Pharmacology Flashcards
1
Q
Define pharmacodynamics
A
The biochemical, physiological and molecular effects of a drug on the body
= What the body does to the drug
2
Q
Define pharmokinetics
A
The fate of a chemical substance administered to a living organism
= what the body does to the drug
3
Q
Why is pharmacology important?
A
Knowledge to support safe, legal and efficient prescribing
4
Q
4 pharmokinetic processes
A
- Absorption
- Distribution
- Metabolism
- Excretion
5
Q
Which types of administration gives 100% dose?
A
IV
IA (intra-arterial)
6
Q
4 mechanisms for drugs to permeate across cell membrane
A
Diffusion through pores or channels
Passive diffusion (lipid soluble)
Carrier protein mediated
Pinocytosis
7
Q
3 factors affecting drug absorption
A
Drug structure
Ionised drugs give poor lipid solubility
Large or hydrophilic poorly absorbed
Medicine formulation
Coating or modified release slows rate
Oral drugs must cross many barriers
Weak acids or bases
Acids - best absorbed in stomach
Bases - best absorbed in intestine
8
Q
What is first pass metabolism?
A
Metabolism of drugs preventing them from reaching the systemic circulation
9
Q
2 sites of first pass metabolism
A
- Degradation of enzymes in the intestinal wall
- Absorption into hepatic portal vein and then metabolism via liver enzymes
10
Q
Define bioavailability
A
Proportion of administered dose which reaches the systemic circulation
11
Q
Does bioavailability rely on rate of absorption?
A
No!
Extent of absorption and first pass metabolism
12
Q
Inhaled absorption pro and cons
A
Well perfumed, large SA and blood flow
Limited by risk of toxicity to alveoli so restricted to volatiles
13
Q
Pros and cons of intramuscular absorption
A
Can make slow release drug by incorporating lipophilic
Increase in blood flow or water solubility removes drug quicker
14
Q
4 factors affecting drug distribution
A
Size of the molecule
Lipid solubility
Protein binding
Volume of distribution
15
Q
3 ways for drugs to reach CNS
A
High lipid solubility
Intrathecal administration
Inflammation causes leaky barrier
16
Q
What is Vd?
A
Volume if distribution (higher if drugs are well distributed)
17
Q
Why is caution required for drugs in elderly?
A
Leads to smaller Vd, higher plasma concentration and more likely to cross BBB
18
Q
Should we dose smaller or larger in obese patients?
A
Smaller !
Drugs not distributed to fat so dose based on ideal body weight not actual
19
Q
2 processes of drug elimination
A
Metabolism - modification of chemical structure for lipid soluble drugs
Excretion - of unchanged drug
20
Q
How does sepsis affect pharmokinetics
A
Leaky blood vessels increases distribution and greater penetration of BBB
21
Q
How does liver impairment affect pharmokinetics
A
Hypoalbuminaemia leads to more drug crossing BBB
22
Q
2 phases of drug metabolism
A
Phase 1 - oxidation/reduction/hydrolysis by CP450 adds reactive group to make drug polar
Phase 2 - conjugation of functional group to produce hydrophilic inert molecule for excretion
23
Q
4 types of metabolisers
A
Poor - minimal therapeutic effect
Intermediate - reduced effect
Extensive- converted to morphine
Ultra-rapid - risk of toxicity
24
Q
Excretion types
A
Liquids - urine, bile, sweat
Solids - faeces
Gases - expired air
25
3 processes accounting for renal excretion of drugs
1. Glomerular filtration
2. Active Tubular secretion
3. Passive reabsorption
26
What happens in reduced kidney function?
Accumulation and toxicity of renally cleared drugs e.g. gentamicin
27
Define first order kinetics
Rate of elimination is proportional to the plasma drug concentration
(Constant % is eliminated)
28
Define zero order kinetics
Rate of elimination is NOT proportional to the plasma drug concentration
(Constant and unaffected by conc so caution when adjusting doses)
29
Differences between first and zero order kinetics
First - process do not become saturated
Zero - processes become saturated
30
What is clearance?
