50
What are the 2 types of adverse event?
1) Predicted - those that may occur in all treated patients - so normal, dose related effects or a consequences of overdose
2) Unpredicted -those that do not reflect normal pharmacological effects of the drug - e.g. anaphylactic shock
51
What are the main ways that GI disease affects drug absorption
- Change in gut pH
- Alteration to absorptive surface
- Increase gut transit time or vomiting
- Long term diarrhoea (can also affect absorptive surface)
52
What are the main ways that renal disease can affect drug therapy
- Pharmacokinetics - can decrease elimination, decrease protein binding or decrease the hepatic metabolism (due to accumulation of metabolites that impair it)
- Drug effect may be altered - may have increased drug sensitivity
- Existing clinical condition may have worsened
- Can affect total body water
- Adverse effects may be enhanced (especially if electrolytes are disturbed)
53
What are the main ways that liver disease can influence drug action?
Pharmacokinetics
- Increased bioavailability from reduced first pass (or alternatively if prodrugs need metabolising then decreased activation)
- Decreased protein binding
- Decreased clearance/elimination - because the liver is a major site of biotransformation
Altered drug effect - hepatic encepahlopathy or clotting problems
Worsening of metabolic state
54
How can congestive heart failure affect the pharmacokinetics of drugs
Mainly by altering Vd - due to:
- Decreased tissue perfusion (e.g. lidocaine)
- Increase Vd for water soluble drugs due to oedema
- Decreasing elimination
- Oxidising capacity (hypoxia - e.g. lidocaine and theophylline)
Likely to onlymake a difference in very severe cases
55
Which drug can be affected by thyroid disease?
Digoxin - increased TH decreases its effect
56
What does POM-V mean
It means a prescription only medicine - can only be supplied by a vet or pharmacist (with a prescription from a vet) - and the animal must have been clinically assessed by the vet and be under their care
57
What does POM-VPS mean?
This is a prescription only medicine that must come from a vet, pharmacists or suitabily qualified person
But the animal does not have to be under their care and they do not have to have clinically assessed them
58
What does NFA-VPS mean?
This is a non-food animal medicine - that a vet, pharmacist or suitably qualified person can prescribe
These drugs cannot enter the food chain
59
What does AVM-GSL mean?
An authorised veterinary medicine - general sales list - do not have to be prescribed unless they are being used outside their marketing authorisation (e.g. as part of the cascade)
60
Give 5 examples of things that must be included on a writte prescription
- Name, address and telephone number of the person prescribing
- Qualifications of prescriber
- Name and address of owner
- Identification of animals to be treated
- Date and signature
- Name and amount of product prescribed
- Dose and administration instructions
- Necessary warnings and precautions
- Withdrawal period if necessary
- Statement if prescribed under the cascade
- Storage/disposal instructions
61
What is the legal time limit for authorising repeat prescriptions in advance
6 months
62
What are the 5 options in the cascade?
1 - product licensed for the species and condition under treatment
2 - If this is not possible then a product licensed for another condition in the same species
3 - Product licensed for use in another species
4 - Product licensed for human administration
5 - A special product made up under veterinary prescription by an authorised person
63
Give 3 key requirements in the cascade system
- Once you reach option 3 - a food animal can no longer enter the food chain
- Must keep records for 3 years
- Horses are classified as good animals - so need to sign out of the food chain if wanting to use certain drugs
- Not allowed to use generic versions of drugs where there are veterinary specifics
- If using options 3-5 you must state the number of animals at a specified holding that are being treated -food FPAs
64
What are the roles of:
- The misuse of drugs act 1971
- The misuse of drug (safe custody) Regulations 1973
- Misuse of drugs regulations 2001
1) Controls the availability of drugs considered 'dangerous or otherwise harmful'
2) Describes the requirements for storing CDs
3) Classifies the CDs into 5 schedules
65
What are the 5 schedules listed under the Misuse of Drugs Regulations 2001?
1) Minimal to no therapeutic use and harmful - have no use within veterinary medicine and a vet cannot prescribe them
2) Therapeutic value but are highly addictive and therefore subject to abuse - need strict storage and prescribing and use protocols (e.g. fentanyl, morphine, methadone, ketamine)
3) Have therapeutic value and the potential for abuse is less - e.g. tramadol, buprenorphine, phenobarbital, gabapentin
4) Not subject to safe custody or storage requirements - kepp invoices for 2 years - include diazepam
5) Low strength paracetamol - no requirements except that invoices must be kept for 2 years
66
What are the restrictions for a written prescription for a schedule 2 or 3 controlled drug?
