Pharmacology and Therapeutics Flashcards
What is a prescription?:
- A legally binding document and must be written in indelible ink or sent electronically for printing
- By adding your signature, you take responsibility for the prescription
Factors driving increased medication use: (4)
- Ageing population
- Multimorbidity
- Guidelines
- EBM
Harmful effects of drugs: (5)
A
S
T
Tb
D
- Anaphylactic reactions
- Side effects
- Teratogenicity
- Treatment burden
- Dependency / addiction
Benefit versus risks: Number Needed to Treat
- The number of patients you need to treat to prevent one additional bad outcome (stroke, death, etc.)
Benefit versus risk: Number Needed to Harm (NNH)
- A derived statistic that tells us how many patients must receive a particular treatment for 1 additional patient to experience a particular adverse outcome
Relationship between NNT & NNH:
- Lower NNT and higher NNH values are associated with a more favourable treatment profile
Pharmacokinetics (PK): definition
- What the body does to the drug
Pharmacodynamics (PD):
- What the drug does to the body
Pharmacokinetics :
A
D
M
E
Absorption
Distribution
Metabolism
Elimination
Enteral routes of administration:
- Definition
- Examples (4)
- Routes in which the drug is absorbed from the GI tract
- Sublingual, buccal, oral and rectal routes
Oral route: Pros (4)
- Simple
- Cheap
- No equipment
- Acceptable to patients
Oral route: cons (5)
S
I
P
A
F
- Slow absorption
- Incomplete absorption (bioavailability)
- Preparation must be stable in gastric acid
- Affected by food, vomiting and GI motility
- First-pass metabolism via gut wall and liver
Injection route: Pros (4)
- Reliable
- Rapid absorption
- 100% bioavailability
- No first-pass metabolism
Injection route: cons (5)
- Inconvenient, invasive
- Requires training
- Infection control
- Equipment required
- Expense
Factors affecting drug distribution:
C
R
V
BC
F
D/L
- Cardiac output
- Regional blood flow
- Vascular permeability
- Fat/muscle body composition
- Fluid compartment volumes
- Drug solubility / lipophilicity (pKa)
Metabolism: phase 1 reactions (modification)
- Phase 1 reactions modify the chemical structure of the ingested drug. This can turn an inactive pro-drug (aspirin) into an active drug (Salicylic acid)
Metabolism: phase 2 reactions (conjugation) (2)
- Conjugation reactions often produce less active metabolites
- They also increase a metabolites polarity and water solubility, increasing renal excretion
Renal excretion: determined by (2)
- Plasma drug concentration
- Glomerular filtration rate
Digoxin:
- Effect
- Use
- Excretion
- Slows conduction at the cardiac AV node
- Used for arrhythmia management and heart failure
- It is renally excreted
Pharmacodynamics:
- Mechanism of action
- Dose response
- Molecular target (enzyme, receptor)
- Affinity, efficacy and potency
Molecular targets: (4)
- Enzymes
- Ion channels
- Transmembrane receptors
- Nuclear receptors
Transmembrane receptors: (3)
- Ligand-gated ion channels
- G protein-coupled receptors
- Hormones
B2-adrenoreceptors and asthma:
- Relation
- Salbutamol
- Propranolol
- B2 activation causes bronchial smooth muscle relaxation
- Salbutamol: short-acting B2 agonist asthma reliever
- Propranolol: Non-selective Beta antagonist
Anticholinergic effects:
- Smooth muscle
- Secretions
- Pupils
- CVS
- CNS
- Inhibits smooth muscle: constipation, urinary retention
- Reduced secretions: Dry mouth, eyes, skin
- Pupillary dilatation: blurred vision
- CVS: vasodilation, tachycardia
- CNS: Confusion, agitation
Clinical guidelines:
- What?
- Based on??
- Includes
- Recommend how clinicians should care for people with specific conditions
- Based on best available evidence
- May include recommendations on: prevention, diagnosis, treatment
NOT MANDATORY
What is a drug? (definition):
- Any synthetic or natural chemical substance that can alter biological function; it may be used in treatment, prevention, or diagnosis of disease
Attributes of a drug?: (2)
- Must be selective for a target
- Must give beneficial rather than adverse (side) effects
Drugs produce side effects when: (2)
- The target is too widespread in the body
- The drug hits other targets (lack of selectivity)
Molecular targets:
- R
- E
-T
- Receptors: transduce signal from drug
- Enzymes: activate or switch off
- Transporters: carry molecule across membrane
Molecular targets:
- I
- N
- M
- Ion channels: open or close
- Nucleic acids: affect gene transcription
- Miscellaneous: lipids, metal ions etc
Cyclooxygenase: enzyme inhibitors
- Inhibitors for pain relief, particularly due to arthritis
Angiotensin Converting Enzyme (ACE) inhibitors:
- For high blood pressure, heart failure, chronic renal insufficiency (captopril, ramipril)
Drugs as enzyme substrates:
- Inactive prodrugs are metabolized to active forms
Antimetabolite action of sulphonamides:
- Sulphonamides mimc the natural structure of a bacterial amino acid called PABA.
