ICS: Pharmacology (with Prescribing) Flashcards
1
Q
two main physiological factors of a patient to consider when prescribing
A
- renal disease (=kidney!!)
- hepatic disease (liver!)
2
Q
define synergy
A
- where action of two or more drugs combine
- can be positive or negative
3
Q
example of synergy
A
paracetamol & codeine: increases analgesic effect
4
Q
define antagonism
A
one drug blocking the mechanism of another
5
Q
define pharmacokinetics
A
action of the body on the drug: how it’s broken down
6
Q
factors affecting pharmacokinetics
A
or = p. kinetics = (ADME)
- absorption
- distribution: bloodstream, fats, protein binding
- metabolism: how is it broken down and
- excreted
7
Q
factors affecting absorption of a drug
A
- motility
- acidity of the drug
- solubility of bloods
- formation of drug
- action on enterocytes (grapefruit juice inhibit drug transporter!)
8
Q
What is an important SE of erythromycin?
A
direct GI stimulation therefore affecting motility of drug
9
Q
Which particular food may change how warfarin is absorbed?
A
Avocado - has been shown to decrease effectiveness of warfarin, therefore increasing risk of clotting.
- stays in GI tract longer due to high fat content
- also a CYP450 inductor - increases drug metabolism so gone before it makes a diff
Ginger also reduce effectiveness of anticoag so + risk of bleeding
10
Q
what is a prodrug?
A
a drug that needs to be broken down in order to work
11
Q
what are CYP450’s
A
cytochrome P450
- hemeproteins - in mito or ER
- metabolises many substrates, most drugs undergo deactivation by CYPs direct or facilitated
- regulates detox (= defence mechanism)
- class 1, 2, 3 most important in humans
12
Q
two ways, involving CYP450, through which the metabolism process of a drug can be affected
A
inhibition & induction
13
Q
define inhibition?
A
drug A, inhibiting CYP 450, blocks the metabolism of drug B, leaving more free drug B in the plasma therefore increasing effect of drug B
14
Q
Examples of food CYP450 inhibitors? (3)
A
grapefruit juice (CCB), soya (NSAID, warf)
→ they decrease metabolism of a drug = increase effectiveness / build up toxicity
15
Q
define induction?
A
drug C induces CYP450 isoenzyme, leading to increased metabolism of drug D resulting in decreased therapeutic effects of drug D
16
Q
drugs that induces CYP450?
(beautiful mnemonic)
A
CRAP GPS induces my rage (increase drug met so gone before effect)
- carbamazepine
- rifampin
- alcohol
- phenytoin
- griseofulvin
- phenobarbital
- sulfonylureas
17
Q
significance of grapefruit juice on medications
A
- inhibit p-glycoprotein - a drug transporter - therefore affects absorption of the drug
- CYP450 inhibitor - subtype CYP3A4 → can make a drug more effective/toxic as it stays longer in body
18
Q
significance of st john’s wort (Hypericum perforatum) on medications
A
CYP450 inductor = increases metabolism of medications = makes them less effective.
on Warfarin, digoxin, cyclosporin, phenytoin, antiretrovirals
19
Q
how are drugs first broken down in the liver, and in the kidneys?
A
- most are renal excretion = kidneys, which is pH dependent
- some are biliary excretion
20
Q
pH principles in relation to excretion of a drug
A
- most drugs are excreted renally, which is pH dependent
- clears faster if urine is opposite pH of drug
- weak bases - cleared faster if urine acidic
- weak acids - cleared faster if urine is alkali
21
Q
define bioavailability
A
amount of drug that reaches the systemic circulation as a proportion of amount administered
22
Q
method of administration with the highest bioavailability
A
IV
23
Q
bioavailability formula
A
AUC oral / AUC IV x 100
24
Q
What other factors can reduce bioavailability other than method administered
A
- area of gut
- gastric pH!
25
define pharmacodynamics
action of the drug on the body: how the drug is used and its effect on cellular receptors via signal transduction
26
what types of ligands can there be?
ligands can be **exogenous** (drugs) or **endogenous** (hormones, neurotransmitters etc)!
27
types of receptors a drug can target?
* ligand gated ion channels (nicotinic ACh receptor, binding allows + to move in)
* G protein coupled receptors (muscarinic, beta 2 adreno)
* Kinase linked receptors (for growth factors - tyrosine phosphorylation)
* cytosolic / nuclear receptors (for steroids - can modify gene transcription)
28
Briefly outline how will a ligand-fated ion channel act as a receptor fro drugs
* pore forming membrane proteins, allows ions to pass through the channel pore
* ligand is the interactor which allows pore to open and move
* once open, transduce external signals to inside of the cell
29
Briefly outline how will a G protein coupled receptor work as a receptor for drugs
* transmembrane receptors, targeted by \> 30% of drugs
* changes conformation: hydrolyse GTP to GDP = switch on or off, elicit downstream signalling for effect of the receptor
* majority of GPCR interact with PLC or AC
30
Briefly outline how will a kinase linked receptor work as a receptor for drugs
* **kinase** = enzymes that catalyze the transfer of phosphate groups between proteins (= phosphorylation)
* so regulating phosphorylation = way to activate signalling
* extracellular bind = intracellular activity = transmembrane signalling
* kinase themselves can be ligands
31
Briefly outline how will a cytosolic / nuclear receptor work as a receptor for drugs
* works by modifying gene transcription (activate or repress)
* e.g. tamoxifen
32
examples of diseases where an imbalance of chemicals led to pathology?
* **allergy**: increased histamine
* **parkinson's**: decreased dopamine
33
examples of diseases where an imbalance of receptors led to pathology?