CL = removal of drug by all eliminating organs per unit time
31
Cmax vs Tmax
C - maximum plasma concentration
T - time taken to reach Cmax
32
How does a prolonged release oral does affect Tmax?
Slower absorption so increases Tmax and reduces Cmax
33
Define half life
t 1/2 - time taken for plasma drug concentration to fall 50%
34
Half life equation
T 1/2 = 0.693k = ln2
35
Half life depends on
Clearance
Volume of distribution - large Vd cleared more slowly
36
What needs to be taken into account with a short half life?
Frequent dosing
Increases risk of withdrawal symptoms
37
After how many half lives is a drug considered cleared?
5
38
What happens to half life in organ dysfunction
Is increased
= dose reduction required
39
Define steady state
When rate of drug input is equal to rate of drug elimination
40
What is Css?
Drug plasma concentration at steady state
Time to Css = 5 x t 1/2
41
Why is steady state important?
Repeated dosing causes peaks and troughs around mean plasma concentr
42
When is a loading dose required?
When urgently need to reach steady state e.g. antibiiotics
43
Water soluble vs lipid soluble drugs rate of distribution depends on…
Water - rate of passage across membranes
Lipid - blood flow to tissues
44
Rate of elimination is inversely proportional to..
Vd
45
Define pharmacogenetics
The use of genetic and genomic information to tailor pharmaceutical treatment to an individual
46
How can genomics affect pharmacodynamics
Variations in drug receptor varies efficacy and increased incidence of adverse drug reactions
47
How can genomics affect pharmokinetics
Variations in drug metabolism
48
4 drug targets
Receptors
Enzymes
Transporters
Ion Charles
49
Define enzyme inhibitor
A molecule that binds to an enzyme and decreases its activity
50
2 types of enzyme inhibitors
Irreversible- changes enzyme chemically
Reversible - binds non-covalently
51
Describe how statins work
Blocking the rate limiting step HMG-CoA reductase in the cholesterol pathway
= reduces cholesterol and Cardiovascular diseases
52
What happens when ACE is inhibited?
Reduction of Angiotensin 2 production reduced blood pressure
53
3 types of protein ports (active transport)
Uniporter - Uses energy from ATP
Symporter - Use movement of one molecule to pull in another
Antiporter - once substance moves against its gradient using energy from another moving gown the gradient
54
Example of a symporter
Na-K-Cl Co transporter (NKCC) all in the same direction
= Furosemide in oedema inhibits so allows for Na, K, Cl loss in urine
55
Types of ion channels and examples
Metabolic (K) - diabetes
Receptor activated (Cl) - epilepsy
Epithelial (Na) - heart failure
Voltage gated (Ca, Na) - nerve, arrhythmia
Active ion transporter (3Na, 2K)
56
Example of irreversible enzyme inhibitor
Organophosphate inhibit cholisterase
E.g. insecticides, nerve gases
Muscarinic, Nicotinic and CNS symptoms
57
Define xenobiotics
Foreign compounds to the organisms normal biochemistry
58
Describe xenobiotic metabolism
Metabolic breakdown occurs through specialised enzymatic systems and generates readily excreted compounds
Most undergo deactivation by CYP enzymes
59
What does rate of metabolism determine?
A drugs duration and intensity
60
What is a receptor?
A component of a cell that interacts with a specific ligand and initiates a change of biochemical events leading to the ligands observed effects
61
Exogenous v endogenous receptors
Exo - drugs
Endo - hormones, neurotransmitters
62
3 chemical for communication
Neurotransmitters (Ach, serotonin)
Hormones (hydrocortisone, testosterone)
Autacoids (local infections - cytokines, histamine)
63
Examples of an imbalance in chemicals and receptors
Allergy - increased histamine
Parkinson’s - reduced dopamine
Myasthenia gravis - loss of Ach receptors
64
4 types of receptors
Ligand gated ion channels - conformational change generates and electrical charge e.g. Ach
G protein coupled - largest group of molecular switches activated by many different ligands eg. Beta -adrenoreceptor
Kinase linked - enzymes of phosphorylation (growth factors)
Cytosolic / nuclear -specific domains on DNA e.g. steroid
65
How do G proteins work?
