Pharmacology Flashcards
1
Q
What are the 2 routes of administration of a drug?
A
Systemic and local
2
Q
What are the 2 branches of systemic administration of a drug?
A
Enteral (GI tract) and Parenteral (not GI tract)
3
Q
What are the different types of local routes of administration?
A
Topical e.g. topical steroid creams for eczema
Intranasal
Eye drops
Inhalation - can also be systemic depending on drug e.g. salbutamol only affects airways but anaesthetic drug sevoflurane is also given by inhalation but has systemic effects)
Transdermal - can also be systemic depending on drug
4
Q
What is systemic administration of a drug?
A
Covers the whole system
5
Q
What is local administration of a drug?
A
Targets a specific area of pathology, without exposing the rest of the system to drugs unnecessarily
6
Q
What are the different types of systemic enteral administration?
A
Oral (PO)
Rectal (PR)
Sublingual
7
Q
What are the different types of systemic parenteral administration?
A
IV/IM/SC
Inhalation
Transdermal
8
Q
What are pharmacodynamics?
A
Action of the drug on the body (its use!)
9
Q
What are pharmacokinetics?
A
Action of the body on the drug (how it’s broken down)
10
Q
How do drugs cross membranes?
A
Passive diffusion
Facilitated diffusion
Active transport
Endocytosis
11
Q
By what route of administration is a drug absorbed the quickest?
A
IV - directly into bloodstream and no membrane crossing or first pass metabolism
12
Q
How are drugs absorbed into the bloodstream?
A
Unless given straight into the bloodstream (IV), drug will need to pass though membranes
13
Q
How are water soluble drugs absorbed?
A
Water soluble molecules move through membrane by diffusion
14
Q
How are lipid soluble drugs absorbed?
A
Lipid soluble drugs can cross phospholipid membrane directly
15
Q
How are larger drugs absorbed?
A
Larger drugs might need facilitated diffusion from carrier proteins in the membrane, ATP dependent active transport, or are engulfed by the cell through endocytosis
16
Q
What is absorption dependent on?
A
Solubility of drug Size of molecules pH Surface area Perfusion
17
Q
What happens to a drug if it is taken orally?
A
If taken orally, not all of the drug taken gets to the bloodstream – the gut and liver will both start metabolising it first before reaching circulation
18
Q
When is bioavailability assumed to be 100%?
A
It is assumed to be 100% if a drug is given IV, but lower if given orally
19
Q
How is bioavailability calculated?
A
AUC oral / AUC IV x 100
20
Q
What is bioavailability?
A
Rate and extent to which an administered drug reaches the systemic circulation
Fraction of drug that reaches systemic circulation unaltered
21
Q
What are the drug target types?
A
Cellular receptors
Enzymes (ACE inhibitors)
Membrane ion channels (lidocaine)
Membrane transporters (PPIs)
22
Q
What does drug distribution depend on?
A
Blood flow to area Permeability of capillaries Binding to proteins (albumin = slower) Lipophilicity Volume of distribution
23
Q
Give an example of how blood flow to an area affects distribution.
A
Drug will get to the brain (if can pass through BBB) faster than the skin
24
Q
How does permeability of capillaries affect drug distribution?
A
Some capillaries have slit junctions that allow drugs through – many in the liver (allows metabolism), none in the brain so harder to get through
25
How does binding to protein affect drug distribution?
Drugs may also travel in the blood bound to albumin, which slows the process of distribution as the drug must be FREE FROM ALBUMIN to cross membranes
26
How does lipophilicity affect drug distribution?
Lipophilic drugs can penetrate the cell membrane easily
27
How does volume of distribution affect drug distribution?
Higher volume of distribution = drug more in tissues, less in plasma, need to give higher concentration
28
Where can drug targets be found?
Cellular receptors but not all drug targets are receptors on cells (e.g. ramipril, lidocaine, proton pump inhibitors)
29
What is ramipril?
An ACE inhibitor which blocks the angiotensin converting enzyme
30
What is lidocaine?
Blocks sodium ion channels and is a local anaesthetic
31
What are proton pump inhibitors?
Inhibit membrane transporters
32
Give an example of a proton pump inhibitor.
Omeprazole
33
Why is the liver key in the excretion of drugs?
Kidney can't excrete lipid soluble drugs so liver converts lipid soluble drugs into water soluble drugs so they can be excreted by the kidney (2 stages)
34
Summarise the first phase of drug excretion.
Make drug hydrophilic (cytochrome p450 catalyses)
35
Summarise the second phase of drug excretion.
If still too lipophilic, add something else to make it polar so the drug can’t be absorbed - e.g. acetylation/adding glutathione)
36
How do drugs affect cytochrome P450 enzymes?
Drugs can alter the activity of cytochrome P450 enzymes, and therefore alter the rate of metabolism of other drugs
37
How does alcohol abuse affect drug excretion?
Alcohol abuse, both chronic and acute can mess up the P450 system
38
What is a CYP450 inducer?
Increases cytochrome P450 activity, and speed up metabolism of other drugs – may result in sub-therapeutic dose
39
What is a CYP450 inhibitor?
Decreases cytochrome P450 activity, reduce metabolism of other drugs – may result in toxicity
40
Give some examples of CYP450 inducers.
```
Anti-epileptics: phenytoin, carbamazepine
Rifampicin
St John's Wort
Chronic Alcohol intake
Smokers (CYP1A2)
```
41
Give some examples of CYP450 inhibitors.