* **myasthenia** **gravis**: loss of nicotonic ACh receptors
* **mastocytosis**: increase in C-kit receptor
34
what is the two state model of receptor activation?
describes how drugs activate receptors by **inducing or supporting a conformational change in the receptor** from ‘off' to ‘on’
35
define agonist
- binds to receptor and \*\*activates it\*\*
- can be full or partial
- e.g. salbutamol (asthma) = beta 2 agonist
36
define antagonist
- binds to receptor and **prevents its activation**
- can be reversible or irreversible
- main site or allosteric site
- e.g. propanolol = beta blocker
37
define potency
binding affinity of the drug to the receptor = how well a drug works
38
What does it mean to say that drug A is more potent than drug B?
Lower concentrations of drug A will give an equal or greater response than drug B
= aka drug A is more efficacious than drug B
39
what is EC50
concentration of a drug that gives half the maximal response
40
significance of a narrow therapeutic range
- increased risk of toxicity
- decreased chance of effective dose
- e.g. digoxin, lithium, genta/vancomycin
41
SE simvastatin when prescribed with a potential interactor
Rhabdomyolysis = muscle aches
42
SE warfarin when prescribed with a potential interactor (antibiotic mycins, amiodarone, opioid)
Increased risk of bleeding
43
How would you combat warfarin interactive SE?
Monitor INR (= prothrombin time, time for the blood to clot) at day 3, then weekly up to 4 weeks post commencement
44
SE SSRI when prescribed with TCA & tramadol
serotonin syndrome
45
What is the triple whammy?
1. NSAID or COX2
2. ACE-i
3. Dehydration or furosemide
gives you **major renal failure**
46
What does the concentration response curve describe?
* amount of response per amount of stimuli (dose)
* always on a log scale, sigmoid curve shape
47
Define efficacy
maximum response achievable, how well a ligand activates the receptor
(only agonists show this! antagonist doesn't activate!)
48
Define intrinsic activity
ability of drug receptor complex to produce a maximum functional response
= Emax of partial agonist / Emax of full agonist
49
Define affinity
describes how well a ligand binds to the receptor
(shown in both antagonist and agonist!)
50
What is receptor reserve?
= spare receptors
property a tissue needs to have should it be targeted by full agonists (full = block all receptors!)
51
Difference between a full agonist and a partial agonist
in **full agonist**s - all receptors will be blocked so there needs to be a receptor reserve
in **partial agonist**s - even if all receptors are occupied, max response is not seen
52
What is signal amplification?
* a signal cascade is initiated before a response
* signal amplification will determine how powerful response will be, but it does not necessarily equal to amplified response!
53
What is allosteric modulation?
Binding of an allosteric ligand to a receptor can affect the effect of an agonist on the receptor
* can be modulation in affinity or efficacy
* modulation can be positive = allosteric or negative = orthosteric
* benzodiazepine = allosteric ligand
54
Define tolerance?
= reduction in drug (agonist) effect over time
* seen with continuous, repeated high concentration over drug over time
55
What is desensitisation of receptors?
* three ways: uncoupled, internalised, degraded receptors → binding is affected
* rapid process!
56
Term to describe specificity of drug?
* no drug is ever truly specific ;)
* **_selective_** is the better term
57
Which enzyme is a known clot buster?
Streptokinase
58
How do NSAIDs work?
by inhibiting COX enzymes which takes part in prostaglandin synthesis
59
Actions of NSAIDs?
* analgesic
* anti-pyretic
* anti-inflammatory
60
Role of COX enzymes in prostaglandin synthesis?
breaks down **arachidonic acid** into **prostaglandin H2**
NSAIDs competitively inhibit COX enzymes so a. acid cannot reach active site
61
prostaglandin effect
* group of lipids made at site of tissue damage / infection
* controls inflammation, blood flow, formation of blood clots and induction of labor
62
Forms of COX enzymes?
COX 1 - found _normally_ and _widely_ in the body
COX 2 - this is induced, and found mainly in _inflammation_ only!
63
Types of NSAIDs and how they act on COX enzymes
Aspirin - non-selective, irreversibly blocks active site = inactivation of _both_ COX enzymes
= also reduce platelet aggr
Celecoxib / etoricoxib - selective, only act on COX-2
= reduces GI effects
64
How do Angiotensin-converting enzyme inhibitors (ACEi) work?
* blocks action of ACE therefore blocks the conversion of angiotensin I to angiotensin II
* angiotensin II = vasoconstrictor
* blocked A-II = reduced peripheral vascular resistance (afterload)
* also aldosterone level is reduced so sodium and water excretion promoted
65
Indications of ACEi's
* hypertension
* chronic heart failure
* ischaemic heart disease
* diabetic neuropathy and CKD with proteinuria
66
Examples of ACEi's
ramipril, lisinopril, perindopril
67
Important SE of ACEi !!!
**_dry cough!_**
also dizziness after first dose (from profound hypotension - titrate up)
68
How do statins work? (3)
* reduce serum cholesterol levels by inhibiting HMG CoA reductase, enzyme involved in making cholesterol
* decrease cholesterol production by liver and increase LDL clearance from blood
* indirectly reduce triglyceride and slightly increase HDL levels
69
Actions of statins?
* reduce cholesterol / triglyceride production, LDL levels
* slow the atherosclerotic process or reverse it
70
Indications of statins?
* prim and second prevention of cardiovascular events
* primary hyperlipidaemia
71
SE and interactions for statins?
* headache, GI disturbances
* metabolism reduced by cytochrome P450 inhibitors (amiodarone, macrolides)
72
three types of protein ports and how they work?
