sa8318icacuk Adapted from Shayaan Akhtars slides Pharmacology Tuesday 15 th March 2022 1 LO please insert relevant Learning objective reference here 2 Topics to cover Principles of pharmacology ID: 935964
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Slide1
Shehzar Alam- 4th year Pharm BSC student, sa8318@ic.ac.ukAdapted from Shayaan Akhtar’s slides
Pharmacology
Tuesday 15th March 2022
1
Slide2LO: please insert relevant Learning objective reference here
2
Topics to cover
Principles of pharmacology
Pharmacology of diabetes
Pharmacology of epilepsy
Pharmacology of depression
Pharmacology of asthmaPharmacology of hypertensionPharmacology of GORD/PUDPharmacology of CKDAdverse Drug reactions
MentimeterWhich topics would you like me to focus on?https://www.menti.com/s7bkkjhv2x
Slide3Principles of pharmacology
3
Pharmacodynamics
Pharmacology
–
study of interaction between living organisms and chemicals
Therapeutics
– concerned with the treatment of patientsDrug Targets – site usually a protein in the body where a drug binds ReceptorsEnzymesIon channels
Transport proteinsPharmacodynamics
Slide4Principles of pharmacology
4
PD - Selectivity (specificity) and Dosing
Selectivity
–
the degree to which a drug to acts on a given target relative to other targets
Lock and Key
Effective therapeutic agent high degree of selectivity for particular drug targetsDrug can act on multiple targets therapeutic (and non-therapeutic
) effectsDosing can be manipulated based on drug selectivity propertiesPharmacodynamics Selectivity and Dosing
Slide5Principles of pharmacology
5
PD - Affinity, Efficacy and Potency
Affinity
–
determines strength of binding of drug to the receptor
Efficacy
– ability of individual drug molecule to produce effect once boundAgonist – affinity with efficacy; Partial agonist – affinity with partial efficacy
Antagonist – affinity without efficacyBoth Affinity and Efficacy determine the potency of the drug
binds and produces effect
binds but no effect; blocks agonist binding
Pharmacodynamics
Selectivity and Dosing
Affinity, Efficacy and Potency
Slide6Principles of pharmacology
6
PD - Affinity, Efficacy and Potency (continued)
Potency
–
concentration (EC50) or dose (ED50)
of drug required to produce a defined effect,
i.e. higher potency = lower EC/ED50EC50 in vitro, 50% responseED50 clinical, 50% participants ‘respond’Competitive antagonist – Reversible binding to the
same site as the agonist - surmountableNon-competitive antagonist – Non-reversible binding to allosteric site – insurmountablePharmacodynamics Selectivity and Dosing Affinity, Efficacy and Potency
Slide7Q1: Which of these is the false statement?
Highly selective drugs will produce fewer side effects.Both affinity and efficacy affect the potency of a drug.
Non-competitive antagonists will lower the theoretical maximal response.Agonists at higher concentrations can still achieve maximal tissue response in the presence of competitive antagonists.
A more potent drug will cause a right-shift on the log dose-response curve.
SBA 1
1.Principles of pharmacology
7
Pharmacodynamics
Selectivity and Dosing Affinity, Efficacy and Potency
Slide8Q1: Which of these is the false statement?
Highly selective drugs will produce fewer side effects.Both affinity and efficacy affect the potency of a drug.
Non-competitive antagonists will lower the theoretical maximal responseAgonists at higher concentrations can still achieve maximal tissue response in the presence of competitive antagonists.
A more potent drug will cause a right-shift on the log dose-response curve.
SBA 1
1.Principles of pharmacology
8
Pharmacodynamics
Selectivity and Dosing Affinity, Efficacy and Potency
Slide91.Principles of pharmacology
9
Pharmacokinetics
‘What the body does to the drug’
Amount of drug reaching tissue is dependent upon pharmacokinetic factors:
Absorption
Distribution
MetabolismExcretionPharmacokinetics
Slide101.Principles of pharmacology
10
PK – Absorption and bioavailability
Absorption
–
passage of a drug from the
site of admin
into the plasmaBioavailability – fraction of the dose that reaches the systemic circulationSite of administration main determinant of absorption and bioavailability Drugs move around the body in 2 ways (to intended site of action):Bulk flow transfer
– i.e. in the blood stream (IV route)Diffusional transfer – i.e. molecule by molecule across short distances (all other routes – as they cross at least one lipid membrane)Other routes incl. oral, inhalation, intradermal, intramuscular, subcutaneousPharmacokinetics Absorption and bioavailability
Slide111.Principles of pharmacology
11
PK – Diffusion
4 methods of diffusion across plasma membranes:
Diffusion across lipid membranes – common, lipid soluble drugs
Carrier mediated transport – affinity for protein
Diffusion – across aqueous pores – minor (gaps between epi/endothelial cells)
Pinocytosis – not relevant for drugs, cell membrane envelopes forming vesicle
Pharmacokinetics Absorption and bioavailability Diffusion
Slide121.Principles of pharmacology
12
PK – Lipid solubility
Most drugs are either
weak acids
or
weak bases
∴ exist ionised or unionisedUnionised drug – lipid soluble, likely to diffuse across membrane
Ionised drug – water soluble for transport, impermeable to lipid membranes (req. transport protein)Ionisation state depends upon:Dissociation constant pKa of drugpH of environment in particular part of the body [DH] ↔ [H]+ + [D]- Pharmacokinetics Absorption and bioavailability Diffusion Lipid solubility
Slide131.Principles of pharmacology
13
PK – Lipid solubility (continued)
If
pKa
= pH drug equally dissociated
Weak acid (e.g. aspirin), donate protons when
ionised, pKa 3.5 (low) –
if pH < pKa unionisedif pH > pKa ionisedWeak base (e.g. morphine), accept protons when ionized, pKa 8.0 (high) – if pH < pKa ionisedif pH > pKa unionised[DH] ↔ [H]+ + [D]-
↑
[AH]
↔
↑[H]
+
+ [A]
-
[AH]
↔
↓[H]
+
+
↑
[A]
-
[B]
↔
↑[BH]
+
+
↓[H]
+
↑
[B]
↔
[BH]
+
+
↑
[H]
+
[AH]
↔ [H]
+
+ [A]
-
[B] + [H]
+
↔ [BH]
+
Pharmacokinetics
Absorption and bioavailability Diffusion
Lipid solubility
Slide141.Principles of pharmacology
14
PK – Distribution
After absorption…distribution of drug to various tissues depends upon:
Regional blood flow
– organ and activity (e.g. eating vs exercise) dependent
Liver (27%), Kidneys (22%), Muscles (20%), Brain (14%), Heart (4%)
Plasma protein binding - reversible equilibrium with protein (e.g. albumin)Dependent on drug affinity to plasma protein. Only free drug can diffuse out of blood
D (Free Drug) + P (Protein binding site) ↔ DP (Drug-protein binding site)Pharmacokinetics Absorption Distribution
Slide151.Principles of pharmacology
15
PK – Distribution (continued)
3.