Guanine nucleotide binding proteins involved in transmitting signals from GPCRs and downstream signalling
66
Agonists vs Antagonists
Agonist - high affinity, high efficacy
Antagonist - high affinity, low efficacy
67
Potency vs efficacy
P - concentration that elicits a response
E - how great of a response is elicited
68
Competitive vs non-competitive antagonists
C - binds to same site
NC - binds to allosteric site
69
2 categories of cholinergic receptors
Agonist - Antagonist
Muscarine - Atropine
Nicotine - Curare
70
Define signal transduction
Process converting a signal from outside the cell to a different functional change within the cell
71
What is a receptor reserve?
Some agonists only need to activate a small fraction of receptors for a maximum response which allows for a second wave (not possible for partial agonist)
72
Tolerance vs desensitisation
T - slow reduction in effect over time due to repeated, continuous high
D - rapid internalised degraded ligands uncouples whole system
73
Specificity vs sensitivity
Sp - no compound is truly ever specific
Se - describes enhanced activity
74
What is allosteric modulation?
Agonist binds to site and allosteric ligand binds to different site for a combined therapeutic response
75
What is inverse agonism
Interacts with the same receptor as the agonist but reduces the response
76
Current steps of drug development
Lead compound identification
Pre-clinical research
Doing for regulatory status
Clinical trials on humans
Marketing the drug
77
Define drug ability
The ability of a protein target o bind to small molecules with high affinity
78
Drugs are developed from:
Plants - digitalis foxis
Inorganic elements
Organic molecules - chloroform, phenol
Bacteria/ fungi/ molds
Sterioisomers
Immunotherapy antibodies
From animals
Gene therapy
79
Recombinant proteins in clinical use
Insulin
Erythropoietin
Growth hormone
Interleukin 2
Gamma interferom
Interleukin 1 receptor
80
3 mechanisms of gene therapy
1. Synthesis
2. Replication of DNA e.g. cisplatin
3. Incorporation e.g. purines into DNA
81
Define gene therapy
An experimental technique which repairs or replaces a mutated gene
82
What is rational drug design?
The process of finding we educations based on the knowledge of a biological target
83
Pharmokinetics issues for immunotherapy
1. Immunoglobulin not filtered by kidney
2. FcRn receptor absorb IgG
3. Mouse antibodies not suitable for humans
84
What is tumour necrosis factor a?
Cytotoxic factor released by activated macrophages, stimulates acute phase proteins
85
Routes of opioid administration
Oral
Bioavailability
First pass metabolism - 50% of oral morphine is metabolised, halve dose if IV / IM
86
What is the controlled drug (CDs) legislation?
Misuse of drugs act 1971
Opioids - class A drugs
Practical issues is secure storage and CD books (2 signatures needed)
87
How do opioids work?
Inhibition of descending pathways of pain to euphoria
Natural endorphins activate G protein coupled receptors for secondary messengers
88
Down regulation with prolonged use leads to
Tolerance
89
Side effects of opioids
Respiratory distress
Sedation
Nausea and vomiting
Constipation
Itching
Immune suppression
Endocrine effects
90
Treatment of Opioid induced respiratory distress
Call for help ABC
Naloxone (IV)
Titrate to effect - 1ml to 10ml saline
Beware of short half life
91
Opioids for non cancer pain
Opioids are marketed aggressively
But loses effectiveness quickly and causes addiction
92
Metabolism of morphine in renal failure
Morphine is metabolised to morphine 6 glucuronide which is more potent and renally excreted
In renal failure, builds up and causes respiratory distress
93
Parasympathetic vs sympathetic ganglia
Both preganglionic release Ach acting on Nicotinic receptors
P - Ganglia near targets with short post-ganglionic neurone, Ach acts on Muscarinic receptors
S - Ganglia near spinal chord with long post-ganglionic neurone, NAd acts on A/B adrenergic receptors
94
Cholinergic and adrenergic pharmacology controls
Blood pressure
Heart rate and contractility
Anaesthetic agents
Airways
Pressure in eyes
Control of GI
Muscle contraction
95
5 types of adrenergic receptors
A1 - postsynaptic vasoconstriction
A2 - presynaptic negative feedback
B1 - increase HR and contractility
B2 - bronchodilation
B3 - reduces over active bladder
96
Alpha agonists vs blockers
Agonist - Adrenaline raises blood pressure
Antagonist - doxazosin lowers blood pressure for hypertension
97
Drug side effects of Beta
Too much beta 1 can affect beta 2 (bronchoconstriction) and vice versa (tremors)
98
Which nerve supplies parasympathetic to all organs?