- This disrupts the bacterial DNA production by creating a false metabolite (lethal synthesis)
Receptor super families: Ionotropic
- Mechanism
- Time
- Receptor-operated channels
- Fast (msecs)
Receptor super families: Metabotropic
- Mechanism
- Time
- G-protein coupled
- Medium (secs to mins)
Receptor super families: TKR
- Mechanism
- Time
- tyrosine kinase receptors
- Medium (mins)
Receptor super families: DNA-linked
- Mechanism
- Time
- Intracellular
- Slow (hours)
receptor subtype importance:
- The existence of multiple receptor subtypes provides the opportunity to develop more specific drugs
Drug binding obeys the law of Mass Action:
Rate of association = K+1 [D][R]
Rate of dissociation = K-1 [DR]
Affinity equation:
- Quantified by the term …..
- Equation
- KD: dissociation equilibrium constant for binding
- KD = [D][R] / [DR]
What does the KD display about a drug:
- Relation to affinity
- The KD is the concentration of a drug that occupies 50% of the receptors, since at 50% occupancy [R] = [DR]
- THE LOWER THE KD, THE HIGHER THE AFFINITY
Total number of receptors (RT):
- equation
- How to use this to get P (fractional receptor occupancy)
[RT] = [DR] +[R] which means [R] = [RT] - [DR]
P = [D] / [D] + KD
Efficacy definition:
- A drugs ability to activate receptors and produce a response
Pharmacological response: relationship between response and occupancy
- Positional relation
- Curve separation
- Binding curve is always to the right of the functional response curve, you don’t need to occupy all receptors to get maximum response
- The higher the efficacy, the greater the separation of the two curves
Factors that determine the position of the concentration-response curve along the conc. axis (3)
- Affinity
- Efficacy
- Receptor number
Potency:
- How much drug is needed to produce a particular response
Partial agonism:
- Partial agonists occupy all receptors to evoke their maximum response, they leave no spare receptors
Efficacy and receptor number:
- Efficacy is a ….
- Description for low efficacy drugs
- Description for high efficacy drugs
- Efficacy is a spectrum
- drugs with low efficacy may appear to be full agonists in tissues with large receptor numbers but will mostly appear as partial agonists
- High efficacy drugs will primarily appear as full agonists as they do not require a large number of receptors to achieve full agonism
Therapeutic value of partial agonists: Why can’t adrenaline be used to treat asthma attacks?
- What needs to be achieved
- Adrenaline effects
- Need to relax smooth muscle of bronchi by activation of beta2 adrenergic receptors
- Adrenaline will achieve this but also activate heart B1 and the few B2 receptors, increasing HR and force of contraction. May cause heart attack
Therapeutic values of partial agonists: Salbutamol in asthma attacks
- Salbutamol characteristics
- Relevancy of this
- Salbutamol effects
- Salbutamol is a selective B2 adrenoceptor partial agonist
- The magnitude of its effect is determined by the receptor number. Bronchi smooth muscle is abundant in B2 receptors, while the heart has very few
- Salbutamol evokes significant bronchi relaxation with little or no effect on the heart
Types of drug antagonism: Competitive
- Binds at the agonist recognition site, preventing the access of the normal ligand
Types of drug antagonism: Non-competitive
- Does not bind at the agonist site but inhibits agonist binding in another way
Types of drug antagonism: Uncompetitive
- Binding occurs to an activated form of the receptor (i.e. use-dependant)
Types of drug antagonism: Physiological
- When the effect of a neurotransmitter/hormone is countered by the action of another neurotransmitter/hormone
Effect of competitive antagonist (B) on the concentration-response curve:
- Shape
- Placement
- Effect of increasing conc. B
- Adding a fixed concentration of reversible competitive antagonist will not affect the shape of the curve
- The curve will shift to the right, as more agonist must be added to overcome the antagonism
- Greater shift to the right
Competitive irreversible antagonism:
- Effect of increasing agonist conc.