* **uniporter** - uses ATP to pull one molecule in
* **symporter** - uses movement of one molecule to pull in another against [gradient]
* **antiporter** - uses movement of one substance moving down the gradient (usually Na+, K+ or H+) to transport another substance against its gradient
73
Example of medication that targets a symporter to achieve therapeutic effect?
loop diuretics e.g. furosemide, bumetanide
* inhibits sodium-potassium chloride co transporter (NKCC) in ascending loop of henle by binding to it
* causes Cl & K loss in urine
74
indications of loop diuretics?
* relief of breathlessness in **acute pulmonary oedema**
* fluid overload in both **chronic heart failure** and **other oedematous states**
75
Types of channels a drug can target (major elements)?
Sodium, Calcium, Potassium, Chloride
76
Example of medication that targets epithelial sodium channels?
* amiloride & thiazide
77
How do thiazides work? Indication?
* thiazide diuretics **inhibit the Na/Cl co-transporter in the distal convoluted tube of the nephron** → _prevents_ reabsorption of sodium → diuretic
* also vasodilate but mechanism unknown
* indication = hypertension, first line alt or add on
78
SE & CI thiazide diuretics?
* hyponatraemia
* hypokalaemia → cardiac arrhythmia
* CI gout as reduce uric acid excretion
79
Examples of thiazide diuretics?
thiazide - bendroflumethiazide
thiazide like - indapamide, chlortalidone (works the same)
80
Example of medication that targets voltage gated calcium channels?
Calcium Channel Blockers = CCB's
e.g. amlodipine, nifedipine, diliazem, verapamil
81
How do CCB's work?
* decreases movement of calcium into vascular smooth muscle and cardiac muscle cells → **relaxation** and **vasodilation**
* within heart, it **reduces** myocardial **contractility**, suppress conduction
* reduced cardiac rate, contractility and afterload **reduce myocardial oxygen demand** → prevents angina
82
Types of CCB's?
* Dihydropyridines = selective for vasculature = amlodipine & nifedipine
* Non-dihydropyridines = more selective for the heart = verapamil & diltiazem (some effect on blood ves)
83
CCB indications?
* **all** **CCB's** = stable angina (alt = beta blocker)
* **amlodipine** (& nifedipine but less) - 2nd line hypertension & CVD prevent
* **diltiazem & verapamil** = rate control in supraventricular tachy, AF, flutter
84
Important and common SE of amlodipine (& nifedipine)
* **_peripheral oedema_**
* flushing, headaches, palpitations
85
Common SE verapamil
* constipation
* more seriously, bradycardia, heart block and cardiac failure
* diltiazem = any of them
86
Medication which targets voltage gated sodium channels?
lidocaine - anaesthetic
= blocks transmission of action potential in voltage gated sodium channels.
→ reduces arrhythmia!
87
What does it mean if a channel is voltage gated
action potential will induce a conformational change of the channel
88
Medication which targets voltage gated potassium channels?
Sulphonylureas → lowers blood glucose
89
Where are voltage gated potassium channels found?
* in excitable tissues like muscles and neurones (selective for K=)
* beta islets of Langerhans - regulates insulin in pancreas
90
How do sulphonylureas work?
stimulates pancreatic insulin secretion by
* blocks ATP dependent K+ channels in pancreatic beta cells
* membrane depolarise, calcium channels open → stimulating insulin secretion
91
Indications for sulphonylureas & SE?
* mono or with metformin
* DM type 2, but **only** effective if patient has **residual pancreatic function**
* SE **weight gain** (insulin = anabolic hormone!), GI upset, hypo, rarely hypersensitive reaction (hepatic, blood, rash etc)
92
Medication that targets the **sodium potassium pump**?
Digoxin
93
How does the NA/K pump work
* antiporter: moves both against their [gradient]
* 3 NA out against every 2 K ions
94
Define inotropic
related to force of contraction of the muscle - positive = increase etc
95
Define chronotropic
related to change in heart rate
96
How does digoxin work?
* competes with K to bind to Na/K ATPase pump
* **inhibits Na/K ATPase pump** causing Na to accumulate in cell thereby increasing contractile force (**inotropic**), treating **_heart failure_**
* increase vagal (parasympathetic) tone, **reducing conduction at AV** **node** thereby preventing some impulse transmission to ventricles, treating **_AF**_ and _**flutter_**.
97
Digoxin - SE & CI?
* SE typical present: GI upset, brady, rash, dizziness, visual disturbance (yellow vision)
* CI renal failure, heart block (2nd and interm), ventricular arrhythm, preexisting electrolyte disturbances (
98
Digoxin - indication
* **AF and flutter** but rarely on its own, also beta blocker and CCB better
* **severe heart failure**, preexisting AF or later option for those already on ACEi, beta blocker and an ald antag / angiotensin receptor blocker
99
Medication that inhibits K/H ATP-ase irreversibly to induce therapeutic effect?
omeprazole
100
How do Proton Pump Inhibitors work?
They reduce gastric acid secretion - by:
* irreversibly inhibiting H/K ATPase in gastric parietal cells
* ( = inhibited proton pump responsible for secreting H+ and generating gastric acid)
* = almost complete suppression
101
Proton Pump Inhibitors - indications!
* prevention and treatment of **peptic** **ulcers** including those assoc. w/ **NSAIDs**
* Symptomatic relief of **dyspepsia** and **GORD**
* **eradication of** ***Helicobacter pylori*** (combined with antibiotics - clarithromycin / metronidazole & amoxicillin & PPI)
102
Examples of PPI's!
lansoprazole, omeprazole, pantoprazole
103
PPIs - SE & CI
* SE GI disturbances & headache
* CI elderly at risk of osteoporosis
104
3 main fluid compartments of the body?