Capillary permeability
– lipid soluble drugs diffuse, water soluble req. gaps
‘Continuous’ – prevention (BBB), ‘Discontinuous’ open - (Liver), ‘Fenestrated’ – (Kidney)
4. Tissue localization – lipid vs water soluble drug est. equilibrium with tissueBrain (high fat content) + omental fat
localises lipid soluble drug > water soluble drugPharmacokinetics Absorption Distribution
Slide161.Principles of pharmacology
16
PK – Drug Metabolism
‘Conversion of drugs to metabolites to decrease lipid solubility for excretion’
Liver - cytochrome P450 enzymes
Phase 1
– introduces a reactive polar group to the drug –
Oxidation (most common)May unmask existing functional groups. May produce pharmacologically active metabolites from pro-drugs (or toxic!)Phase 2 – adds conjugate to reactive group
Pharmacokinetics
Absorption
Distribution
Drug metabolism
Slide171.Principles of pharmacology
17
PK – First pass metabolism
‘
First pass metabolism’ –
basically oral drugs go through the liver first…
Oral drug
small intestine absorption hepatic portal circulation liverLiver heavily metabolises drug ∴ little active reaches systemic circulationPresents a problem of bioavailbility for oral drugs must admin higher doses
N.B. extent of first pass metabolism varies between individuals as CYP450 enzyme activity is heavily genetically determined this means SE are hard to predict + vary by individualsPharmacokinetics Absorption Distribution Drug metabolism First pass metabolism
Slide181.Principles of pharmacology
18
PK – Renal excretion
Kidney excretion takes place by 3 major routes:
Glomerular filtration
– <20,000 Daltons, faster excretion for smaller molecules
Active tubular secretion
– most important method, excretion against gradientPassive reabsorption – drugs reabsorbed into blood (lipid > water soluble)Urine pH dependent – acidic reabsorbed at lower pH, basic at higher pH
Pharmacokinetics Absorption Distribution Metabolism Renal excretion
Slide191.Principles of pharmacology
19
PK – Biliary Excretion
Liver excretion via bile, excreted into intestines, eliminated as
faeces
Particularly effective at removing glucuronide metabolites, slowed by…
Enterohepatic recycling
– prolongs elimination time
Pharmacokinetics Absorption Distribution Metabolism Renal excretion Liver excretion
Slide201.Principles of pharmacology
20
SBA 2
Q2: Suggest which phenomenon accounts for the slower elimination time of general
anaesthetic
drugs in a BMI 40+ patient vs a BMI 20 patient
Low capillary permeability at the BBB, stops GA drugs leaving.
Enterohepatic cycling prolongs hepatic clearance of GA.GAs are lipid soluble thus localise to omental fat tissue more than blood so equilibrium does not favour free drug eliminationGA binds strongly to plasma proteins, so less free drug is eliminatedGA drugs are too big to be filtered by the glomerulus
Pharmacokinetics Absorption Distribution Metabolism Excretion
Slide211.Principles of pharmacology
21
SBA 2
Q2: Suggest which phenomenon accounts for the slower elimination time of general
anaesthetic
drugs in a BMI 40+ patient vs a BMI 20 patient
Low capillary permeability at the BBB, stops GA drugs leaving.
Enterohepatic cycling prolongs hepatic clearance of GA.GAs are lipid soluble thus localise to omental fat tissue more than blood so equilibrium does not favour free drug eliminationGA binds strongly to plasma proteins, so less free drug is eliminated
GA drugs are too big to be filtered by the glomerulusPharmacokinetics Absorption Distribution Metabolism Excretion
Slide221.Principles of pharmacology
22
SAQ 3
Q3 How does giving IV Sodium bicarbonate increase aspirin excretion?
Aspirin is a weak acid with
pkA
= 3.5
IV Sodium bicarbonate enters blood circulation…reaches kidney + filtered…Urine pH increases pH = 5 8 i.e. becomes alkalineEffect on aspirin? pkA = 3.5, Urine pH = 8 Which state is now predominant?Ionised form predemoniates
More aspirin remains water soluble Reduced passive reabsorption in DCT Aspirin renal excretion increasedPharmacokinetics Absorption Distribution Metabolism Excretion[AH] ↔ [H]+ + [A]- [AH] ↔ ↓[H]+ + ↑[A]-
Slide232.Pharmacology of diabetes
23
Pharmacology of diabetes
Metformin
DPP-4 inhibitors/Gliptins
Sulfonylureas
SGLT-2 inhibitors
Thiazolidinediones/GlitazonesGLP-1 agonistsManagement guidelines
Slide242.Pharmacology of diabetes
24
Overview of diabetes
Type 2 Diabetes Mellitus:
Persistently high blood glucose (+ excess production)
Insulin resistance (reversible)
later beta cell dysfunction, insulin deficiency
Overweight/ObesityHyperlipidaemiaCVD co-morbidities – hypertension, heart disease
Other drugs – orlistat, statins, antihypertensives etc…Overview
Slide252.Pharmacology of diabetes
25
Overview of pharmacology
Sourced from: MM Endo 3: Diabetes (Mustafa al-
Zubaidy
)
Overview
Pharmacology
Slide262.Pharmacology of diabetes
26
Metformin
Mechanism of action:
Activates
AMPK
(enzyme) in
hepatocyte mitochondria Inhibits ATP production ↓ gluconeogenesis in liver ↓ hepatic glucose outputAlso blocks adenylate cyclase (enzyme)
↑ fat oxidation ??↓ HGO + ↑ fat oxidation Restore insulin sensitivityMetformin therapeutic effects:Increases insulin sensitivity