- Why is there a decrease in max response at higher conc.
- Irreversible binding means that antagonism is not overcome by increasing agonist
concentration - A decrease in maximum response occurs as there are not enough receptors for the higher concentrations
Non-competitive antagonism: (2 types)
- Allosteric: binds and changes the binding of agonist to site
- Binds and antagonises response by blocking later in the pathway (enzyme inhibitor or Ca channel blocker)
Gaddum-Schild equation: (antagonism)
[D1] / [D1]’ = 1 + [B] / KB
Major routes of drug administration: Enteral (GI tract) (3)
- Oral
- Sublingual
- Rectal
Major routes of drug administration: Parenteral (non-GI tract) (9)
In.V
In.M
S
In.D
In.N
InH
E
Tr
To
- Intravenous
- Intramuscular
- Subcutaneous
- Intradermal
- Intranasal
- Inhalation
- Epidural
- Transdermal
- Topical
Oral bioavailability:
- Fraction of oral dose that reaches the systemic circulation
Factors affecting oral bioavailability: (3)
- Poor absorption in the gut
- Breakdown of drug in the gut
- 1st pass effect
Factors affecting drug absorption at a membrane:
- Main factor
- Other factors (6)
p
D
A
R
P
- Lipid solubility of a drug, higher the better
- pKa of the drug and pH at the absorbing surface
- Drug preparation
- Area of absorbing surface
- Rate of blood flow to other side of absorbing surface
- Presence of food/drugs affecting stomach emptying/gut motility
Henderson-Hasselbalch equation: relating pH, pKa and ration of ionised to unionised drugs
- Acids
- Bases
- Acids
pH = pKa + log([A-]/[HA]) - Bases
pH = pKa + log([B]/[BH+])
Apparent volume of distribution (Vd):
- What does it show?
- Equation
- A measure of how widely a drug distributes throughout the body compartments
- Vd = amount of drug in body / Cp
How common is poisoning in UK EDs?
- Poisoning accounts for 1-2% of UK ED attendances
- Most commonly intentional self-poisoning or inadvertent overdose
Poisoning risk assessment factors (4)
- Suspected drug/toxin and amount
- Time since exposure
- Clinical features, symptoms and signs
- Laboratory investigations
Pharmacology versus toxicology : (overdose)
-In overdose the pharmacokinetics and pharmacodynamics may be different
Pharmacology versus toxicology : (overdose)
-In overdose the pharmacokinetics and pharmacodynamics may be different
Toxidrome:
- definition
- Use
- A cluster of clinical features that help to identify a specific toxicological mechanism
- Allows appropriate antidote / other treatments to be selected
Toxidrome:
- definition
- Use
- A cluster of clinical features that help to identify a specific toxicological mechanism
- Allows appropriate antidote / other treatments to be selected
Opioid toxidrome:
- Cause
- Antidote
- Opioid analgelsics (morphine)
- Nalaxone (antagonist)
Opioid toxidrome:
- Symptoms (4)
- CNS depression e.g. coma
- Respiratory depression
- Hypotension
- Miosis “pinpoint pupils”
Sedative hypnotic toxidrome:
- Causes (4)
- Action
- Ethanol, benzodiazepines, GHB, zolpidem
- Alter GABAergic transmission, GABA is the main inhibitory transmitter in the CNS
Sedative hypnotic toxidrome clinical features: (4)
- Slurred speech, ataxia, disinhibition
- CNS depression (stupor-coma-death)
- Respiratory depression
- Hypotension
Serotonergic toxidrome:
- Causes
- action
- Caused by classes of drugs that treat depression. SSRIs, MAOIs, TCAs
- Enhance serotonergic transmission in central nervous system
serotonergic toxidrome:
- Clinical features (5)
- Fever / delirium
- Hyper-reflexia myoclonus (jerky muscle contractions)
- Seizures
- Mydriasis (pupil dilation)
- Labile HR and BP
Anticholinergic toxidrome:
- Description
- Causes
- Agents that block muscarinic receptors and, at higher doses, nicotinic receptors in autonomic ganglia and the NMJ
- Atropine, tricyclic antidepressants, antispasmodics
Anticholinergic toxidrome:
- Clinical features (5)
- Hyperthermia
- Flushing
- Dry skin and mouth
- Blind as a bat
- Delirium
Anticholinergic antidote:
- Physostigmine: Reversible inhibitor of acetylcholinesterase (AChE), enzyme responsible for breakdown of AcH
Cholinergic toxidrome:
- Clinical features
CNS (2)
NMJ (2)
ANS muscarinic (4)
ANS nicotinic (3)
- CNS: delirium, seizures