CN 10 - vagus
99
5 Muscarinic receptors located in
M1 - CNS, brain
M2 - heart
M3 - glands and smooth muscle
M4 + 5 - CNS
100
Anti-cholinergic side effects
Worsen memory and cause confusion
101
Atropine function
Blocks parasympathetic by competing with acetylcholine
But:
Cross BBB and causes confusion in elderly
Only used in life threatening bradycardia
102
Reversal of muscle relaxants
Neostigimine blocks breakdown of acetylcholine so muscles work again
103
What kind of receptors are nicotinic?
Ligand gated ion channels
104
Beta blockers function
Lowers blood pressure
105
Nicotinic antagonist
Trimetaphan
106
M1 receptor function and antagonist
Increases motility, secretions in gut and CNS effect
= Atropine (crosses BBB) + Glycopyrrolate (doesn’t cross BBB)
107
M2 receptor function and antagonist
Bradychardia, reduced contractility
= Hyoscine
108
M3 receptor function and antagonist
Vasodilation, bronchoconstriction, pupil dilation
= Ipratropium
109
A drug interaction occurs when:
Pharmacodynamics - drugs have an effect on the same target or system
Pharmokinetics - a drug affects the expected performance of another
110
4 types of pharmacodynamic drug interactions
Synergy - interaction of drugs with same effect totals greater effect
Antagonism - substance acts and blocks action of another
Summation - different drugs used together has the same effect as a single drug
Potentiation - enhancement of one drug by another so effect is greater than total
111
Examples of synergetic interactions
Morphine for pain relief and lorazepam for anxiety both agonists
= Increased risk of sedation
Amlodipine and ramipril for hypotension both reduce vasoconstriction
= Some drug interaction are beneficial!
112
Example of antagonism interaction
Atenolol for hypertension and Salbutamol for asthma both compete at B2 receptors
= reduced bronchodilation
113
4 Mechanisms by which one drug can affect the absorption of another (Pharmokinetics)
1. Alters pH and pKa
2. Formation of insoluble drug complex
3. Slowing gut motility
4. P-glycoprotein drug transporters inhibited or induced
114
How can a drug affect the distribution of another?
If both drugs compete for protein binding plasma albumin, more drug is free and therapeutic effect increases
115
How may a drug affect metabolism of another?
CYP450 enzyme metabolise molecules via phase 1 reactions to create hydrophilic molecules for kidney excretion
Inhibition of CYP450 blocks metabolism and excretion of drug, so increased effect and vice versa
116
How may a drug affect excretion of another?