Can only be dispensed once and only within 28 days (cannot do single prescriptions with multiple dispenses)
Best practice to only dispense 28 days worth at a time
67
What is the difference between an anitmicrobial and an antibiotic?
AM - any substance of natural, semi-synthetic or synthetic origin that kills or inhibits the growth of a microorganism, but causes little or no host damage
AB - A substance produced by a microorganism that, at low concentrations, inhibits or kills other microorganisms
68
What is a bacteriostatic antimicrobial
It stops an organism from multiplying but does not kill it
| All AMs are bacteriostatic at some concentrations
69
Describe the action of bactericidal Abs
This is where the organism is killed - it can occur if the concentration of antibiotic is high enough, or if the rate and extent of antibmicrobial activity is sufficient
- this could be concentration dependent (AGs), time dependent (beta-lactams) or a combination of both (fluoroquinolones)
70
What are the four main categories of antibiotics
1) Inhibit cell wall synthesis (penicillins and cephalosporins)
2) Inhibit bacterial protein synthesis (AGs and tetracyclines)
3) Inhibition of nucleic acid synthesis/function (FQs and nitroimidazoles)
4) Disruption of cell wall function (polymixin B/E)
71
Draw out the bacterial diagram of the classes of antibiotics
(see L5 notes)
72
How do topoisomerase inhibiting Abs work?
They decrease DNA synthesis by preventing alteration of supercoiling - leads to cell death
73
How do bacterial cell wall inhibitors like beta-lactams work?
They prevent polymer cross-linking and can also activate autolysins - which leads to cell lysis and death
74
How do nitroimidazoles work?
The nitrogroup is reduced by an electron transport protein in anaerobic bacteria (e.g. metronidazole) - the reduced drug then causes strand breaks in the DNA
Mammallian cells lack enzymes to reduce these ntro groups - so the drugs have no effect
75
Give examples of folate inhibiting antibiotics and how they work
Trimethoprim and sulphonamides
| Inhibit enzymes in the folate production pathway which inhibits bacterial growth
76
Give 3 examples of the ways in which protein synthesis inhibiting Abs can work
1) Decrease DNA synthesis (quinolones)
2) Inhibit RNA polymerase (rifampin)
3) Inhibit splicing (translation - tetracyclines)
4) Inhibit initiation complex (AGs)
5) Inihibit tRNA (chloramphenicol, erythromycin, clindamycin)
77
What are the main contributing factors to Ab diffusion to the site of infection?
- Blood flow through the tissue - depends on the surface area:volume ratio
- Acute vs chronic infections - changes in blood flow, pus formation, fibrosis
- Permeability rate (Abs should be lipophilic)
- Where the organisms is hiding
78
Give some examples of Abs that have:
- Low Vd
- Average Vd
- High Vd
Low - penicillins, cephalosporins and AGs
Average - sulphonamides, florphenicol
High - FQ, TM, tetracyclines, macrolide, Chloramphenicol, metronidazole and rifampicin
79
Give some examples of Abs that are:
- Acidic
- Basic
- Amphoteric
Acidic - penicillins, cephalosporins, sulphonamides
Basic - AGs, macrolides, chloramphenicol, TM
Amphoteric - FQs and tetracyclines
80
Draw out a table with the pharmacokinetic properties of commonly used Abs
Lecture 5 notes
81
What are the broad guidelines for Ab selection for the following?
- Gram +ve
- Gram -ve
- Anaerobes
- Mycoplasma
- Systemic fungal infections
- Gram +ve - isaxozyl penicillins (e.g. clozacillin), cephalosporins such as cephalexin are good for skin
- Gram -ve - 3rd generation cephalosporins, TMPS (particularly for urinary tract), amoxycillin (resp infections or otitis media)
- Anaerobes - metronidazole and clindamycin
- Mycoplasma - macrolides
- Systemic fungal infection - amphotericin
82
Give some examples of synergistic Ab combinations
- TMPS - inhibit different steps in the same pathway
- AG and BL - faclitates entry of one drug by another
- Inhibition of inactivating enzymes (amoxyclav)
- prevention of emergence of resistant populations (erythromycin-rifampin)
83
What conditions are required for a microorganism to be considered susceptible to an Ab
If the MIC is <1/4 of the steady state peak concentation
| But bactericidal activity may only be produced if the peak concentration is 8-16x the MIC
84
Which Ab is steady-state trough concentration important for?