Reduces glucose production
Weight loss
Metformin side effects:
GI (20-30%) – nausea,
diarrhoea
,
abdo
pain
Risk of lactic acidosis at high doses + low clearance ∴ avoid if eGFR <36ml/min
Monitor eGFR (45-60), consider 50% dose if 30-45
Overview
Metformin
Slide272.Pharmacology of diabetes
27
GLP-1 and DPP-4 incretin pathway
Overview
Metformin
Incretin pathway
Slide282.Pharmacology of diabetes
28
DPP-4 inhibitors
Dipeptidyl-peptidase 4 inhibitors – e.g. Sitagliptin
Mechanism of action:
Drug inhibits
DPP-4
(enzyme that metabolises incretins) on vascular endothelium ↑ Plasma incretin levels
DPP-4 inhibitors side effects:GI – nausea, diarrhoea, abdo painFlu-like symptoms – headache, runny nose↑ URTIs (5%)Skin reactions – red/purple rash
DPP-4 inhibitors therapeutic effects:
↑
Stimulation of insulin production
↓ Production of glucagon by the pancreas
Slower digestion, ↓ appetite
Overview
Metformin
Incretin pathway
DPP-4 inhibitors
Slide292.Pharmacology of diabetes
29
Sulfonylureas
E.g. Gliclazide
Mechanism of action:
Inhibits
K
ATP channel (ion channel) on pancreatic beta cell K+ builds up inside the cell depolarization of cellStimulates Ca2+
influx insulin vesicle exocytosis ↑ insulin secretionSulfonylureas therapeutic effects:Increases insulin secretion
Sulfonylureas side effects:
Weight gain
Hypoglycaemia
Overview
Metformin
DPP-4 inhibitors
Sulfonylureas
Slide302.Pharmacology of diabetes
30
SGLT-2 inhibitors
Sodium-glucose co-transporter inhibitors e.g. Dapagliflozin, Empagliflozin
Mechanism of action:
Reversibly inhibits
SGLT-2
(transport protein) in renal PCT↓ glucose reabsorption ↑ urinary glucose excretion
SGLT-2 inhibitors therapeutic effect:↓ Blood glucose↓ CVD mortality in T2DM pts(Weight loss + ↓ BP)
SGLT-2 inhibitors side effects:
Urogenital infections (5%) ∵ ↑ glucose load
Slight ↓ in bone formation
Worsens DKA (stop immediately)
Overview
Metformin
DPP-4 inhibitors Sulfonylureas
SGLT-2 inhibitors
Slide312.Pharmacology of diabetes
31
Other drugs
Thiazolidinediones/
Glitazones
– e.g. Pioglitazone
Mechanism of action:Binds PPAR-𝜸 (nuclear receptor) in adipocytes ↑ adipogenesis + ↑ fatty acid uptake↓ Lipid availability to muscles + liver ↑ Insulin sensitivitySE:
Hypoglycaemia, bone fractures, leg swelling, ↑LFTs; CI: Heart failure, osteoporosisGLP-1 analogues – e.g. Liraglutide N.B. Subcutaneous injectionsMechanism of action:Mimics action of GLP-1 (incretin) activates GLP-1 receptor on pancreas beta cells↑Endogenous incretin effects (same as DPP-4 inhibitors)SE: Nausea, vomiting, rarely acute pancreatitis; Useful in BMI >35 and alternative to insulinOverview Metformin DPP-4 inhibitors Sulfonylureas SGLT-2 inhibitors Other drugs
Slide32If HbA1c rises to 48 on lifestyle intervention - Offer metformin tablets 500mg ODAim to maintain HbA1c of 48
First intensification: If HbA1c rises to 58, consider dual therapy of:- Metformin + DPP-4 inhibitor - Metformin + Thiazolidinedione
- Metformin + Sulfonylurea - Metformin + SGLT-2 inhibitor Aim to maintain HbA1c of 53Second intensification: If HbA1c rises to 58, consider insulin-based treatment or triple therapy:
- Metformin + DPP-4 inhibitor + Sulfonylurea
- Metformin + Thiazolidinedione + Sulfonylurea
- Metformin + Thiazolidinedione + SGLT-2 inhibitor
Aim for HbA1c of 53
Consider injectables – Insulin & GLP-1 agonists. GLP-1 agonists may be initiated earlier (CVD benefit)2.Pharmacology of diabetes
32Diabetes ManagementOverview Metformin DPP-4 inhibitors Sulfonylureas SGLT-2 inhibitors Other Management
Slide33If HbA1c >48 + after lifestyle advice – start MetforminIf HbA1c >58 – Metformin + anything…
If HbA1c >58 on step 2 – Metformin + any 2 others – personalised to individual co-morbidities and side-effects:
Sulfonylureas are v. effective but cause weight gain + hypoglycaemia riskGLP-1 agonists and SGLT-2 inhibitors are good for CVD risk prevention
DPP-4 inhibitors are moderately effective and most tolerable
Thiazolidinediones are effective but CI in heart failure and ↑ SE
Consider injectables – insulin and GLP-1 agonists if not already tried
2.Pharmacology of diabetes
33
Diabetes Management Simple SummaryOverview Metformin DPP-4 inhibitors Sulfonylureas SGLT-2 inhibitors Other Management
Slide34Q4 Which anti-diabetic drug(s) could theoretically work despite dysfunctional pancreatic β cells?Metformin
Sitagliptin LiraglutideGliclazide Empagliflozin
Pioglitazone
2.Pharmacology of diabetes
34
SBA 4
Overview
Metformin DPP-4 inhibitors Sulfonylureas SGLT-2 inhibitors Other Management
Slide35Q4 Which anti-diabetic drug(s) could theoretically work despite dysfunctional pancreatic β cells?Metformin (Biguanide)
Sitagliptin (DPP-4 inhibitor)Liraglutide (GLP-1 agonist)Gliclazide (Sulfonylurea)
Empagliflozin (SGLT-2 inhibitor)Pioglitazone (Thiazolidinediones)
2.Pharmacology of diabetes
35
SBA 4
Overview
Metformin DPP-4 inhibitors Sulfonylureas SGLT-2 inhibitors Other Management
Slide363.Pharmacology of epilepsy
36
Pharmacology of epilepsy
Lamotrigine
Sodium valproate
Diazepam
Levetiracetam
Carbamazepine (will not go through these, mechanisms not clear, be aware of them)TopiramateEthosuximidePhenytoinManagement of epilepsy