```
Abx: ciproflaxacin, erythromycin
Isoniazid
Amiodarone
Allopurinol
Anti-fungal: ketoconazole, fluconazole
SSRI: fluoxetine, sertraline
Sodium Valproate
Acute Alcohol
```
42
By what type of kinetics are most drugs eliminated?
Most drugs are eliminated through first order kinetics
43
What is first order kinetics?
Catalysed by enzymes, rate of metabolism directly proportional to drug concentration
The capacity of the elimination system is higher than the concentration of the drug
44
What is zero order kinetics?
Enzymes saturated by high drug doses, rate of metabolism is constant, e.g. ethanol, phenytoin
45
When might doses of drugs need to be altered?
Renal failure
46
Other than the kidneys, how else can drugs be excreted?
Some also excreted by the liver in the bile and then faeces
47
What is signal transduction?
Binding of drug to extracellular or intracellular receptor
48
How does signal transduction occur?
Via a variety of receptors: ligand-gated ion channels, G protein-coupled receptors etc
49
What does signal transduction lead to?
Amplification or down-regulation of signals
50
What is an agonist?
Binds to receptor and activates it by mimicking the endogenous substance
51
What response does an agonist induce?
Can be full (causes same response as endogenous substance) or partial
52
Give an example of an agonist.
Salbutamol (asthma) is beta 2 agonist
53
What is an antagonist?
Binds to receptor and prevents its activation - can also bind at another site to the main active site (allosteric site)
54
What type of reaction takes place when an antagonist binds to a receptor?
Can be reversible or irreversible (if a covalent bond forms)
55
Give an example of an antagonist.
Propranolol (hypertension) is a beta blocker
| Beta blockers like bisoprolol
56
What do beta blockers do?
Block the adrenergic receptors of the sympathetic nervous system
57
When should beta blockers be avoided?
Avoid beta blockers in asthmatic patients
| Use cardio-selective ones (bisoprolol) if absolutely necessary, rather than propranolol (non-selective)
58
What is efficacy?
How well the ligand (drug) activates the receptor – e.g. full or partial agonist?
59
What is potency?
Binding affinity of the drug for the receptor
60
What is first pass metabolism?
Metabolism of the drug by the gut and liver before it reaches the bloodstream
61
What does a narrow therapeutic range indicate?
Increased risk of toxicity, decreased chance of effective dose
62
Give some examples of drugs with a narrow therapeutic range.
```
Digoxin
Theophylline
Lithium
Phenytoin
Gentamicin, Vancomycin
```
63
What happens to paracetamol following a therapeutic dose?
Paracetamol is mostly converted to non-toxic metabolites via Phase II metabolism
64
What happens to paracetamol during phase II metabolism?
Here, it conjugates with sulfate and glucuronide, with a small portion being oxidized via the cytochrome P450 enzyme system
65
What do the cytochromes do to a small fraction of paracetamol during its metabolism?
Cytochromes P450 2E1 and 3A4 convert approximately 5% of paracetamol to a highly reactive intermediate metabolite, N-acetyl-p-benzoquinone imine (NAPQI)
66
What happens to NAPQI under normal conditions?
NAPQI is detoxified by conjugation with glutathione to form cysteine and mercapturic acid conjugates.
67
What happens to the phase II metabolic pathways after a paracetamol overdose?
The phase II metabolic pathways become saturated, and more paracetamol is shunted to the cytochrome P450 system to produce NAPQI
68
What happens as a result of increased NAPQI concentration from a paracetamol overdose?
Hepatocellular supplies of glutathione become depleted, as the demand for glutathione is higher than its regeneration
69
What happens once there is not enough glutathione to detoxify NAPQI after a paracetamol overdose?
NAPQI therefore remains in its toxic form in the liver and reacts with cellular membrane molecules
70
What can paracetamol overdose result in?
Widespread hepatocyte damage and death, leading to acute liver necrosis
71
What is the first treatment considered for a paracetamol overdose?
Activated charcoal should be considered if patient presents within 1 hour of ingestion of >150mg/kg paracetamol
72
What treatment is given for patients where paracetamol overdose has occurred within the last 8 hours?
You should wait until 4 hours from ingestion then measure plasma level and send for urgent analysis. Await result before deciding whether treatment is required.
73
What is given if results suggest acute liver injury from paracetamol overdose?
Double-check history of paracetamol ingestion, especially the timing, and consider treatment with intravenous N-acetylcysteine.
74
What treatment is given if a patient has taken a staggered overdose of paracetamol?
The treatment nomogram in unreliable and instead based on paracetamol levels and further blood tests
75
What is classed as a staggered paracetamol overdose?
Paracetamol taken over a period of more than 1 hour
76
What might be needed if damage to the liver becomes severe from a paracetamol overdose?
Liver transplant
77
What is the need for a liver transplant from a paracetamol overdose?
Low blood pH, high blood lactate, poor blood clotting, or significant hepatic encephalopathy
78
What is the prognosis of paracetamol overdose with early treatment?
Liver failure is rare and death only occurs in about 0.1% of cases
79
What is the nervous system divided into?
CNS and PNS
80
What is the CNS?
Brain and spinal cord
81
What is the PNS?
All the nerves that connect the central nervous system to the muscles and organs
82
What is the PNS divided into?
Somatic nervous system and autonomic nervous system
83
What is the somatic nervous system?
Controls skeletal muscles
84
What is the autonomic nervous system?
Further divided into the sympathetic and the parasympathetic and controls internal organs
85
What are cholinergic receptors?