Renal
- pH dependent ( weak bases cleared faster if urine is acidic and vice versa)
- Competing for transporters in kidney tubules reduces elimination
117
Drug interactions to be wary of
Codeine + Morphine = double opioid agonists
NSAIDs + ACEi = acute kidney injury
Warfarin + many vitamin K food / drugs = enzyme induction
118
Define an adverse drug reaction
Unwanted or harmful response to a drug or combination of drugs under normal conditions
119
Define side effects
An unintended effect of a drug including unexpected benefits
120
What types of Adverse Drug Reactions are there? (Rawlin’s Thompson)
A. Augmented - exaggerated effect at therapeutic dose, common + reversible
B. Bizarre - not predictable and not drug or dose related
C. Chronic - continue after the drug has been stopped
D. Delayed - becomes apparent time after stopping drug
E. End of use - occurs abruptly after drug withdrawal
F. Failure of treatment - unexpected due to interaction
G. Genetic - drug causes irreversible damage to genome
121
Alternate way of classing ADRs (DOTs)
Dose
- hyper susceptibility (at low doses)
- Collateral (side effects)
- toxic effects (at high doses)
Timing
- Time dependent or independent
Susceptibility
- Certain groups (ages, gender, disease)
122
What stages are ADRs identified?
Preclinical - toxicity in animals
Clinical - efficacy and safety
Post market surveillance (black triangle) - to find susceptibility
Pharmacovigilance - everyday reports for safe prescribing
123
What is a yellow card and when to report?
=A system to record every day ADRs
(Confidential, quick, accessible)
Report when
- serious ADR
- Unlicensed use (herbal, illicit)
- Any ADR with black triangle
124
When should we suspect ADRs?
Symptoms:
- after new drug started
- after dosage increase
- disappears when drug stopped
- reappear when drug restarted
125
4 important information to record on a yellow card
Suspected drug
Suspect reaction
Patient details
Reporter qualifications
126
Who may have an ADR?
= Anyone taking drugs
127
Who is at increased risk of ADRs?
Polypharmacy
Multimorbidity
Extreme weight
Liver or kidney impairment
Children, neonatal, elderly
Genetic variants
Atopic (increased allergies)
128
Common ADRs
Confusion
Nausea
Balance problems
Diarrhoea
Constipation
Hypotension
129
What to do if there is an ADR?
Assess if treatment required
Take history
Review profile of suspected drug
Modify dose, swap or stop
Document ADR in patient record
If criteria met, report
130
Define hypersensitivity
Objectively reproducible symptoms or sign caused by exposure to a stimulus at a dose tolerated by normal people. May be caused by immunologic (allergic) and non-immunologic (no prior exposure, direct mast cell degranulation) mechanisms
131
Define anaphylaxis
An acute allergic reaction to an antigen which the of has become hypersensitive
(First exposure may not be medical e.g. penicillin in dairy)
132
Does anaphylaxis have a linear reaction to dose?
No! Small dose may cause severe reaction
133
Describe type 1 hypersensitivity
Acute anaphylaxis:
Prior exposure to antigen
IgE is expressed as cell surface receptors on mast and leukocytes
Re-exposure causes mast cell degranulation
134
Describe type 2 hypersensitivity
Antibody dependent cytotoxicity:
Drug or metabolite combines with a protein. Body treats as foreign and forms antibodies which activates
135
Describe type 3 hypersensitivity
Immune complex deposition:
Small blood vessels are damaged or blocked so leukocytes are attracted to site and inflammatory response
136
Describe type 4 hypersensitivity
T-lymphocytes develop antigen specific receptors and subsequent administration leads to local or tissue allergic reactions
137
Main symptoms of anaphylaxis
Immediate rash - vasodilation
Hypotension
Cardiac arrest
Swelling of lips, oedema, central cyanosis
Wheeze - Bronchoconstriction
138
Management of anaphylaxis
Basic life support - ABCDE
Remove trigger, position flat, legs up
Adrenaline - IM 500ug
High flow oxygen, IV fluids
Antihistamines and steroids
139
Action of adrenaline
Vasoconstriction:
A1 = increased vascular resistance
A2 = Inhibition of transmitter release
B1 = Increased HR and contractility
B2 = bronchodilation, reduces oedema
140
Clinical criteria for allergy to drug
Doe not correlate with drug pharmacological properties
Reaction similar to those with allergens
Induction period of primary exposure
Disappearance on cessation
141
Risk factors for hypersensitivity
Host - females more, uncontrolled asthma, prev drug reactions, EBV, HIV
Genetic factors
Medicine factors - protein or polysaccharide based macromolecules