Slide373.Pharmacology of epilepsy
37
Overview of epilepsy
Epilepsy syndromes
–
characterised
by repeated seizures
Seizures
– Sudden bursts of electrical activity in the brain causing changes in muscle tone, behaviour or awarenessDiagnosed with EEGs (seizure type) and MRI (organic causes)
Seizure classification:
Partial seizures
one hemisphere
Simple
– conscious
Complex
– unconscious
Generalised
seizure
both hemispheres
Generalised
seizure types:
Tonic-
clonic
LOC, stiffens, jerking, deep sleep
Absence
staring +
behaviour
arrest
Tonic/atonic
muscle stiffness/loss of control
Myoclonic
sudden brief muscle contractions
Status epilepticus
>5m uncontrolled seizure activity
Overview
Slide383.Pharmacology of epilepsy
38
Overview of epilepsy pharmacology
Valproate
Lamotrigine
Levetiracetam
VG Na+ channel
Inhibitory GABAergic neurons
Excitatory Glutamatergic neurons
Overview
Pharmacology
Slide393.Pharmacology of epilepsy
39
Lamotrigine
Mechanism of Action:
Blocks
Voltage-gated Na+ channel
(ion channel) on
presynaptic glutamatergic neurons prevents Na+ influx prevents depolarization ↓ glutamate excitotoxicity N.B. Introduce Lamotrigine gradually and titrate up dose ↓ frequency of skin reactions
Lamotrigine drug-drug interactions:Lamotrigine safe in pregnancy, present in but not harmful for child during breastfeedingCOCP induces UDPGA ↑ lamotrigine metabolism less seizure control
Lamotrigine side effects:
Maculo-papular rash (10%)
Drowsiness
Steven-Johnson’s syndrome (1 in 1000)
Suicidal thoughts (rare)
VG Na+ channel
Lamotrigine
Overview
Lamotrigine
Slide403.Pharmacology of epilepsy
40
Levetiracetam
Mechanism of action:
Inhibits
SV2A
on
excitatory presynaptic neuronal vesicles prevents vesicle exocytosis ↓ Glutamate secretion presynaptically ↓ glutamate excitotoxicity
Levetiracetam drug-drug interactions:None – no CYP450 enzyme interactionRequires good renal function
Levetiracetam side effects:
Dizziness, headache
Somnolence
Fatigue
Overview
Lamotrigine
Levetiracetam
Slide413.Pharmacology of epilepsy
41
Sodium Valproate
Mechanism of action:
Inhibits
GABA transaminase
(enzyme) inside
presynaptic GABAergic neurons and non-neuronal cells prevents breakdown of GABA Directly ↑ GABA concentrations in synapse (presynaptically) Indirectly prolongs GABA in synapse ∵ ↓
extraneuronal metabolism of GABA slower removal of GABA from synapse↑ GABA availability inhibitory activity on postsynaptic neurons (GABAA receptor)
Sodium Valproate drug-drug interactions:
Broad CYP450 enzyme inhibitor ∴ most other co-admin drugs req. reduced doses
Avoid before conception, during pregnancy & breastfeeding
Sodium Valproate side effects:
GI - Nausea,
abdo
pain,
diarrhoea
Drowsiness, weight gain, hair loss
Hepatotoxicity, teratogenicity, pancreatitis
Valproate
Overview
Lamotrigine Levetiracetam
Sodium Valproate
Slide423.Pharmacology of epilepsy
42
Benzodiazepines
Benzodiazepine
(Drug class) e.g. Diazepam, Midazolam, Lorazepam
Mechanism of action:
Binds
GABAA (receptor) via benzodiazepine site on postsynaptic neurons↑ Cl- ion influx hyperpolarisation of excitatory neuronsN.B. Diazepam not used long-term, individuals can be prone to tolerance/addiction
Benzodiazepine therapeutic usage:Status epilepticus (seizure lasting >5m)Chlordiazepoxide given for alcohol withdrawalSedation effects/ short term for anxiety
Benzodiazepine side effects:
Drowsiness
Respiratory depression (
i.v.
or ↑ dose)
Haemolytic
anaemia
, jaundice
Overview
Lamotrigine Levetiracetam Sodium Valproate
Benzodiazepines
Slide43Epilepsy Management
3.Pharmacology of epilepsy
43
Overview
Lamotrigine Levetiracetam Sodium Valproate Benzodiazepines
Management
Slide44Epilepsy syndromes managementFocal seizures – CarbamazepineAbsence seizures – Ethosuximide
Everything else (generalized tonic-clonic, myoclonic, tonic/atonic) – ValproateNO Valproate in pregnancy or breastfeeding (also no Carbamazepine) ∴ consider other 1
st line options in women of child-bearing age:Lamotrigine is a harmless 1st line alternativeLevetiracetam
is a harmless 2
nd
line/adjunct
Valproate
CYP450 inhibitorCarbamazepine CYP450 inducer3.Pharmacology of epilepsy
44Epilepsy Management Summary
Status epilepticus management
First line –
Benzodiazepines
IV
Lorazepam
OR
Buccal
Midazolam
OR
Rectal
Diazepam
Overview
Lamotrigine Levetiracetam Sodium Valproate Benzodiazepines Management
Slide45Q5 A 28yo lady has been newly diagnosed with epilepsy, describing her seizures as muscle stiffening then jerking while unconscious, lasting 3m. She is not on the COCP and is currently trying for children. Which anti-epileptic medication is appropriate for her?
DiazepamSodium ValproateLamotrigineEthosuximide
Levetiracetam
3.Pharmacology of epilepsy
45
SBA 5
Overview
Lamotrigine Levetiracetam Sodium Valproate Benzodiazepines Management
Slide46Q5 A 28yo lady has been newly diagnosed with epilepsy, describing her seizures as muscle stiffening then jerking while unconscious, lasting 3m. She is not on the COCP and is currently trying for children. Which anti-epileptic medication is appropriate for her?