Receptors on the surface of cells that bind acetylcholine (ACh)
86
What are the 2 types of cholinergic receptors?
Muscarinic and nicotinic
87
What do preganglionic and postganglionic neurons release in the sympathetic nervous system?
Different neurotransmitters
88
What do preganglionic neurons do in the sympathetic nervous system?
Release the neurotransmitter ACh, which binds to nicotinic receptors on the cell membrane of postganglionic neuron cell bodies
89
What do postganglionic neurons do in the sympathetic nervous system?
Most postganglionic neurons release the neurotransmitters adrenaline (epinephrine) and noradrenaline (norepinephrine) which bind to adrenergic receptors on the plasma membrane of the target organ cells.
90
What do preganglionic neurons do in the parasympathetic nervous system?
The ACh released by preganglionic neurons binds to nicotinic receptors on postganglionic neuron cell bodies
91
What do postganglionic neurons do in the parasympathetic nervous system?
Release ACh and it binds to the muscarinic receptors on the target organ cells
92
What are cholinergic drugs divided into?
Cholinergic agonists and antagonists
93
What are cholinergic agonists?
Drugs that mimic or enhance the action of ACh at the neuromuscular junction
94
What are the effects of cholinergic agonists?
Increases GI and GU tone, increases bronchial tone and respiratory secretions. Enhances PSNS activity
95
What are cholinergic antagonists?
Drugs that inhibit the action of ACh
96
What are the effects of cholinergic antagonists?
Blocks the ability of acetylcholine to initiate involuntary muscle movements in the lungs, GI tract and GU tract. Balances production of dopamine. Enhances SNS activity
97
What is the mechanism of direct-acting cholinergic agonists?
Mimic ACh and bind to ACh receptors
98
Give some examples of direct-acting cholinergic agonists and their therapeutic use.
Carbachol (constrict pupil)
Bethanechol (increase smooth muscle tone in GI and GU tract)
Pilocarpine (stimulate saliva secretion)
99
What is the mechanism of indirect-acting cholinergic agonists?
Inhibit enzyme AChE, increasing the concentration of ACh available at the synapse
(Reversible)
100
Give some examples of indirect-acting cholinergic agonists and their therapeutic use.
Neostigmine, Pyridostigmine (myasthenia gravis, reverse anesthesia)
Donepezil, Rivastigmine, Galantamine (boost cholinergic activity in Alzheimer’s)
101
What is the mechanism of nicotinic antagonists?
Compete with ACh for binding to the nicotinic receptor
102
Give some examples of nicotinic antagonists and their therapeutic use.
Curare, Pancuronium (relax skeletal muscles during surgery)
103
What is the mechanism of muscarinic antagonists?
Compete with ACh for binding to the muscarinic receptor
104
Give some examples of muscarinic antagonists and their therapeutic use.
Atropine, Scopolamine, Belladonna alkaloids (treat bradycardia, diarrhoea, bladder spasms; dilate bronchi, reduce secretions, dilate pupils; as sedatives, respectively)
105
What are the catecholamines?
Adrenaline and noradrenaline
106
What are adrenergic receptors?
Receptors on the surface of cells that get activated when they bind a type of neurotransmitters called a catecholamine
107
What are catecholamines involved in?
Stimulation of our organs by the sympathetic nervous system (fight or flight)
108
What type of receptor is an adrenergic receptor?
One type of G-protein coupled receptors or GPCR, because they work directly with intracellular proteins called guanine nucleotide-binding proteins or G proteins
109
What do adrenergic receptors bind to other than catecholamines?
They bind to a guanosine diphosphate or GDP molecule when they’re inactive, and to a guanosine triphosphate or GTP molecule when they’re active.
110
What are the different types of adrenergic receptors?
⍺₁, ⍺₂, β₁ and β₂
111
What do ⍺₁ adrenoreceptors do?
```
Vasoconstriction
Increased peripheral resistance
Increased blood pressure
Mydriasis
Increased closure of internal sphincter of the bladder
```
112
What do ⍺₂ adrenoreceptors do?
Inhibition of noradrenaline release
Inhibition of acetylcholine release
Inhibition of insulin release
113
What do β₁ adrenoreceptors do?
Tachycardia
Increased lipolysis
Increased myocardial contractility
Increased release of renin
114
What do β₂ adrenoreceptors receptors do?
```
Vasodilation
Decreased peripheral resistance
Bronchodilation
Increased muscle and liver glycogenolysis
Increased release of glucagon
Released uterine smooth muscle
```
115
What do α-agonists do?
Bind to α-receptors on vascular smooth muscle and induce smooth contraction and vasoconstriction, thus mimicking the effects of sympathetic adrenergic nerve activation to the blood vessels.
116
Give an example of an alpha-1 agonist.
Decongestants (phenylephrine)
117
Give an example of an alpha-2 agonist.
Centrally-acting vasodilators e.g. clonidine, ⍺-methyldopa
118
Give an example of a beta-1 agonist.
Inotropes (epinephrine, dopamine, dobutamine)
119
Give an example of a beta-2 agonist.
SABA/LABA
120
Give an example of an indirect agonist.
Cocaine
| Amphetamine
121
Give an example of an alpha-1 antagonist.
Tamsulosin
| Doxazosin
122
Give an example of an alpha-2 antagonist.
Yohimbine
123
Give an example of a beta-1 antagonist.
Selective/Non-selective beta-blockers
124
Give an example of a beta-2 antagonist.
Non-selective beta-blockers
125
What do alpha-blockers (alpha-1 adrenergic receptor antagonists) do?