- NMJ: muscle weakness, fasciculations
- ANS muscarinic: Salivation, vomiting, bradycardia, incompetence
- ANS ganglionic nicotinic: hypertension, sweating, tachycardia
Cholinergic toxidrome:
- Clinical features
CNS (2)
NMJ (2)
ANS muscarinic (4)
ANS nicotinic (3)
- CNS: delirium, seizures
- NMJ: muscle weakness, fasciculations
- ANS muscarinic: Salivation, vomiting, bradycardia, incompetence
- ANS ganglionic nicotinic: hypertension, sweating, tachycardia
Cholinergic toxidrome:
- Causes (2)
- Acetylcholine agonists (pilocarpine, muscarine)
- Drugs that inhibit acetylcholinesterase (neostigmine, novichok)
Treatment of cholinergic toxidrome:
- Regular (3)
- Organophosphate
- Atropine to dry secretions
- Benzodiazepines to control seizures
- Intravenous fluids
- Pralidoxime to reactivate AChE in organophosphate (pesticide) poisoning
Paracetamol overdose:
- Prevalence
- Risk
- Treatment
- 50% of self-poisoning in UK
- Paracetamol metabolised to N-acetyl-p-benzoquinone-imine (NAPQI) that can cause fatal liver damage
- N-acetylcysteine (Parvolex) giver intravenously
Paracetamol overdose management:
- Bloods
- Monogram
- After treatment
- Bloods taken anytime from 4-hours after ingestion
- N-acetylcysteine administered if concentration is above the treatment line on the monogram
- Patients reviewed by mental health specialist
t0.5 (half-life):
- Definition
- Relevance
- The time it takes for the Cp of a drug to fall to half its initial value
- A short t0.5 means that the body eliminates the drug quickly and that oral doses have to be given more often than drugs with long t0.5
Quantification of elimination:
Rate of elimination = Clearance X Cp
therefore
Clearance = Rate of elimination / Cp
What is clearance?
- It is equal to the amount of plasma which is cleared of its drug content in unit time
- Clearance (Cl) stays fairly constant but can vary
First order elimination: (2)
- The t0.5 is constant
- Rate of elimination depends on how much is present and is faster with a higher Cp
Zero order elimination:
- Rate of process is independent of drug concentration, the t0.5 can vary
t0.5 equation for 1st order elimination:
t0.5 = (0.693 X Vol) / Cl
Intravenous infusion:
- The drug is being eliminated as its being infused, Cp rises until a steady state (Css) is reached
- At Css, Rate of infusion = rate of elimination
Rate of infusion equation:
- Requirement
- Steady state must have been reached
Rate of infusion = Css X Cl
How many half lives (time) does it take to reach Css?:
- What if you increase rate of infusion?
- 5, irrespective of rate of infusion
- The Css value will be greater, but the time taken will not vary
Loading infusion:
Maintenance infusion:
Loading: A high rate of infusion, utilised temporarily for low t0.5 drugs to get Cp to therapeutic levels
Maintenance: A lower rate of infusion, designed to maintain Cp within the therapeutic window
Oral dosing:
- Multiple doses required to reach the Css average
CssAv = individual dose (D) X Oral bioavailability (F) / time interval between doses (T) X clearance (Cl)
CssAv = (D X F) / (T X Cl)
Hepatic drug metabolism: phase 1
- Drug derivative formed by oxidation, reduction or hydrolysis, often introducing a reactive site into, or exposing a reactive site on, the drug molecule
Hepatic drug metabolism: Phase 2
- Conjugation (joining) of the species formed in phase 1 with polar molecules, making the metabolite less lipid soluble, and hence easier to excrete in urine
Hepatic drug metabolism: phase 1 enzymes
- Purpose
- Example
- In the endoplasmic reticulum of the liver, microsomal enzymes catalyse oxidation reactions
- The most important group being cytochrome P450
phase 2 hepatic metabolism reactions:
- Where
- Examples (3)
- Occurs in the cytosol of liver cells
- Glucuronidation
- Acetylation
- Glycine/sulphate conjugation
Factors affecting metabolism: enzyme induction (2)
- Some drugs and environmental pollutants induce increased expression of cytochrome P450 enzymes
- This increases clearance and can cause a failure to produce a significant therapeutic effect
Factors affecting drug metabolism: enzyme inhibition (2)
- Some drugs directly inhibit cytochrome P450 enzymes.