DiazepamSodium ValproateLamotrigine
EthosuximideLevetiracetam
3.Pharmacology of epilepsy
46
SBA 5
Overview
Lamotrigine Levetiracetam Sodium Valproate Benzodiazepines Management
Slide474.Pharmacology of depression
47
Pharmacology of depression
Sertraline
Citalopram
Fluoxetine
Venlafaxine
MirtazapineTri-cyclic antidepressants (TCAs)Monoamine oxidase inhibitors (MAO inhibitors)Management of depression
Selective serotonin reuptake inhibitors (SSRIs)Serotonin and noradrenaline reuptake inhibitors (SNRIs)
Slide48Monoamine theory of depression:Depression – functional deficit of central monoamine transmission – noradrenaline (NA) and serotonin (5-HT)
Antidepressants aim to increase NA and 5-HT availability:
Block reuptake channels (SSRIs, SNRIs, TCAs)Increased NA and 5-HT secretion (
Mirtazapine
)
Inhibit breakdown of NA and 5-HT (
MAO inhibitors
)Diagram from CrashCouse Psychiatry
Overview of depression4.Pharmacology of depression48Overview
Slide494.Pharmacology of depression
49
SSRIs General class
Selective serotonin reuptake inhibitors – Sertraline, Citalopram, Fluoxetine
Mechanism of action:
Blockade of
serotonin reuptake pumps
on pre-synaptic neuronal membraneAccumulation of serotonin in the synapse improves mood, anxiety, happiness
SSRI General side effects:Upon initiation – GI disturbance (N&V, diarrhoea, abdo pain)Upon initiation – anxiety and agitation (∴ morning pill)Insomnia + weight loss (sometimes weight gain)
Sexual dysfunction (anorgasmia, delayed ejaculation)
Hyponatraemia
Overview
SSRIs General class
Slide504.Pharmacology of depression
50
SSRIs Pharmacology
Half-life – long (particularly fluoxetine)
Gradually reduce doses on discontinuation or switching
Other amine effects at higher doses (through receptor or transporter blocks)
Histaminergic (sedation, weight gain)
Adrenergic (postural hypotension, dizziness)Dopaminergic (parkinsonism or dopamine excess)Anticholinergic (urinary retention, constipation)CYP450 metabolism – fluoxetine inhibits, sertraline partially inhibitsEffects on other liver metabolized drugs
Overview SSRIs General class SSRI Pharmacology
Slide514.Pharmacology of depression
51
SNRIs - Venlafaxine
Serotonin-noradrenaline reuptake inhibitor – Venlafaxine
Mechanism of action:
Blockade of
noradrenaline
and serotonin reuptake pumps on presynaptic neuronsAccumulation of noradrenalin and serotonin in CNS synapses regulates emotions, cognitions and improves moodSNRI General side effects:
Same as per SSRIsHypertension at higher dosesOverview SSRIs SNRI - Venlafaxine
Slide524.Pharmacology of depression
52
Mirtazapine
NaSSA
- Noradrenergic and Specific Serotonergic Antidepressant
Mechanism of action:
Antagonises
𝛼2-adrenergic (receptors) on presynaptic neurons ↑release of serotonin and noradrenaline regulates emotions, cognitions and improves mood
Antagonises 5-HT2 (receptors) leaves 5-HT1 receptors unopposed anti-depressant effectsMirtazapine side effects:Histaminergic (H1 receptor block) – sedation, weight gainLower probability of sexual dysfunction (switch from SSRI)Overview SSRIs SNRI – Venlafaxine Mirtazapine
Slide534.Pharmacology of depression
53
TCAs
Tricyclic antidepressants
–
Amitriptyline
Mechanism of action:
Blockade of noradrenaline and serotonin reuptake pumps on presynaptic neuronsAccumulation of noradrenalin and serotonin in CNS synapses regulates emotions, cognitions and improves moodOther receptors blocked many SE + cardiotoxicity
N.B. Narrow therapeutic index, toxicity risk high, easy overdoseOverview SSRIs SNRI – Venlafaxine Mirtazapine TCAs
Table from
CrashCourse
Psychiatry
Slide544.Pharmacology of depression
54
Depression Management
Moderate or moderate-severe depression – Start
SSRI
first line
Trial at least 2
SSRIs until failure or intolerance before switching classPossible treatment failureUnacceptable SE: commonly sexual dysfunctionTry an SNRI or MirtazapineConsider TCAs, if catatonic depression consider ECTSSRIs – Sertraline, Fluoxetine, Citalopram,
Paroxetine (1st line)SNRIs – Venlafaxine, Duloxetine (2nd line, ↑ SE > SSRIs)Mirtazapine (2nd line, SE: sedation + weight gain)TCA – Amitriptyline, Imipramine (3rd line, ↑↑ SE) Overview SSRIs SNRI – Venlafaxine Mirtazapine TCAs Management
Slide554.Pharmacology of depression
55
SBA 6
Q6 Which of these drugs causes significant blockade of the noradrenaline reuptake transporter at therapeutic dose?
Citalopram
Fluoxetine
Sertraline
MirtazapineVenlafaxineOverview SSRIs SNRI – Venlafaxine Mirtazapine TCAs Management
Slide564.Pharmacology of depression
56
SBA 6
Q6 Which of these drugs causes significant blockade of the noradrenaline reuptake transporter at therapeutic dose?
Citalopram (SSRI)
Fluoxetine (SSRI)
Sertraline (SSRI)
Mirtazapine (NaSSA)Venlafaxine (SNRI)
Overview SSRIs SNRI – Venlafaxine Mirtazapine TCAs Management
Slide575.Pharmacology of asthma
57
Pharmacology of asthma
Salbutamol
Fluticasone
Mometasone
Budesonide
PrednisoloneMontelukastManagement of asthma
CorticosteroidsLeukotriene receptor antagonistβ2 agonist
Slide585.Pharmacology of asthma
58
Overview of asthma and pharmacology
β2 agonist
– Salbutamol (short-acting),
Salmeterol (long-acting)
Corticosteroids
– Fluticasone, Mometasone, Budesonide, Prednisolone Leukotriene receptor antagonist - Montelukast Bronchodilation Salbutamol, Salmeterol, Leukotriene RAAnti-inflammatory (eosinophilic) Corticosteroids, Leukotriene RAShort term PRN – relieve symptoms during attack
Long term regular – prevent asthma attacks, improve lung functionOverview
Slide595.Pharmacology of asthma
59
β2 agonists
Short acting β2 agonists (SABA)
– Salbutamol (half-life – 2.5-5h)
Long acting β2 agonists (LABA)
– Salmeterol (half-life – 5.5h)
Mechanism of action:Agonist at β2 (receptor) on airway smooth muscle cells ↓Ca2+ entryPrevents smooth muscle contraction
Dilates airwaysSide effects from non-selective adrenergic activation:β1 agonist activity tachycardia/arrhythmias, palpitation, agitation/tremorHypokalaemia ∵ effect on Na+/K+ ATPase (exacerbated by corticosteroids)Overview β2 agonists
Slide605.Pharmacology of asthma
60
Corticosteroids
Inhaled corticosteroids
– Fluticasone, Budesonide, Mometasone (Asthma)
Intranasal corticosteroids
– Mometasone (Allergy)
Oral steroids – Prednisolone (Severe asthma, many inflammatory conditions)Mechanism of action:Agonist to glucocorticoid (nuclear) receptor in inflammatory cells eosinophils, mast cells, monocytes/macrophages and dendritic cells ↓Cell activity, ↓cytokine production and release, ↓cell recruitment
↓inflammationSide effects:Locally – candidiasis/opportunistic infections, sore throat, hoarse voiceSystemic – Hyperglycaemia, ↓Bone mineral density, Immunosuppression + moreOverview β2 agonists Corticosteroids
Slide615.Pharmacology of asthma
61
Montelukast
Mechanism of action:
Competitive antagonist at the
CystLT
1
(receptor) on surface of: Eosinophils ↓eosinophil migrationMast cells ↓inflammation + ↓oedemaAirway smooth muscle cells
↓broncho-constrictionOral drug – slower onset of action, taken 2h before exercise for prophylaxisSide effects:Mild – nausea & vomiting,
diarrhoea
, fever, headaches
Serious – mood changes, anaphylaxis
Overview
β2 agonists
Corticosteroids
Montelukast
Slide62Inhaled drugs:Local adminLower dosesMild systemic effectsOptimised
with spacerOral drugs:Slow absorptionFirst pass metabolismLow bioavailability/high doses
Strong systemic effects
Asthma pharmacology
5.Pharmacology of asthma
62
Overview
β2 agonists Corticosteroids Montelukast Pharmacology
Slide635.Pharmacology of asthma
63
Asthma management
Step 1:
SABA PRN
Step 2:
SABA PRN + low-dose ICS regular
Step 3: SABA PRN + ICS/LABA regular OR
SABA PRN + ICS + LTRAStep 4: ICS dose increaseStep 5: Add oral steroidOverview β2 agonists Corticosteroids Montelukast Pharmacology Management
Slide645.Pharmacology of asthma
64
SBA 7
Q7 Which of these drugs directly cause bronchodilation?