Bind to and inhibit type 1 alpha-adrenergic receptors and thus inhibit smooth muscle contraction
126
What do beta lactams contain?
Beta-lactam ring in their molecular structure
127
Give some examples of beta lactams.
Penicillin derivatives, cephalosporins, monobactams and carbapenems
128
How do beta lactam antiobiotics act?
Inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls
129
What is the purpose of the peptidoglycan layer in bacteria?
Important for cell wall structural integrity, especially in gram-positive organisms, being the outermost and primary component of the wall
130
What is the most widely used group of antibiotics?
Beta lactams
131
What does vancomycin do?
Inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminal of the growing peptide chain during cell wall synthesis, resulting in inhibition of the transpeptidase, which prevents further elongation and cross-linking of the peptidoglycan matrix
132
What do polymyxins target?
Outer membrane of gram-negative bacteria
133
How do polymyxins work?
Because of an electrostatic interaction occurring between the α,γ-diaminobutyric acid (Dab) residue of the positively charged polymyxin on one side and the phosphate groups of the negatively charged lipid A membrane on the other side, divalent cations (Ca2+ and Mg2+) are displaced from the negatively charged phosphate groups of membrane lipids. The lipopolysaccharide (LPS) is therefore destabilized, consequently increasing the permeability of the bacterial membrane, leading to leakage of the cytoplasmic content and ultimately causing cell death
134
Explain the endotoxin effect of polymyxins.
The endotoxin of gram-negative pathogens corresponds to the lipid A portion of the LPS; polymyxins have the ability to bind to and neutralize this LPS molecule released during cell lysis. Finally, another mode of action of the polymyxins is the inhibition of vital respiratory enzymes (inhibition of type II NADH-quinone oxidoreductases [NDH-2]) in the bacterial inner membrane
135
Which antibiotics interfere with folic acid synthesis?
Sulfonamides and trimethoprim
136
Which bacteria do quinolones treat?
Wide variety of gram-negative and gram-positive bacterial infections
137
Why is quinolone usage threatened?
Rising occurrence of resistance, which has been observed in every species that is treated by this drug class
138
How do quinolones work?
Quinolone antibiotics inhibit DNA synthesis by targeting two essential type II topoisomerases, DNA gyrase and topoisomerase IV, into toxic enzymes that fragment the bacterial chromosome
139
How does rifampicin work?
inhibits bacterial DNA-dependent RNA synthesis by inhibiting bacterial DNA-dependent RNA polymerase and is used as part of the RIPE regime for the treatment of TB
140
Which antibiotics interfere with nucleic acid synthesis?
Sulfonamides
Trimethoprim
Quinolones
Rifampicin
141
Which antibiotics interfere with protein synthesis?
Macrolides
| Tetracyclines
142
How do macrolides work?
Inhibit bacterial protein biosynthesis, and they are thought to do this by preventing peptidyltransferase from adding the growing peptide attached to tRNA to the next amino acid (similarly to chloramphenicol) as well as inhibiting bacterial ribosomal translation
143
How do tetracyclines work?
Inhibit bacterial protein synthesis by preventing the association of aminoacyl-tRNA with the bacterial ribosome and are used to treat both gram-positive and gram-negative bacterial infections
144
Give some examples of penicillins.
Penicillin V/G
Amoxicillin
Ampicillin
Piperacillin/Tazobactam (Tazocin)
145
Give some examples of macrolides.
Clarithromycin
| Azithromycin
146
Give some examples of tetracyclines.
Doxycycline
147
Give some examples of cephalosporins.
Cefuroxime
| Cephalexin
148
Give some examples of quinolones.
Ciprofloxacin
149
What are the 2 different types of NSAIDs?
Non-selective NSAIDs
| COX2-selective NSAIDs
150
What are non-selective NSAIDs?
Competitive reversible inhibitors of COX1 and 2
151
What are COX2-selective NSAIDs?
Selectively inhibit COX2 therefore have a different side effect profile
152
Give some examples of non-selective NSAIDs.
Diclofenac
Ibuprofen
Naproxen
153
Give some examples of COX2-selective NSAIDs.
Celecoxib
| Rofecoxib
154
What is the role of the cyclooxygenase (COX) enzyme?
Converts arachidonic acid into thromboxanes, prostaglandins, and prostacyclins
155
What is the role of thromboxanes?
Platelet adhesion
156
What is the role of prostaglandins?
Vasodilation, increase the temperature set-point in the hypothalamus, and play a role in anti-nociception
157
What does aspirin do?
Irreversibly inhibits COX-1 and modifies the enzymatic activity of COX-2
158
What is the role of COX-1?
Gets constitutively expressed in the body, and it plays a role in maintaining gastrointestinal mucosa lining, kidney function, and platelet aggregation
159
What is the role of COX-2?
Is not constitutively expressed in the body, and instead it inducibly expresses during an inflammatory response
160
What do NSAIDs inhibit?
Most of the NSAIDs are nonselective and inhibit both COX-1 and COX-2
161
When should a COX-2 selective NSAID be used?
Because COX-1 is the prime mediator for ensuring gastric mucosal integrity and COX-2 is mainly involved in inflammation, COX-2 selective NSAIDs should provide anti-inflammatory relief without compromising the gastric mucosa
162
What effects does aspirin have in addition to being anti-inflammatory?
Anti-platelet effects
163
How does aspirin work?
Aspirin irreversibly inhibits COX-1/2 = Decreased Thromboxane A2 = Decreased Platelet Aggregation = Increased Bleeding time
164
How does clopidogrel work?