* intracellular - ⅔ of body weight
* extracellular - ⅓ of body weight
* interstitial fluid - ¾ of e.cell
* plasma fluid - ¼ of e. cell
105
Principle of drug distribution & exactly how are they distributed to compartments?
* drug is distributed in plasma according to chemical properties and molecular size
* proteins / large molecules → plasma
* water soluble molecules → plasma & interstitial compartment
* lipid soluble molecules → intracellular fluid
106
How would you calculate the volume of distribution of a drug?
Volume of distribution = total amount of drug in body / concentration of drug in plasma
= volume a drug would occupy if it was distributed through all the compartments as if they were all plasma
107
e.g.'s of drugs found in each fluid compartment?
_Plasma_
- warfarin
_Interstitial_
- Aspirin / other NSAIDs
- antibiotics
_Intracellular_
- ster/opioids
- Paracetamol
- local anaes
- Amiodarone!
108
Define clearance?
Removal of drug from plasma by either liver or kidney
109
From which compartment is a drug eliminated?
Plasma!
110
How can clearance be measured?
* volume of plasma that is completely cleared of drug per unit time
* rate at which plasma drug is eliminated per unit plasma concentration
111
What are some ways to measure renal clearance?
* renal blood flow (18% of cardiac output 1L/min)
* renal plasma flow (60% of blood flow 600ml/min)
* glomerular filtrate (12% of renal blood flow 130 ml/min)
112
Marker substance in kidneys?
Creatinine
113
How is hepatic clearance measured?
Hepatic extraction ratio - proportion of drug removed by one passage through liver
* affected by **liver enzymes**
* high = clearance is only limited by hepatic blood flow = quick
* low = process is slow and not efficient
114
Define first pass metabolism
drug has a high hepatic extraction ratio
metabolism of the drug by the gut and liver before it reaches the bloodstream
115
Where are pro-drugs broken activated usually?
liver!
* where Cytochrome P450 comes in!
* e.g. hydrocortisone is cleaved into active drug crotisol via metabolism
116
If a drug has limited therapeutic utility it means ..
it might not have reached the intended site (lol)
117
Free card for a break
118
What are the divisions of the autonomic nervous system?
Sympathetic & parasympathetic
119
What is the sympathetic system responsible for?
* fight or flight system
* sweat glands, blood vessels
120
Features of sympathetic ganglion?
ganglion is within a chain **_next to the spinal cord_**
121
What is the parasympathetic system responsible for?
* rest and digest
* heart, gut, bladder
122
Features of parasypathetic ganglion?
ganglion is **_within or very close_** to the effector organ
123
What are the two main neurotransmitters in the body?
* Acetylcholine - ACh
* Noradrenaline - NAd
124
What neurotransmitters can be found in the sympathetic system?
Both ACh & NAd
125
What neurotransmitter is used in the preganglionic segment in the sympathetic pathway?
Acetylcholine ACh
126
What receptor is used in the preganglionic segment in the sympathetic pathway?
Nicotinic receptors → used for preganglionic segments in both symp & parasymp pathways
127
What are nicotinic receptors?
* found in preganglionic segments of both symp & parasymp pathways
* Only **ACh** acts on them
* is a **channel protein**, upon binding by ACh, opens to allow diffusion of cations
(all you need to know)
128
What neurotransmitter is used in the postganglionic segment of the sympathetic pathway?
noradrenaline
129
What is the exception to which noradrenaline is _not_ used in the post-ganglionic sympathetic system (& what receptors are used?)
When _innervating sweat glands_, post ganglionic sympathetic fibres release **ACh** acting on **muscarinic receptors (M3!)**.
130
What receptors are used in the postganglionic segment of the sympathetic pathway?
adrenergic receptors
131
Types of adrenergic receptors?
4 in total - alpha 1, 2 & beta 1, 2
132
Differentiate between alpha and beta receptors (general)?
| (your trick!)
think animal kingdom!
**alpha1** (2 is mixed) causes smooth muscle contraction, **beta2** (1 is mixed) causes smooth muscle relaxation
**alpha** also higher affinity for **NOradrenalinE** as there is NO E in alpha; **bEta** is **adrenaline** as there is an E!
133
Noradrenaline is a?
| (nature of molecule)
neurotransmitter
134
Adrenaline is a?
| (nature of molecule)
hormone
135
Both adrenaline and noradrenaline are?
| (nature of molecules)
Catecholamines
136
Production pathway of nor/adrenaline?
Tyrosine → DOPA → dopamine → noradrenaline → adrenaline
137
reminder - what are agonists?
molecule capable of functionally activating a target
138
reminder - what are antagonists?
molecule that binds to a target & prevents others from binding to it. does not activate target!
139
effect of alpha 1 agonists?
| (activation of alpha 1)
* causes **vascoconstriction**, in skin and abdominal bed → will **raise** **BP** & cardiac
* less in brain, lung, heart
140
pharmacological benefit of alpha 1 agonists?
* IV noradrenaline: support septic & anaphylactic shock
* xylometazoline - nasal decongestion
141
effect of alpha 1 antagonists (alpha blockers) with examples?
* lowers BP through vasodilation - **doxazosin**
* treats catecholamine secreting tumour (phaeochromocytoma)- **phenoxybenzamine**
* alpha 1A receptor blocking in prostate - treating benign prostatic hypertrophy - **tamsulosin**
142
effect of alpha 2 _agonists_?
* reduce BP, but also vascular tone (ex **clonidine**)
* neuro - used to help ADHD to help concentration
* no useful alpha 2 blockers
143
alpha blockers CI?
postural hypotension
144
tip to remembering main beta receptor effects respectively?
beta 1 - heart!
beta 2 - lungs!
you have 1 heart 2 lungs :)
145
effect of beta 1 agonists?