Fluticasone
Salbutamol
Budesonide
MontelukastMometasone
Overview β2 agonists Corticosteroids Montelukast Pharmacology Management
Slide655.Pharmacology of asthma
65
SBA 7
Q7 Which of these drugs directly cause bronchodilation
Fluticasone
Salbutamol
Budesonide
MontelukastMometasone
Overview β2 agonists Corticosteroids Montelukast Pharmacology Management
Slide666.Pharmacology of hypertension
66
Pharmacology of hypertension
ACE inhibitors
ARBs
Calcium channel blockers
Thiazides or thiazide-like diuretics
Management of hypertension
Slide67Angiotensin converting enzyme (ACE) inhibitors Ramipril, Lisinopril, PerindoprilInhibits ACE (enzyme)
on lung endotheliumPrevents conversion of AT1 AT2 ∴
↓AT2Angiotensin receptor blockers (ARBs)Losartan, Irbesartan, CandesartanNon-competitive antagonist at AT
1
receptor
on
kidneys/adrenals
and vasculatureBlocks action of peripheral AT2RAAS blockers ↓BP via many mechanisms
6.Pharmacology of hypertension67Renin-angiotensin-aldosterone system inhibitors RAS inhibitors
Slide686.Pharmacology of hypertension
68
RAAS inhibitors (continued)
Most ACE inhibitors and ARBs are pro-drugs
require first pass metabolism generate active metabolite therapeutic effects
Trials indicate ACE inhibitors > ARB
Both cause
foetal injury ∴ avoid in pregnant women
ACE inhibitor and ARB side-effects:Cough – ACEi only common reason to switch to ARBHypotensionHyperkalaemia (monitoring needed) beware K+ supplements and K+ sparing diureticsRenal failure (eGFR monitoring needed) esp. in renal artery stenosis
Uritcaria
/angioedema -
ACEi
only
RAS inhibitors
Slide696.Pharmacology of hypertension
69
Calcium channel blockers
Calcium channel blockers: e.g. Amlodipine, Felodipine, Nifedipine
Mechanism of action:
Blocks
L-type calcium channels
(ion channel) on vascular smooth muscle↓Ca2+ influx inhibition of myosin light chain kinase + reduced cross-bridge formation↓Smooth muscle contraction vasodilation
↓peripheral resistanceCCB Side effects:Ankle oedemaPalpitationsFlushing/headachesConstipations
N.B. 2 types of CCBs:
Rate slowing
Cardiac arrhythmias
Non-rate slowing
Antihypertensives
RAS inhibitors
CCB
Slide706.Pharmacology of hypertension
70
Thiazides or thiazide-like diuretics
Thiazides
e.g.
Bendroflumethiazide,
Thiazide-like diuretics e.g. IndapamideMechanism of action:Inhibits Na+Cl- co-transporter (transport protein) in the renal DCT ↓reabsorption of Na+
& Cl-Osmolarity of tubular fluid increases ↓osmotic gradient for water reabsorption↓Water reabsorption ↓Blood volume ∴ ↓Venous return ∴ ↓Cardiac output ↓BPThiazides and thiazide-like diuretic side effects:Hyponatraemia d) Hyperglycaemia (∵ hyperpolarized pancreatic beta cells)Hypokalaemia (+ Metabolic alkalosis ∵ ↑H+ excretion)Hyperuricaemia (& hypercalcaemia) RAS inhibitors CCB Thiazides or thiazide-like diuretics
Slide716.Pharmacology of hypertension
71
Hypertension management
A,
if intolerant
B
C
(A / B) + (C or D)C + (A / B or D)(A / B) + C + DReconfirm resistant hypertension, check adherence, seek another causeConsider adding Spironolactone or ⍺-blocker or β-blocker
If
<55y
and not
Afro-Caribbean
If
>55y
OR
Afro-Caribbean
Step 1
Step 2
Step 3
Step 4
A –
ACE inhibitor
B –
ARB
C –
CCB
D –
Thiazide(-like) diuretic
RAS inhibitors
CCB Thiazides or thiazide-like diuretics
Management
Slide726.Pharmacology of hypertension
72
SBA 8
Q8 A 67yo Asian man is on stage 3 management of his hypertension. On his last GP visit, it was noted his potassium was high at 5.6mmol/L. Which of his medications is most likely to be responsible?
Ramipril
Nifedipine
Indapamide
BendroflumethiazideAmlodipine
RAS inhibitors CCB Thiazides or thiazide-like diuretics Management
Slide736.Pharmacology of hypertension
73
SBA 8
Q8 A 67yo Asian man is on stage 3 management of his hypertension. On his last GP visit, it was noted his potassium was high at 5.6mmol/L. Which of his medications is most likely to be responsible?