The thienopyridine derivatives are metabolised in the liver to active compounds which covalently bind to the adenosine phosphate (ADP) receptor on platelets and dramatically reduce platelet activation
165
How does ticlodipine work?
The thienopyridine derivatives are metabolised in the liver to active compounds which covalently bind to the adenosine phosphate (ADP) receptor on platelets and dramatically reduce platelet activation
166
How does dipyridamole work?
Inhibits phosphodiesterase, which inactivates cyclic AMP . It also stimulates prostacyclin release and inhibits thromboxane A2 formation, like aspirin. This leads to decreased platelet aggregation and vasodilation
167
Give some examples of anti-platelet drugs.
Aspirin
Clopidogrel, ticlodipine (thienopyridine derivatives)
Dipyridamole
168
What is the purpose of anti-coagulants?
Act at different points within the coagulation cascade to prolong clotting time.
169
What is the purpose of the coagulation cascade?
Stabilise the platelet plug with a fibrin mesh
170
What happens in the coagulation cascade?
Two pathways, intrinsic and extrinsic, originate separately but converge at a specific point, leading to fibrin activation
171
Give somme examples of direct inhibitors of factor Xa.
Apixaban
Rivaroxaban
Betrixaban
Edoxaban
172
What are the side effects of direct inhibitors of factor Xa?
Bleeding (no reversal agent)
173
What does heparin do?
Activates antithrombin (decreased thrombin and factor Xa)
174
What is a commonly used LMWH?
Dalteparin
175
What does dalteparin do?
Activates antithrombin (decreased factor Xa) and have longer half-life
176
How do you monitor use of heparin?
Monitor using anti-factor Xa assay
177
What are the side effects of heparins?
Bleeding, heparin-induced thrombocytopenia, osteoporosis
178
How does warfarin work?
Decreased FII (prothrombin)/VII/IX/X and Protein C/S
179
What are the vitamin K dependent clotting factors?
The vitamin K dependent clotting factors can be remembered by 1972 – with the 1 standing for factor X, and then 9, 7 and 2
180
What is prothrombin time?
Blood test that measures how long it takes blood to clot
181
What is INR (international normalised ratio)?
Calculation based on the results of a prothrombin time that is used to monitor individuals being treated with blood-thinners
182
What are the side effects of warfarin?
Bleeding, Skin/Tissue Necrosis, Teratogenic
183
How are the side effects of warfarin reversed?
Vitamin K
184
What does warfarin increase?
International Normalised Ratio/ prothrombin time
185
Give some examples of thrombolytics.
Alteplase/Tenecteplase (tPA), Streptokinase
186
How do thrombolytics work?
Activate Plasminogen, which forms the cleaved product Plasmin. Increased PT
187
What is plasmin?
Plasmin is a proteolytic enzyme that is capable of breaking cross-links between fibrin molecules, which provide the structural integrity of blood clots
188
What are the side effects of thrombolytics?
Bleeding
189
What are diuretics used to treat?
These are indicated for the treatment of hypertension and oedema often caused by ischaemic heart disease or chronic kidney disease
190
How do loop diuretics work?
These act at the ascending limb of the loop of Henlé and reversibly inhibit the Na/K/Cl cotransporter, inhibiting the reabsorption of filtered sodium and chloride ions. This reduces the hypertonicity of the renal medulla, thus inhibiting water reabsorption by the collecting ducts
191
Give some examples of loop diuretics.
Bumetanide (Bumex), Ethacrynic acid (Edecrin), Furosemide (Lasix), Torsemide
192
What is the most commonly prescribed loop diuretic?
Furosemide
193
What are the side effects of furosemide?
Dizziness, electrolyte imbalance, fatigue and headache
194
What are thiazide diuretics prescribed for?
Hypertension and heart failure, as well as nephrogenic DI
195
How do thiazide diuretics work?
Inhibiting reabsorption of sodium and chloride ions for the distal convoluted tubule by blocking the thiazide-sensitive Na-Cl symporter. This also means the reabsorption of water is also inhibited, as water follows sodium
196
Give some examples of thiazide diuretics.
Clorothiazide and bendroflumethiazide
197
What are the common side effects of thiazide diuretics?
Alkalosis hypochloraemic; diarrhoea; hyperglycaemia and hyperuricaemia
198
What is spironolactone used to treat?
heart failure, hyperaldosteronism, hypertension, and nephrotic syndrome
199
What are the common side effects of spironolactone?
Drowsiness, dizziness, nausea, vomiting
200
What are the severe side effects of spironolactone?
Hyperkalaemia and anti-androgen effects, e.g. gynaecomastia, loss of libido, erectile dysfunction
201
How does spironolactone work?
Within the collecting tubules of the nephron, spironolactone binds competitively to the aldosterone receptor (AR) at the aldosterone-dependent sodium-potassium exchange site. This promotes sodium and water excretion and potassium retention
202
What is affinity?
Describes how well a ligand binds to the receptor
203
What is intrinsic activity?
Emax of partial agonist ÷ Emax of full agonist
204
What are partial agonists?
Partial bind/activation at receptor
205
Give an example of a partial agonist.
Buprenorphine for opiod addiction
206
Give an example of an agonist.
Alcohol and benzodiazepine at GABA A receptor
207
What does a competitive antagonist do?
Instead they reverse the effects of agonists by competing with the agonist to bind (but not activate) receptors thereby preventing agonist from having an effect
208
What happens to the dose curve by adding a competitive antagonist?