Aminoglycosides - in order to prevent oto and nephrotoxicities
85
What are the 3 key factors in determining the optimum Ab dosing interval
- The time required for the most effective kill
- Duration of post-antibiotic effects
- Time for bacterial lag phase
86
Which Abs are not given orally
Aminoglycosides
87
Why are oral Abs rarely given to cattle
Becuase there is slow release from the rumen and they can be metabolised by rumen microflora
88
In what conditions are i.v Abs preferred
- In life threatening conditions
- When im is contraindicated
- When there is risk of tissue irrritation
- When there is dehydration - as this can limit absorption
- When steady sustained concentrations are required (rarely indicated)
89
When should s/c Abs be avoided
- When the drug is irritating
- When ambient temperature is cold
- When the animal is dehydrated
90
What are the forms of im/sc rate controls for Ab release
Simple neutral salts in an aqueous vehicle are rapidly absorbed
Oily vehicles, esters, procaine salts etc are more slowly released
91
What are the main targets for antifungals?
- Beta glucan synthesis (-candins)
- Ergosterol biosynthesis (amphotericin, azoles and terbinafine)
- Chitin synthesis (lufenuron, nikkomycins)
- Protein synthesis (sodarins)
- Nucleic acid synthesis (flucytosine)
92
What is the mechanism of action of azole antifungals
They inhibit Erg11 - which blocks ergosterol production and causes accumulation of toxic sterol intermediates
93
What is the mechanism of action of amphotericin B (polyenes)
They bind to ergosterol and form pores in the cell membrane
94
How does the antifungal 5-flucytosine work?
By inhibiting DNA and RNA synthesis
95
How do echinocandin antifungals work?
They inhibit beta-1,3-D-glucan synthase which disrupts cell wall integrity
96
What are the key features/uses of amphotericin B?
- Often used for systemic mycoses
- IV/SC - protein bound
- Metabolised at membranes
- No urinary or biliary excretion
- Nephrotoxic - especially in cats
- Synergistic with flucytosine
97
What are the key features/uses of griseofulvin?
- Often used for dermatophyte infection
- PO (enhanced by a fatty meal)
- Liver metabolism
- GIT, liver and BM toxicity and is teratogenic
98
What are the key feaures/uses of the azole antifungals
- Often used for systemic fungal infections
- PO - food needed as it is weak base to acid increases uptake
- Protein bound
- Lipid soluble so large Vd and takes 6-14d to reachadequate plasma levels
- Concentrate in skin
- Liver metabolism
- Biliary and little renal excretion
- GI and hepatotoxicity and steroid effects
99
What are the 5 main antiviral drug classes used?
- Recombinant interferons
- Nucleotide analogues (acyclovir)
- Nucleotide reverse transcriptase inhibitors
- Neuramidase/sialidase inhibitors (human drugs) - zanamivir and oseltamivir
- M2 ion channel inhibitors (amantadine and rimantadine)
100
Describe the action/use of feline type 1 interferon
It is an anti-viral the promotes the synthesis of enzymes involved in interfering with viral replication
Used for FIV, FIP, FeLV, cat flu and stomatitis, as well as enteric parvo in dogs
101
WHat are the common uses for acyclovir
It inhibits herpes viral DNA polymerase - used for ocular disease
102
Give 4 examples of first line Abs used in farm animals
- All penicillins
- TMPS
- Florfenicol
- Tetracyclines
- Tysolin
- AGs
103
What are the 3 Ab groups that require justification to use in farm animals
- 3rd and 4th generation cephalosporins
- FQs
- Macrolides with extended activity
104
Which Abs are prohibited in farm animals
Chloramphenicol and metronidazole
105
What are the minimum statutory withdrawal periods?
- 7 days for eggs and milk
- 28 days for meat from poultry and mammals
- 500 degree days for fish
This is if not specified on the actual medicine
106
What drugs are food producing animals allowed?
- Substances in table 1 of EU reg 37/2010 with standard withdrawal
- Listed on essential substances - 6 months mandatory withdrawal
- Not on the prohibited list - table 2