Ramipril (ACE inhibitor)
Nifedipine (CCB)
Indapamide (Thiazide-like diuretic)
Bendroflumethiazide (Thiazide diuretic)Amlodipine (CCB)
RAS inhibitors CCB Thiazides or thiazide-like diuretics Management
Slide747.Pharmacology of GORD/PUD
74
Pharmacology of GORD/PUD
NSAIDs & Aspirin
Proton pump inhibitors
H2 receptor antagonists
Paracetamol
Prostaglandin analoguesManagement
Slide757.Pharmacology of GORD/PUD
75
Overview of GORD/PUD
Imbalance of protective vs aggravating factors in stomach
↑ acid + damage
Aggravating drugs:
NSAIDs
AspirinProtective drugs (therapeutic):PPIsH2 receptor antagonistsProstaglandin analogues
Peptic Ulcer Disease (9:57)https://www.youtube.com/watch?v=RpgqcJo9uUcVisit for more detail…Overview
Slide767.Pharmacology of GORD/PUD
76
Arachidonic acid metabolism
Arachidonic acid
Leukotrienes
Cyclo-
oxygenases
Prostaglandins
ProstaglandinsCOX-1COX-2Lipo-oxygenases
Gastroprotective
Maintains renal blood flow
Thromboxanes
Enhances platelet aggregation
Inflammation, pain, fever, oedema
Anti-coagulant effect
Anti-inflammatory
Anti-pyretic
Afferent constriction
↓GFR, ?nephritis
Acid production
Ulceration
Bronchoconstriction
NSAIDs
NB. Montelukast – blocks
CystLT
receptor to cause bronchodilation
Overview
Arachidonic acid metabolism
Slide777.Pharmacology of GORD/PUD
77
NSAIDs & Aspirin
Non-steroidal anti-inflammatory drugs: Ibuprofen, Naproxen, Diclofenac,
Celocoxib
Mechanism of action:
Reversibly inhibits
COX (enzymes) at many sites prevents formation of prostanoidsPeripheral nociceptive nerve endings indirect analgesic effect
Hypothalamus ↓body temperature (anti-pyretic)Vascular & inflammatory cells ↓inflammationAdverse effects ∵ ↓prostanoids and ↑leukotrienesStomach gastric irritation, ulceration and bleedingKidney afferent arteriolar constriction, ↓GFR, ↑Creatinine, ?nephritisLungs bronchoconstriction (in susceptible individuals – asthmatics)Adverse cardiovascular effects (hypertension, stroke, MI) over prolonged useOverview Arachidonic acid NSAIDs & Aspirin
Slide787.Pharmacology of GORD/PUD
78
NSAIDs & Aspirin (continued)
Non-selective COX inhibition
Aspirin
Irreversible, non-selective COX inhibitor
Ibuprofen, Naproxen
Reversible, non-selective COX inhibitorDiclofenac Reversible, semi-selective COX inhibitor (↑COX-2 activity)Celecoxib
Reversible, COX-2 selective inhibitorCOX-2 selective inhibitionNSAIDs – other SE – skin rashes, allergies, tinnitus, dizzinessAspirin – therapeutic use with anti-platelet, CVS risk preventionAspirin – risk of Reye syndrome (post-viral encephalitis) in children <16yGI risk CVS risk Overview NSAIDs & Aspirin
Slide797.Pharmacology of GORD/PUD
79
PPIs
Proton pump inhibitors - Omeprazole
Mechanism of action:
Irreversible inhibition of
H
+/K+ ATPase (enzyme-linked transporter) in gastric parietal cells
inhibit basal and stimulated gastric acid production by >90%PPI Pharmacology:Given orally but degrades rapidly in low pH admin as coated capsulesPPIs are pro-drugs activated by accumulation in acidic environmentCYP2C19 inhibitor stops clopidogrel activation
PPI Side effects:
Headache
GI –
Diarrhoea
, bloating,
abdo
pain
Rashes
Long-term osteoporosis risk
Overview
NSAIDs & Aspirin
PPIs
Slide807.Pharmacology of GORD/PUD
80
H2 receptor antagonists
Histamine (H2) receptor antagonists - Ranitidine
Mechanism of action:
Reversible inhibitor of
H2 receptor
on gastric parietal cell inhibits stimulatory activity of histamine from ECL cellsReduced cAMP-dependent stimulation of H+
K+ ATPase inhibits H+ secretion by 60%H2RA Side effects (generally low incidence):
Headaches, drowsiness
Diarrhoea
Muscle pain
Transient rashes
Overview
NSAIDs & Aspirin PPIs
H2RAs
Slide817.Pharmacology of GORD/PUD
81
Prostaglandin analogues
Prostaglandin analogues – Misoprostol
Mechanism of action:
Mimics prostaglandins multiple cytoprotective effects on gastric mucosa
Side-effects –
diarrhoeaContraindicated in pregnancy – effects on foetus
Overview
NSAIDs & Aspirin PPIs H2RAs
Prostaglandins
Slide827.Pharmacology of GORD/PUD
82
Paracetamol
Aka. Acetaminophen - Not an NSAID
Mechanism of action unknown nervous tissue with central and peripheral action
Possible interaction with COX-3 isoform?