The dose response curve shifts to the right thereby meaning more agonist is required to illicit the same response
209
What does a non-competitive antagonist do?
Binds near the receptor and prevents activation of it but does not bind directly to it so the agonist is still able to bind but just not activate the receptor
210
What happens to the dose curve by adding a non-competitive antagonist?
It results in a shift right & down of the dose response curve thereby meaning even more agonist is required to illicit the same response
211
What is the agonist for muscarinic ACh receptors?
Muscarine
212
What is the agonist for nicotinic ACh receptors?
Nicotine
213
What is the antagonist for muscarinic ACh receptors?
Atropine
214
What is the antagonist for nicotinic ACh receptors?
Curare
215
What is the agonist for histamine receptors?
Histamine
216
What happens when histamine binds to histamine receptors?
- Contraction of the ileum
| - Acid secretion from parietal cells
217
What is the antagonist for histamine receptors?
Mepyramine
218
What is specificity?
No compound is every truly specific. Selectivity is better term to describe activity
219
What happens when mepyramine binds to histamine receptors?
- Reversed contraction of ileum
| - No effect on acid secretion
220
Give an example of selective and non-selective agonists.
Isoprenaline is a NON-SELECTIVE B-adrenoceptor agonist so it activated both B1 (heart) & B2 (lungs) receptors
- Whereas salbutamol is a SELECTIVE B2-adrenoceptor agonist, but at very high concentrations it loses its specificity so will activate both B1 and B2
221
How do you calculate clearance?
Rate of appearance in urine ➗ Plasma concentration
222
What is renal blood flow?
18% of cardiac output = 1L/min
223
What is renal plasma flow?
60% of blood flow = 600mls/min
224
What is glomerular filtration?
12% of renal blood flow = 130mls/min
225
What are first order reactions?
Rate is directly proportional to the concentration of drug (rate ∝ [drug])
226
What are second order reactions?
Rate is directly proportional to the square of the concentration of the drug (rate ∝ [drug]2)
227
What are third order reactions?
Rate is directly proportional to the cube of the concentration of the drug (rate ∝ [drug]3)
228
What are zero order reactions?
Rate is unrelated to the concentration of the drug (rate ∝ [drug]0)
229
What are the 3 compartments of the body according to pharmacokinetic theory?
Plasma (5 litres), Interstitial (15 litres) & Intracellular (45 litres)
230
What affects aspirin uptake?
Gastric pH
231
What does a raised gastric pH do to aspirin uptake?
A raised pH results in the reduced uptake of aspirin from the stomach and thus a reduction in bioavailability
232
Which compartment are proteins/large molecules active in?
Proteins/large molecules are only active in the plasma compartment (5L)
233
Which compartment are water soluble molecules active in?
Water soluble molecules are active in plasma and interstitial compartment
(5L + 15L)
234
Which compartment are lipid soluble molecules active in?
Lipid soluble molecules are only active in the intracellular fluid (45L)
235
How do you calculate volume of distribution?
Volume of distribution = Total amount of drug in body ➗ Concentration of drug in plasma
236
What is volume of distribution?
It is the volume (litres) that the drug would occupy if it was distributed through all the compartments as if they were all plasma
237
What is elimination?
The elimination of a drug is from the plasma compartment
238
What is clearance?
The removal of drug from the plasma by either liver or kidney is CLEARANCE
- The volume of plasma that can be completely cleared of drug per unit time (mls minute-1 (ml/min))
- The rate at which plasma drug is eliminated per unit plasma concentration (mls minute-1 (ml/min))
239
What is hepatic blood flow?
Hepatic blood flow is 24% of cardiac output (3/4 from portal vein and 1/4 from hepatic artery)
240
What is hepatic extraction ratio (HER)?
The proportion of drug removed by one passage through the liver
241
When does liver failure affect drug metabolism?
There is minimal effect on drug metabolism until at least 70% of functioning liver is lost
242
Which drugs have active metabolites?
- Prednisone
- Isosorbide dinitrate - Codeine
- Diamorphine
- L-dopa
- Cortisone
- Morphine
243
What are the adverse effects of muscarinic agonists?
- Diarrhoea
- Urination
- Miosis (excessive pupil constriction)
- Bradycardia
- Emesis (vomiting)
- Lacrimation (tears)
- Salivation/sweating
- Remember by DUMBELS!
244
What does the parasympathetic nervous system do?
* Acetyl choline
* Rest & digest
* Constricts pupils
* Stimulates tears
* Stimulates salivation
* Lowers heart rate
* Reduces respiration
* Constricts blood vessels
* Stimulates digestion
* Contracts bladder
245
What does the sympathetic nervous system do?
```
Noradrenaline
• Fight or flight
• Dilates pupil
• Inhibits tears
• Inhibits salivation
• Activates sweat glands
• Increases heart rate
• Increases respiration
• Inhibits digestion
• Release of adrenaline
• Relaxes bladder
• Ejaculation in males
```
246
How is adrenaline synthesised?
TYROSINE > DOPA > dopamine > noradrenaline > adrenaline
247
What are the effects of alpha-1 adrenoreceptors?
- Vasoconstriction
- Pupil dilation
- Bladder contraction
248
What are the effects of alpha-2 adrenoreceptors?
Presynaptic inhibition of noradrenaline (negative feedback) i.e. when blood sugar is low then alpha-2 in pancreas will be stimulated to reduce noradrenaline release thereby reducing insulin levels being released from the pancreas
249
What are the effects of beta-1 adrenoreceptors?