- This can increase the likelihood of adverse effects/toxicity
Factors affecting drug metabolism: genetic polymorphisms
- Poor ability to metabolise drugs by some groups of people
Factors affecting drug metabolism: disease
- Liver
- Kidneys
- Thyroid
- Cardiovascular
- Disease type determines effect on metabolism
- Liver function: drugs mainly metabolised in the liver (hepatitis, liver cancer, cirrhosis)
- Renal function: drugs excreted unchanged in urine
- Thyroid function: affects liver metabolising enzymes, overactive reduces half life
- Cardiovascular: heart working insufficiently as a pump, affecting blood flow to liver/kidneys
Factors affecting drug metabolism: age
- Drug metabolism is lower in the very young and the elderly
Paracetamol overdose action: (3)
- Acute overdose or prolonged use saturates the Phase 2 conjugating enzymes
- The drug is now metabolised by phase 1 metabolism to a toxic intermediate NAPQI
- NAPQI can still be conjugated by GSH, but when this is depleted, it reacts with cell proteins to cause hepatic cell damage
Paracetamol overdose treatment:
- Activated charcoal very shortly after ingestion
- Acetylcysteine replenishes hepatic glutathione, must be within 24hr of ingestion
Anaphylaxis:
- Onset
- Cause
- Symptoms
- Rapid onset (<1 hour)
- IgE-mediated reaction
- Breathless, rash, facial swelling hypotensive
Anaphylaxis treatment: (3)
- resuscitation
- Adrenaline (IM, IV): reverses vasodilation, dilates airways, inotropic, inhibits histamine/leukotriene release
- IV fluids, oxygen
Definition of adverse drug reaction (ADR):
- Any appreciable harmful or unpleasant reaction, resulting from the use of a medicinal product, which predicts hazards from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product
Classification of ADRs: type A
- Effects
- Character
- Prevalence
- “Augmented” pharmacological effects
- Predictable, dose dependant
- Approximately 80% of ADRs
Type A ADR examples (2):
- Exaggerated drug effect: bleeding with anticoagulant, low BP and antihypertensive
- Unrelated drug effect: thrush with antibiotic, hypokalaemia and loop diuretic
Classifications of ADRs: type B
- Idiosyncratic or “bizarre” reactions
- Often immune mediated
- Unpredictable, dose independent
Type B ADR examples: (2)
- Penicillin anaphylaxis
- Drug-induced vasculitis
Pharmacokinetics - metabolism: Phase 1 modification
- Cytochrome P450
- Enzyme inhibition:
Pharmacokinetics: problems with absorption
- Primarily caused by taking medication at the wrong time. E.g. some medication needs to be taken on an empty stomach
Pharmacokinetics: problems with distribution
- Changes in protein binding can increase toxic effects in highly protein bound drugs
- E.g. warfarin binds to albumin, decreased albumin increases Cp of warfarin
Pharmacokinetics: problems with phase 2 metabolism (conjugation)
- TPMT
- Effect
-Low or absent Thiopurine methyltransferase, TPMT activity causes an accumulation of thiopurines
- Risk enhanced azathioprine-induced marrow toxicity (bleeding, anaemic, infection)
Pharmacokinetics: problems with excretion (2)
- Chronic kidney disease may increase drug effects due to reduced excretion (heart block with digoxin, bleeding with anticoagulants)
- And increase other side effects (lactic acidosis with metformin)
Why do type A (predictable) ADRs occur?
- Unknown (or new) clinical characteristics
- Medication error e.g. in prescribing
- Inappropriate use by patients
Specific high-risk clinical circumstances for ADRs and medication errors : (7)
- Renal impairment
- Hepatic impairment
- Elderly
- Children
- Breast feeding/pregnancy
- Injections
- Narrow therapeutic index drugs
Identification of drug safety issues: (3)
- Spontaneous reporting: yellow card
- Clinical trial safety monitoring
- Post-marketing observational analyses
Role of the UK safety regulator: (MHRA) (7)
- Regulates clinical drug trials
- Post-marketing surveillance
- Authorisation of sale/supply of UK medicines
- Quality surveillance system
- Investigation of counterfeits and internet sales
- Monitors/ensures legal compliance
- Manages key drug data sources
Take a good drug history: NIDDEM
- Name
- Indication
- Details
- Dates
- Effects
- Monitoring
Take a good drug history: Remember the 5 C’s
- Complementary
- over the Counter
- Contraception
- unCommon routes
- Changes
Take a good drug history: Potential problems (the 5 A’s)
- Allergy
- Adverse effects
- Adherence
- Any interactions
- Adjustment