Cannabinoid receptors? Endogenous opioids? 5HT? Adenosine
recpetors?Therapeutic effects:Mild-to-moderate analgesia
Anti-pyreticVery safe drug, few SE, no gastric irritationOverdose serious hepatotoxicity (concern for suicide method)
Overview
NSAIDs & Aspirin PPIs H2RAs Prostaglandins
Paracetamol
Slide837.Pharmacology of GORD/PUD
83
Management of GORD/PUD
Test for
H.pylori
(urea breath test, stool antigen test)
H.pylori
+ve Eradicate with triple therapy –PPI + Clarithromycine & Metronidazole/Amoxicillin
H.pylori –ve Seek and address exacerbating RFs - NSAID/Aspirin related ulcer - remove or lower doseIf NSAID cannot be stoppedConsider Misoprostol Consider switching to COX-2 selective NSAID for anti-inflammatory indicationIf no reversible cause consider long-term acid suppression1st line: PPI (beware SE)2nd line: H2RA (less efficacious but safer)
Overview
NSAIDs & Aspirin PPIs H2RAs Prostaglandins Paracetamol
Management
Slide848.Pharmacology of CKD
84
Pharmacology of CKD
Overview of CKD
Management of CKD
Creatinine and eGFR
Prescribing in CKD
Slide858.Pharmacology of CKD
85
Overview of CKD
Chronic Kidney Disease
– abnormal structure or function for >3 months
Stratified by GFR and A:CR
Commonest causes:
Diabetes (24%)Glomerulonephritis (13%)
Hypertension/renovascular disease (11%)
Exacerbating risk factors & AKI precipitants:
High BP
Poorly controlled diabetes
Volume depletion
Infection/sepsis
Nephrotoxic drugs e.g. NSAIDs
Management approach:
Slow progression of renal disease
Treat renal and extrarenal complications
Prepare for renal replacement therapy
Overview of CKD
Slide868.Pharmacology of CKD
86
Creatinine and GFR
Glomerular filtration rate - measures volume of fluid filtered per unit time
Acts as a measure of kidney function
Creatinine is a waste product of muscle released into plasma - rate of leak consistent
Plasma creatinine determined by gender, age, ethnicity, muscle bulk – acutely fixed
Creatinine is freely filtered, not reabsorbed and not secreted (only slightly)∴ GFR i.e. ability of kidney to filter blood, is only determinant of plasma creatinineeGFR is the estimated GFR derived from plasma creatinine measurement using with formulas – Creatinine slightly overestimates GFR
eGFR > 90ml/min/1.73m2 (Normal), eGFR <60 for >3 months = CKD
Overview of CKD
Creatinine and eGFR
Slide878.Pharmacology of CKD
87
Management of CKD
Slow progression of renal disease
Control BP RAS blockers -
ACEi
or ARBs (not both) aim for 140/90, less in DM
Glycaemic control (if diabetic) HbA1c of 53 – SGLT-2 inhibitors and others…Lifestyle – exercise, lose weight, smoking cessation, reduced salt intake
Treat renal and extrarenal complications - CVD preventionAntiplatelet – low-dose Aspirin usually avoided (benefit does not outweigh harm)Statin Atorvastatin for primary & secondary preventionOther complications anaemia, acidosis, oedema, bone disorders, restless legsPrepare for renal replacement therapyHaemodialysis or peritoneal dialysisRenal transplant
Overview of CKD
Creatinine and eGFR
Management of CKD
Slide888.Pharmacology of CKD
88
Prescribing in CKD
Prescribing in
pt
with reduced renal function (↓GFR ± ↑Creatinine):
NB. Sepsis and low fluid states will predispose AKIs
Will the drug damage the kidney? i.e. worsen renal functionNSAIDs reduce renal blood flow, requires switching alternative drug classRAS blockers or diuretics if ↓blood volume reduces renal blood flow
Some antibiotics Aminoglycosides (gentamicin), others…Anticancer drugs (e.g. cisplatin) and some immunosuppressants (e.g. methotrexate)Heavy metals LeadIs the drug renally excreted? i.e. will it accumulate and cause side effectsMany drugs (do not learn)Dose adjustments required, consider temporary pause or alternative until improved renal function
Overview of CKD
Creatinine and eGFR Management of CKD
Prescribing in CKD
Slide898.Pharmacology of CKD
89
SBA 9
Q9 Which of these statements is false?
The mainstay of preventing CKD progression is controlling BP
Amount of proteinuria and creatinine tells you the CKD severity
Drugs are excreted slower when the kidney is failing
ACE inhibitors and ARBs can treat proteinuria
Naproxen causes afferent vasoconstriction and reduces renal blood flow and GFR
Overview of CKD
Creatinine and eGFR Management of CKD Prescribing in CKD
Slide908.Pharmacology of CKD
90
SBA 9
Q9 Which of these statements is false?
The mainstay of preventing CKD progression is controlling BP
Amount of proteinuria and creatinine tells you the CKD severity
Drugs are excreted slower when the kidney is failing
ACE inhibitors and ARBs can treat proteinuria
Naproxen causes afferent vasoconstriction and reduces renal blood flow and GFR
Overview of CKD
Creatinine and eGFR Management of CKD Prescribing in CKD
Slide91LO: please insert relevant Learning objective reference here
91
Adverse drug reactions
Variations in response in drugs are due to:
Absolute difference
in dose administered (error in prescription, non-compliance)
Relative underdose/overdose
(food/fluid intake, age, disease etc), which can affect absorption, distribution etc
Slide92LO: please insert relevant Learning objective reference here
92
Factors affecting variation in response to drugs
Other drugs
that may inhibit/induce enzymes-
eg
clathrithromycin inhibits Cyt P450, making warfarin more potentFood intake- food components can affect absorption, particularly due to delay in gastric emptying, can affect enzymes (eg grapefruit affects cyt P450)Fluid intake- most drugs better absorbed with water (stimulates gastric emptying)Age (newborn)
- they have more body water, worse renal function, lower drug metabolism capacityAge (elderly)- have general deterioration in functions- absorption (increased gastric emptying, decreased absorptive surface of intestine), distribution (less body water, LIPID soluble drugs more potent, WATER soluble drugs less potent), metabolism (decreased hepatic blood flow), and excretion (poorer renal function)
Slide93LO: please insert relevant Learning objective reference here
93
Factors affecting variation in response to drugs continued
Disease-
general nutritional status (unbalanced diets lead to enzyme deficiencies), GI disorders (affect absorption
eg
Crohn's), heart failure (less blood flow to liver), kidney failure/liver failure
Absolute differences in drug concentration (mistakes in prescription, non compliance by patient, misunderstanding of instructions)
Slide94LO:
94
Important drug examples to rememberClarithromycin and warfarin-
warfarin metabolised by Cytp450 pathway, clarithromycin inhibits it, thus increasing warfarin
potencty
- bad as warfarin has narrow therapeutic window= increased bleeding
Other P450 inhibitors- macrolides, quinolones, antifungal drugs
P450 inducers- St Johns wort, rifampicin (used in TB)St Johns wort often used as antidepressant- increases metabolism of drugs eg warfarin, so they become less potentDigoxin- MUST measure plasma potassium before giving drug, as patient must be normokalaemic- if hyperkalaemic, may indicate kidney disease (
ie digoxin cleared less so more potent),, if hypokalaemic, more digoxin binds to receptors as less competition by K+= digoxin more potent
Slide95LO: please insert relevant Learning objective reference here
95
Pharmacology of pain
Do be wary of this, information about this is not on
Insendi
I believe, but it is in your Sofia learning objectives!