- Increased force of heart contraction (positive inotropic
effect)
- Increased heart rate
- Increased electrical conduction in heart
- Increased renin release from kidney
- Increased blood pressure
250
What are the effects of beta-2 adrenoreceptors?
- Bronchodilation
- Vasodilation
- Reduced GI motility
251
What are the effects of beta-3 adrenoreceptors?
- Increased lipolysis
| - Relaxation of bladder
252
What do adrenergic agonists target?
* Blood vessels (Alpha-1)
* Heart (Beta-1)
* Bronchial smooth muscle (Beta-2)
253
What are the effects of adrenergic agonists?
* Vasoconstriction (Alpha-1)
* Positive inotropic effect (Beta-1)
* Bronchodilation (Beta-2)
254
What is pain?
Unpleasant sensory and emotional experience associated with actual or potential tissue damage
255
What is the positive role of pain?
* Warning of tissue damage
* Immobilisation for healing
* Protection of the species: establishment of memory
256
What are the physiological effects of pain?
* Increased heart rate
* Increased blood pressure
* Increased respiratory rate
257
What is chronic pain?
Ongoing persistent pain greater than 3-6 months
258
Summarise adverse drug reactions (ADRS)
* A - Augmented
* B - Bizarre
* C - Chronic
* D - Delayed
* E - End of use
259
How do you identify the type of ADR?
- Is there a history of allergy? - Type B (Bizarre)
- Is it predictable from the mechanism of action? Does it seem
dose-related? - Type A (Augmented)
- Has the patient been using the medication for a long time? - Type C (Chronic)
- Is the patient withdrawing from a medicine? - Type E (End of Use)
- Has the patient uses a drug in the past that could be causing a problem now? - Type D (Delayed)
260
What is mast cell degranulation?
Cross linking of IgE receptors releasing:
- Histamine
- Thromboxanes, prostaglandins
- Tumour Necrosis Factor (TNF)
261
What are the main clinical features of anaphylaxis?
• Exposure to drug, immediate rapid onset
• Rash withe characteristic blotches
• Swelling of lips, face, oedema, central
cyanosis (go blue/purple)
• Wheeze
• Hypotension (Anaphylactic shock)
• Cardiac arrest
262
What is the alternative presentation of anaphylaxis?
* Cardiorespiratory arrest
| * NO SKIN CHANGES!
263
What markers should be identified if an ADR is suspected?
• Type A : Serum concentration - plasma monitoring
• Type B:
- Tryptase - released from only mast cells - BEST TEST TO CONFIRM ALLERGY BASED ADR
- Urine Methylhistamine - breakdown product of histamine
264
What are the drug risk factors for drug interactions?
- NARROW therapeutic index
- Steep dose/response curve
- Saturable metabolism - e.g. paracetamol and alcohol are metabolised at a SET RATE
265
Give some examples of drugs that are weak acids.
```
• Aspirin - try to alkalinise urine to help increase excretion
with aspirin overdose
• Ibuprofen
• Paracetamol
• Warfarin
```
266
Give some examples of drugs that are weak bases.
* Amphetamine
* Atropine
* Propranolol
* Salbutamol
267
How long are fluids discontinued for after surgery?
Nil by mouth policy for fluids is 2 hours - due to fear of aspiration under anaesthesia
268
What antagonist is given to reverse overdose?
Naloxone
269
How much of an oral drug is the equivalent to it parentally?
10mg orally is equivalent to 5mg parenterally (sub-cutaneous, intramuscular & IV)
270
What do you administer to a patient with opioid induced respiratory depression?
Administer naloxone - IV is fastest route - 400 micrograms per ml
271
What is gate control theory?
- There is a balance of activity between large (A beta fibres) and
small (A delta fibres & C fibres) fibres
- Interneurons of the substansia gelatinosa regulate the input in
Lamina V (dorsal horn of spinal cord)
- If A beta fibres are NOT stimulated by nociceptive stimulus then the pain signal goes through to the brain and is perceived
- If A beta fibres ARE stimulated then the pain signal is halted and does not reach the brain and is thus not perceived
- This means that low intensity stimulation of the skin or peripheral nerves or vibration in order to stimulate the A beta fibres will generate analgesia
272
What are the applications of gate control theory?
* Rubbing site of injury
* Application of heat
* TENS - trans cutaneous nerve stimulation of A beta fibres
* Spinal cord stimulaiton
273
What is adrenaline used for?
* Anaphylaxis - reduced blood pressure & increased bronchoconstriction
* Cardiac arrest
* Acute hypotension
274
What type of drug is adrenaline?
Non-selective since it works at any alpha or beta adrenoceptor
275
Give some examples of selective adrenergic alpha-1 agonists.
Phenylephrine & Oxymetazoline
276
What do phenylephrine and oxymetazoline do?
• Results in vasoconstriction
• Useful as a nasal decongestant since vasoconstriction results in
less fluid leakage from vessels
277
Give some examples of selective adrenergic alpha-2 agonists.
Clonidine
278
What does clonidine do?
It inhibits noradrenaline release therefore is useful as an anti-hypertensive
279
What does dobutamine do?
Have a positive inotropic effect in the heart thus increase force of heart contraction
280
Give some examples of selective adrenergic beta-1 agonists.
Dobutamine
281
Give some examples of selective adrenergic beta-2 agonists.
Salbutamol
282
What does salbutamol do?
Results in bronchodilation
283
Give some examples of selective adrenergic beta-3 agonists.