**_heart and kidneys_**
* increase heart rate (chronotropic) & stroke volume
* release of renin from kidneys - regulates BP
* lipolysis & hyperglycaemia
146
biggest benefit of beta 1 receptors?
equal affinity for nor/adrenaline
= non selective, works at any when used therapeutically
147
effect of beta 1 antagonists (blockers)?
* reduce heart rate & stroke volume, therefore myocardial oxygen demand
* prolongs refractory period of AV node → tx arrhythmias
* lowers BP through renin secretion in kidneys
148
beta 1 selective blockers
at this level?
atenolol, bisoprolol
(also: metoprolol, betaxolol)
→ means they're safe to use in COPD (not asthma!!)
149
examples of beta blockers (general)?
lol ending: bisoprolol, atenolol, propranolol MAIN then metoprolol. carvedilol
150
Indication for beta blockers (general)?
* ischaemic heart disease - angina & ACS
* chronic heart failure & post MI - improve tone
* AF, SVT
* hypertension when other meds are inapp or insuff
151
Why should you be cautious about giving beta blockers to asthmatic patients?
most will already be on beta 2 agonists → block = life threatening!
152
What is beta blocker poisoning and what is the antidote?
* if overdose - heart relaxes - emergency
* antidote is _glucagon_ as it increases MI contractility irrespective of presence of beta blockers (bypass beta adrenergic site)
153
beta blockers, non selective - examples?
propanolol - beta 1 and beta 2
carvedilol - non selective beta & alpha 1 antagonist
154
Propanolol - indications?
* thyrotoxicosis (adjunct), thyrotoxic crisis
* angina, hypertension, stops tremor! others
* **CI** **bronchospasm**! total beta blocker!
155
Carvedilol - effect and indications?
* Affects the heart and cause vasodilation too
* **hypertension**, **angina**
* **chronic** **heart** **failure** but adjunct with others
* **CI** bronchospasm! total beta blocker!
156
beta blockers - CI?
caution - myasthenia gravis
ci - asthma, hypotension, metabolic acidosis // heart block 2&3, heart failure, p's angina
157
effects of beta 2 agonists?
DILATE
* bronchi: bronchodilation (smooth muscle relaxation)
* uterus: inhibition of labour, delay = tocolysis
CONSTRICT (less important?)
* skeletal muscle: increases contraction speed → induce tremor
* pancreas: insulin & glucagon secretion
* bladder wall: inhibits micturition
158
pharmacological application of beta 2 agonists?
* asthma & COPD, both long & short term therapy
* hyperkalaemia (along with insulin, glucose and calcium gluconate)
159
examples and types of beta 2 _agonists_?
Short acting - salbutamol, terbutaline
Long acting - salmeterol, formoterol
160
SE beta agonists?
tremor hyperglycaemia (glucagon release) & tachyarrythmia
161
Nature of adrenaline
non selective! works at any alpha or beta adrenoreceptor
162
Possible targets and effects of adrenaline and receptors?
alpha 1 - blood vessels - vasoconstriction (BP +, but only at large dose)
beta 1 - heart - positive inotropic
beta 2 - lungs - bronchodilation
(at lower doses its mostly beta effects)
163
Possible uses of adrenaline?
anaphylaxis - reduce BP, bronchodilate
cardiac arrest
acute hypotension - large dose
164
What neurotransmitters can be found in the parasympathetic system?
Acetylcholine only
165
Which neurotransmitter is used in the pre-ganglionic segment of the parasympathetic pathway?
ACh
166
Which receptor is used in the pre-ganglionic segment of the parasympathetic pathway?
nicotinic receptors
167
Which neurotransmitter is used in the post-ganglionic segment of the parasympathetic pathway?
ACh
168
What receptors are used in the post-ganglionic segment of the parasympathetic pathway?
Muscarinic receptors
169
What are cholinergic receptors?
receptors which can receive acetylcholine = both nicotinic and muscarinic receptors!
170
Function and types of muscarinic receptors?
= mediates effect of ACh in parasympathetic system, receptive to drug targeting!
= all receptors are found outside the cell & activates intracellular processes through G proteins
= M 1-5 but focus is on M2-3
171
M1, 4 & 5 muscarinic receptors?
M1 brain
M4 & M5 CNS
172
Effects of activating the M2 receptors?
effects mainly **on the heart**
* on SA node: decrease heart rate
* on AV node: decrease conduction velocity, induce AV node block (PR interval +)
173
Effects of activating the M3 receptors?
_Respiratory_: mucus production, bronchoconstriction
_GI tract_: increase saliva production, gut motility, stimulate biliary secretion
_Sweating!_ from ACh sympathetic
_Urinary_: contract detrusor, relax internal urethral sphincter
_Eye_: myosis, + drainage of aqueous humour, secretion of tears
174
Useful M3 agonist?
**Pilocarpine**
* contract iris muscle = increase aqueous humour drainage, reduces ocular pressure → tx **acute glaucoma**
* stimulate saliva production → tx **dry mouth**
* for Sjogren, or post radio
* SE slow heart
175
Adverse effect of muscarinic agonists?
**DUMBELSS**
## Footnote
**D**iarrhoea
**U**rination
**M**iosis → excessive pupil constrict
**B**radycardia
**E**mesis → vomitting
**L**acrimation → tears
**S**alivation / **S**weating
176
Antimuscarinics / Muscarinic antagonists: 4 main uses & mechanism?
as bronchodilators (resp), on the heart, GI, and GU
through competitive inhibition with acetylcholine
177
Antimuscarinic - general side effects?
inhibit parasympathetic M receptors in other area = dry mouth (GI tract blocked so secrete - saliva), urinary retention, worsen glaucoma
178
How are antimuscarinics indicated in the respiratory system?
relieving acute exacerbations short term, and prevention in long term
COPD & asthma
CI type 2 resp failure, CA arrhythmias & urinary
179
Inhaled antimuscarinics: mechanism, ex?