Mirabegron
284
What does mirabegron do?
Results in the relaxation of the bladder
285
What does tamulosin do?
Relaxes bladder neck, thus aids in urination, useful in men with enlarged prostates who find it difficult to urinate
286
What does doxazosin do?
Is a vasodilator, thus reduces blood pressure i.e. is an anti-hypertensive
287
Give some examples of adrenergic alpha-2 antagonists.
Yohimbine
288
What does yohimbine do?
Blocks alpha-2 receptor meaning noradrenaline inhibition DOES NOT OCCUR leading to an increase in noradrenaline and other catecholamines such as dopamine
289
What do adrenergic beta-1 antagonists do?
- Results in a reduction in cardiac output as well as a reduction in renin thus a reduction in blood pressure
- Useful in treating hypertension, angina and arrhythmia
290
What is propanolol?
Non-selective i.e. works on all beta receptors
291
Give some examples of beta-1 selective antagonists.
Atenolol, Metoprolol, Bisoprolol, Betaxolol
292
What is carvedilol?
A non-selective beta & alpha-1 antagonist which not only affects the heart but causes vasodilation too
293
Give some examples of ACE inhibitors.
Captopril and enalapril
294
What are ACE inhibitors?
Anti-hypertensives
295
How do ACE inhibitors do?
Work by inhibiting ACE thereby preventing the conversion of angiotensin I to angiotensin II meaning there is less angiotensin II so less bind to angiotensin receptors (AT1) resulting in reduced vasoconstriction and thus hypertension as well as less aldosterone release further reducing hypertension
296
What type of drug is enalapril?
Pro-drug - this means its ester needs to be enzymatically cleaved by esterase for the drug to be activated
297
How do captopril and enalapril work?
Both captopril and enalapril work by binding to ACE active site thereby meaning it is unable to convert angiotensin I to angiotensin II
298
What does captopril mimic?
mimic dipeptide; His & Leu
299
What does enalapril mimic?
mimics tripeptides; Phe, His & Leu
300
Give some examples of proton pump inhibitors (PPIs).
Omeprazole, lansoprazole, pantoprazole & rabeprazole
301
How are PPIs activated?
Activated in acidic (i.e. stomach) environments
302
What do PPIs do?
They act to inhibit acid secretion
303
What does prostaglandin E2 (PGE2) do?
When prostaglandin E2 (PGE2) released from chromaffin cells, binds to EP3 receptors on parietal cells, this causes a reduction in the concentration of H+ and thus acidity of the stomach by reducing the activity of the H+/K+ ATPase pump - PGE2 INHIBITS PARIETAL CELLS
304
What does histamine do to parietal cells?
When histamine released from histaminocytes, binds to H2 receptors on parietal cells, this causes the H+/K+ ATPase pump to increase activity resulting in a higher concentration of H+ being pumped into the gastric lumen thereby increasing acidity - HISTAMINE ACTIVATES PARIETAL CELLS
305
Describe how PPIs work.
PPIs act to IRREVERSIBLY INACTIVATE the proton pump (H+/K+ ATPase) resulting in a marked reduction in acidity of the stomach, thereby helping with reflux etc.
306
Give some examples of anaesthetics.
Lidocaine and procaine
307
How do local anaesthetics work?
These local anaesthetics work by interrupting axonal neurotransmission in the sensory nerves. They do this by blocking voltage dependent sodium channels thereby preventing the neurones from depolarising meaning threshold isn’t met and thus no action potential is developed to be propagated
308
Why do anaesthetics result in pain relief?
Pain isn’t transmitted to the brain to be perceived
309
Why can local anaesthetics sometimes act on muscles?
Local anaesthetics can diffuse through mucus membranes EASILY thus sometimes can act on muscles too
310
What do opioids use in order to work?
Opioid drugs simply use the existing pain modulation system - natural endorphins (endogenous morphine) and enkephalins
311
How do opioids work?
G protein coupled receptors act via second messengers
They inhibit the release of pain transmitters at spinal cord and midbrain and modulate pain perception in higher centres - euphoria - to change the emotional perception of pain
312
What do opioids block?
Descending pain transmission
313
What are the opioid receptors?
Morphine (MOP)
Delta (DOP)
Kappa (KOP)
Nociceptin opioid-like (NOP)
314
What do kappa agonists cause?
Mental depression instead of euphoria
315
What type of receptors do all the opioids used at present affect?
Morphine - MOP
316
Where are opioid receptors found?
Midbrain
• Spine
• GI tract - can get constipated with opioid use
• Breathing centre - it communicates using opioid receptors, opioid use can cause respiratory depression
317
What are the relative potencies of morphine, diamorphine and pethidine?
- Diamorphine - 5mg (twice as potent as morphine)
- Morphine - 10mg
- Pethidine - 100mg (10 times weaker than morphine)
318
Give some examples of opioids.
```
Morphine
Diamorphine
Pethidine
Methadone
Oxycodone
Codeine
Fentanyl
Hydrocodone
```
319
What are the naturally occurring opioids?
* Morphine
| * Codeine (weak)
320
What are the synthetic opioids?
* Pethidine
* Fentanyl (very potent)
* Alfentanil (very potent)
* Remifentanil (very potent)
321
Which opioid is a synthetic partial agonist?
Buprenorphine - if overdose there is no respiratory depression
322
What are the side effects of opioids?
- Respiratory depression
- Sedation
- Nausea & Vomiting
- Constipation
- Itching
- Immune suppression
- Endocrine effects