_mechanism_: local antimuscarinic delivery to airway → dilation of airway
ex tiotropium, glycopyrronium, umeclidinium, aclidinium
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Antimuscarinics:
**Atropine** - benefits & adverse effects?
1st line bradycardia
_Benefits_: increase heart rate, treat bradyarrthmias & AV node block
_Adverse_: dilated pupils, hallucinations, palpitations, blindness and death
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Antimuscarinics:
**hyoscine & mebeverine** - benefit?
1st line IBS, as an antispasmodic
SE (hyoscine) reduces respiratory secretions so also in palliative care, also for nausea as ACh in somatic too
182
How are antimuscarinics indicated for genitourinary uses?
for overactive bladder, blocks **M3** so
promotes bladder relaxation & increase bladder capacity
→ reduce urinary frequency, urgency & urge incontinence
183
GU antimuscarinic: examples, use & CI?
oxybutynin, tolterodine, solifenacin
1st line for urge incontinence to reduce urgency & urinary frequency _if_ bladder training ineffective
CI UTI, CA elderly, dementia, angle closure glaucoma, arrhy, uri retention
184
Where else in the neuro system is ACh found?
also in somatic system! receptors known as N1 receptors (autonomic is N2)
185
Effect of ACh in the somatic system?
* implicated in memory - anticholinergics SE memory problems
* target tx for nausea
* muscle relaxant in surgery (-onium ending meds)
186
Diseases related to ACh in the somatic system?
clostridium botulinum as botulinum toxin is anti-ACh
myasthenia gravis - blocks normal transmission by inhibiting N1 receptors producing skeletal muscle weakness
187
tx myasthenia gravis (just for fun)
reverse ACh blocking
= anti-cholinesterase
→ increase ACh availability at neuromuscular junction
ex pyridostigmine
→ avoid beta blockers (not ci just ca)
188
Anti-drug to opioids?
Naloxone
189
What is in opium?
Morphine & codeine
190
How does opium work (3)?
* modulate pain perception in higher centres euphoria to change the **emotional perception of pain**
* **inhibit pain transmission to brain** (the release of pain transmitters at spinal cord and midbrain)
* reduce pain by acting on descending pain modulatory system (**inhibition of pain signalling in spinal cord**)
191
How does opium work _chemically_?
* promote potassium conductance: neuron less likely to fire an action potential
* inhibit calcium conductance: neuron less likely to release neurotransmitters
* bind to periaquiductal grey
192
Examples of opioid receptors and their mechanism?
* MOP, KOP, DOP & NOP
* lock and key mechanism with morphine
* located in midbrain, spine, GI tract, breathing center → hence extended use can cause respiratory depression
193
Effective duration of a single dose of morphine?
3-4 hours
never designed for sustained activation: leads to tolerance & addiction
194
Side effects of opioid drugs?
* potential for **respiratory depression** → opioid receptors exist here
* **Sedation, Nausea & Vomiting, Constipation, Itching, Immune suppression, Endocrine effect**s
* titrate up, everyone responds diff!
195
How would you treat an opioid overdose?
* ABC - airways breathing circulation!
* **_IM before IV_** - beware drug addict overdose
* don't repeat prescriptions without seeing the patient
* **naloxone** = antagonist!
* admit **IV** → fastest → **400** **micrograms** **per** **ml**
* titrate dose to suit the patient: 1ml in 10ml saline
* short half life: give depot: some IV some subcutaneous → depot will maintain levels
196
What is potency and relative potency of opioid forms?
binding affinity of a drug, how well does it bind to the receptor - whether it is strong or weak
* diamorphine 5mg
* morphine 10mg
* pethidine 100 mg
197
Define tolerance
* down regulation of receptors with prolonged use
* need higher doses to achieve the same effect
198
Define dependence
* psychological: craving, euphoria
* physical
199
Define addiction
* very big issue in US → careful in using in non-cancer pains!
* don't issue repeat prescriptions without seeing patient
200
When would opioid withdrawal occur and how can you help
* starts within 24 hours, lasts about 72 hours
* can give methadone to slow down → safer
201
How is codeine metabolised by the body?
= a prodrug
* needs to be **metabolised by cytochrome CYP2D6** to morphine to work
* 10% absent, 10% activity decreased for Causasian population = reduced effect
* 5% overactive = increased risk of respiratory depression
202
How is morphine metabolised in the body
metabolised to morphine 6 glucuronide → more potent than morphine & renally excreted, clears up quickly
203
Most common intolerant condition to morphine?
* renal failure: will build up & cause respiratory depression
* \< 30% renal function patients (creatinine clearance \< 30) → reduce dose & timing interval
* use oxycodone instead! or look at acute pain guidance
204
How is tramadol metabolised by the body?
prodrug & weak opioid agonist, slightly stronger than codeine
* needs to be metabolised by **cytochrome CYP2D6** to o-desmethyl tramadol to work
* ineffective in 10% of patients
* secondary effect as serotonin & nor-epinephrine reuptake inhibitor
* ! take care in prescribing it to patients on antidepressants → serotonin syndrome
205
Alternative for morphine if patient has renal failure
oxycodone
206
Commonest! SE of opioid analgesics
respiratory depression
207
Prodrug forms, opioid analgesics?
Codeine, Tramadol
208
Opioid analgesics - if prodrug then metabolised by which P450?
CYP2D6
209
How does naloxone work as a antidote?
via competitive receptor binding
210
What are stereoisomers
have the same molecule formula and sequence of bonded atoms, but differ in the 3D orientations of their atoms in space
211
What is an adverse reaction?
= unwanted or harmful reaction following administration of drug
not side effects - never beneficial, but side effects can be adverse reactions
212
What is a side effect?
unintended effect of a drug related to its pharmacological properties & can include unexpected benefits of treatment
* can be beneficial: PDE5 inhibitors improve urinary flow
213
Types of ADR's?
* hypersusceptibility
* collateral effect
* toxic effects
214
What is a hypersusceptibility ADR & ex?
* below therapeutic range
* sub therapeutic dose
* e.g. anaphylaxis from penicillin
215
What is a collateral effect ADR?
* drug issue is in therapeutic range
* reaction from using a standard dose
216
What is a toxic effect ADR?
can occur if dose is too high or drug secretion is reduced by impaired renal or hepatic function or by interaction with other drugs
217
By the Rawlins Thompson classification, what are the different types of ADR's
**Augmented, Bizarre, Chronic, Delayed, End of treatment, Failure of therapy**
218
What is an Augmented ADR by the Rawlins Thompson classification
* predictable, common, dose dependent; extension of primary pharmaceutical effect
* the more you give the bigger the reaction
* high morbidity low mortality
* risk - renal or hepatic impairment - older, etc
219
What is a Bizzare ADR by the Rawlins Thompson classification
unpredictable, not dose dependent; can't be readily reversed
can be life threatening, can be idiosyncrasy, allergy or hypersensitivity
* idiosyncrasy: inherent abnormal response to a drug
* may be due to genetic abnormality, enzyme deficiency, or abnormal receptor activity
* rare but serious
Low morbidity, high mortality
e.g. anaphylaxis - penicillin
220
What is a Chronic ADR by the Rawlins Thompson classification
occurs after long term therapy
uncommon, related to cumulative dose & time
steroids and osteoporosis
e.g. analgesic nephropathy, colonic dysfunction due to laxatives
221
What is a delayed ADR by the Rawlins Thompson classification
after immunosuppresion
uncommon, dose related, shows after a while of taking the medication
e.g. teratogenesis (congenital malformation) - thalidomide, carcinogenesis - cyclophophamide
222
What is an end of treatment ADR by the Rawlins Thompson classification
when the drug is stopped, withdrawal
e.g. opiate withdrawal, glucocoticoid abrupt withdrawal: adrenocortical infusfficiency, anticonvulsant stopped: withdrawal seizures
223
What is a failure of therapy ADR by the Rawlins Thompson classification
often caused by drug interactions
e.g. failure of the pill with enzyme inducers, failure of therapeutic effect in patients taking warfarin leading to CVA
224
What are a few factors to think of in order to help you determine what kind of reaction it is
**Do**se related
**T**iming
Patient **S**usceptibility
225
What is non-immune anaphylaxis?
* due to direct mast cell degranulation
* some drugs recognised to cause this
* no prior exposure & clinically identical
226
When should you suspect an ADR?
Symptoms that start ...
* soon after a new drug is started
* after a dosage increase
Symptoms that disappear when drug is stopped & reappear when it is restarted
227
What does it mean if a medication has a black triangle on them
medicine is undergoing additional monitoring! watch out for ADR's
228
When should you report an ADR?
all suspected reactions for herbal meds, black triangle meds
all serious suspected reactions (death / life threaten / disability / results prolong hospitalise) for well established drugs and interactions
229
How to report an ADR?
Yellow card - download or at back of BNF
to the MHRA - Medicines and Healthcare products Regulatory Agency
230
Are you obligated to report?
No - a voluntary scheme
but it is your duty to report - important for patient safety!!
Patients can report too
231
Mechanism of action - amlodipine?
Calcium channel antagonist
= block calcium entry in response to depolarisation in blood vessels = **vasodilation**, lowers peripheral resistance
**= lowers systemic blood pressure**
232
Most common SE for CCBs?
ankle swelling
233
Ramipril - mechanism of action?
Angiotensin converting enzyme inhibitor (ACEi)
Blocks action of renin-angiotensin system = indirectly acting vasodilator
234
Mose common SE for ACEi?
dry cough
235
Other common SE for ACEi?
vasodilation, potassium retention & inhibition of salt & water excretion
→ hyperkalaemia = comp!!
236
How is ACEi excreted? Complication?
Renal function
if preexisting impairment = hyperkalaemia can occur
237
Why do Afro-Caribbean patients respond less well to ACEi?
they commonly have **low renin essential hypertension**, where renin angiotensin system is contributing little to their hypertension
238
Mechanism of NSAIDs?
inhibiting cyclo-oxygenase, specifically COX2, which is induced by inflammatory cells
ratio of inhibition COX-1 to COX-2 = determine side effects
239
Contraindications of NSAIDs?
**active or recurrent GI bleeding, ulceration**
**severe heart failure**
**allergy to aspirin**
**avoid** in renal failure & dehydration
240
Why should NSAIDs be avoided in patients with asthma?
→ use NSAID with caution **in any allergic disorders**
8-20% asthmatics experience **_bronchospasm_** following ingestion of aspirin & other NSAID drugs
241
SE NSAIDs (major)?
Renal dysfunction, esp in at risk
= **acute interstitial nephritis**
→ inhibition of prostaglandins are involved in maintenance of renal medullary blood flow
242
How is metformin excreted?
Cleared by active tubular secretion
→ unchanged in urine
243
Define half life in relation to elimination?
elimination half life
= time required for serum concentration of the drug to be decreased by 50%
244
Precautions for patients on metformin requiring a radiological investigation?
measure serum creatinine in the preeceding month
* *\> 100ml contrast required** _OR_
* *serum creatinine raised**,
**_withhold metformin 48 hours before contrast_**
raised creatinine = also withhold 28 hours post contrast
245
How can you alter a prescription to mitigate the effects of reduced renal function?
for drugs that are excreted unchanged, adjust the dose in renal impairment
**→ reduce the dose**
**→ lengthen dose interval**
or **both!**
alt = substitute the drug
246
What is St John's wort & what is it used for?
herbal medicine = complementary!
used for symptoms of mild & moderate depression
247
Significance of St John's Wort & interactions (7)?
**CYP450 inductor** = increases metabolism of medications = makes them less effective.
SSRI, oral contraceptive, warfarin, digoxin, cyclosporin, HIV meds, statins
248
1st line tx for depression?
Selective Serotonin Reuptake Inhibitor
249
Mechanism for SSRi's?
**Inhibit neuronal reuptake of 5-HT from synaptic cleft** → increases availability for neurotransmission
minimum 6 months, don't stop!
250
Examples of SSRIs?
sertraline, citalopram, fluoxetine
251
SE of SSRIs?
Long QT, seizures
Increased suicidal thoughts at the beginning of therapy
serotonin syndrome
252
2nd line tx for depression? what else is it used for?
Tricyclic Antidepressants (TCA)
neuropathic pain!
253
Examples of tricyclic antidepressants?
amitriptyline, lofepramine
254
Mechanism of TCA's?
Inhibit neuronal reuptake of 5-HT **_and noradrenaline_**
also **blocks a range of receptors** e.g. muscarinic, histamine, adrenergic, dopaminergic → SE's
255
Last line depression?
Mirtazapine
256
Advice to those **on the oral contraceptive pill** and have had **several episodes of severe diarrhoea?**
If severe diarrhoea = missed pill on those days
→ take additional contraceptive precautions for following 7 days
257
Name a few contraceptive options?
the pill!
Contraceptive patch / implant / injection
intrauterine device, condoms, contraceptive cap
258
How does the **combined oral contraceptive pill** prevent pregnancy?
**suppress ovulation** by interfering with the gonadotrophin release by the pituitary via **negative feedback** on the hypothalamus
makes **endometrium thinner** & **cervical mucus thicker**
259
Mechanism of loperamide?
**_opioid receptor agonist_**
→ **reduces GI tract motility**
= increases time material stays in intestine = allow for more H2O absorption
260
Treatment in acute Crohn's disease?
* *_Steroids_**
* *mild** = corticosteroids = **budesonide**
* *moderate** = glucocorticoids = **prednisolone**
**severe** = corticosteroids = **_IV hydrocortisone_**
if rectal disease = per rectum
if perianal abscess or perianal disease = **metronidazole**
last = **anti-TNF = infliximab or adalimumab**
261
Mechanism of anti-TNF antibodies in Crohn's disease?
= infliximab, adalimumab
= reduce disease activity by **countering neutrophil accumulation, granuloma formation**, and **activating complement**
262
How might you maintain remission in Crohn's disease?
1st = **Azathioprine**
2nd = **Methotrexate** (+ folic acid)
263
Methotrexate: mechanism of action?
inhibit dihydrofolate reductase
= converts folic acid → FH4
**= prevent cellular replication**
## Footnote
**antiinflammatory & immunosuppression effects against ILs & cytokines**
264
Why must folic acid be prescribed alongside methotrexate?
**_counteract folate-antagonist action of methotrexate_**
= reduce toxicity & improve compliance
= alt days to avoid reducing effectiveness of methotrexate
265
How to monitor patients on methotrexate for adverse drug reactions?
FBC + renal & LFT before tx, every 2-3 weeks until stabilised & every 2-3 months after
266
What receptors do doxazosin and tamulosin act on?
**doxazosin** = alpha 1 adrenergic receptor antagonist
**tamsulosin** = **selective alpha 1A & alpha 1D adrenoceptor antagonist**
267
Important complication for those on alpha-blockers & about to have surgery?
**Intraoperative Floppy Iris syndrome (IFIS)**
→ don't have to stop, just inform & surgeon should be ready to modify technique
268
Main SE of alpha blockers? How might you modify it?
Postural hypotension
Try taking medications at night & if not then swap meds
269
What is retrograde ejaculation?
occurs in 30% of men taking alpha blockers
**seminal fluid flows into bladder** instead of normal antegrade direction → due to **bladder neck failing to close**
270
2nd line BPH treatment?
finasteride
271
Mechanism of **5alpha reductase inhibitors**?
**inhibiting** the **intracellular enzyme 5 alpha reductase,** which converts testosterone to dihydrotestosterone (stimulates prostatic growth)
→ reduces size of prostate gland
272
Why should you review someone's contraception if they're on carbamazepine?
Combined oral contraceptive = **reduced by drugs which induce hepatic enzyme activity** e.g. **carbamazepine**!
273
Contraceptive options if on carbamazepine / other inducer drugs?
Parenteral progesterone only or intra-uterine devices
274
If someone is pregnant while on Carbamazepine - what should they do?
Keep taking carbamazepine as risk of seizure is high, high dose folic acid 5mg to be started immediately
275
Mechanism of aledronic acid?
oral bisphosphonte & inhibits osteoclast mediated bone resorption
276
Advice when taking aledronic acid (4)?
**Take tablets with plenty of water while sitting / standing**
**take on empty stomach 30m before breakfast**
**stay upright at least 30m after**
→ seek help if symptoms of **dysphagia, achalasia, heartburn, retrosternal pain**
277
Indications of letrozole?
Post menopausal women with **oestrogen receptor positive** **_breast cancer_**
278
What is a spacer?
Add on device used to **increase ease of administering inhalers** esp in babies & children
