Pharmacology Flashcards
1
Q
What is the therapeutic window?
A
range of drug concentrations where a clinically useful effect is exerted, but not a exerting toxic effect
2
Q
Give examples of drugs with a narrow therapeutic window
A
- Warfarin
- Aminophylline
- Digoxin
- Aminoglycosides
3
Q
What pharmacokinetic drug interactions can occur in absorption?
A
changes in gut motility
- slow down eg. morphine leads to enhanced absorption
- speed up eg. metoclopramide impairs absorption
drugs can bind to other drugs and reduce their absorption
4
Q
What pharmacokinetic drug interactions can occur in distribution?
A
compete for a common binding site
displacement of object drug by precipitant drug -> total plasma [object drug] increased transiently
5
Q
Why is the rise in [object drug] only transient after displacement by a precipitant drug?
A
increased elimination of object drug due to increased conc
6
Q
What pharmacokinetic drug interactions can occur in metabolism?
A
induction or inhibition of CYP450
7
Q
What pharmacokinetic drug interactions can occur in excretion?
A
changes in protein binding
- increases/deceases conc free drug. unbound drugs can be excreted
inhibition tubular secretion
- results in increased plasma conc
changes to urine flow/pH
- acidic urine = alkaline drugs eliminated at faster rate
- alkaline urine = acidic drugs eliminated at faster rate
8
Q
Which drug groups commonly contribute to drug-frug interactions?
A
- Anticonvulsants
- Anticoagulants
- Antidepressants
- Antibiotics
- Antiarrhythmics
9
Q
What effects does induction of CYP450 enzymes have?
A
accelerates drug metabolism
increases toxicity of drugs that have toxic metabolites
more rapid elimination
10
Q
How does induction of CYP450 occur at a cellular level?
A
implemented by increased transcription, translation or slower degradation of CYP450
11
Q
How long does it take for induction of CYP450 to happen?
A
1-2 weeks
12
Q
Give examples of drugs that induce CYP450
A
- Phenytoin
- Carbamazepine
- Barbiturates
- Rifampicin
- Alcohol (chronic)
- Sulphonylureas and St John’s Wort
13
Q
What effects does inhibition of CYP450 enzymes have?
A
slows drug metabolism
increases action of drugs
14
Q
How long does it take for inhibition of CYP450 to happen?
A
few days
15
Q
Give examples of drugs that inhibit CYP450
A
- Omeprazole
- Disulfiram
- Erythromycin
- Valproate
- Isoniazid
- Cimetidine and ciprofloxacin
- Ethanol (acute)
- Sulphonamides
16
Q
How does cranberry affect CYP450?
A
inhibits CYP2C9
reduces clearance of warfarin
raises INR and increases risk of haemorrhage
17
Q
How does grapefruit affect CYP450?
A
inhibits CYP450
reduces clearance
eg. simvastatin
18
Q
How does renal disease cause disease-drug interactions?
A
falling GFR
reduced clearance of renally excreted drugs
19
Q
How do NSAIDs and ACEi affect the kidney?
A
reduce GFR
due to decreased blood flow
20
Q
How does hepatic disease cause disease-drug interactions?
A
reduced activity CYP450
reduced clearance of hepatically metabolised drugs
longer half lives
21
Q
How does cardiac disease cause disease-drug interactions?
A
reduced cardiac output
reduced organ perfusion
reduced hepatic and renal blood flow
reduced blood clearance
22
Q
How does hypoalbuminaemia cause disease-drug interactions?
A
higher free drug levels
increased free drug conc
increased clearance
23
Q
What is an ADR?
A
an unwanted or harmful reaction
which occurs after administration of a drug or drugs
and is suspected or known to be due to the drug
24
Q
What is an on-target ADR?
A
an ADR due to the exaggerated therapeutic effect of the drug
most likely due to increased dosing or due to factors affecting the PK or PD
includes effects on the same receptor type but found in other tissues.
25
What is an off-target ADR?
an ADR involving the drug interacting with other receptor subtypes secondarily to the one intended for the therapeutic effect.
also occurs with metabolites that can subsequently act as a toxin and Inappropriate immune responses
26
Under what circumstances are drug interactions more likely to occur?
• polypharmacy
• ignorant, inappropriate or reckless prescribing
• patients at the extremes of age
o renal and hepatic insufficiency
o comorbidities
• multiple medical problems
• use of drugs with a narrow therapeutic index
o greater risk of toxicity
• drugs used ear their minimum effective dose
o greater risk of treatment failure if metabolism increased
27
What can alter the absorption of a drug into the GI system?
```
gastrointestinal motility
splanchnic blood flow
molecular size
pH levels
presence of active transport systems
first pass metabolism
```
28
What is first pass metabolism?
any metabolism that occurs before the drug enters the systemic circulation
occurs within gut lumen, gut wall and in the liver
29
How are drugs metabolised in the gut lumen?
gastric acid
| proteolytic enzymes
30
How is drug absorption affected by the gut wall?
P-glycoprotein efflux pumps drugs out of enterocyte and back into the lumen
31
Define bioavailability
the amount of drug which reaches the systemic circulation in an unchanged form (once overcome all barriers to its absorption) relative to that if it was administered via IV.
32
what is bioavailability affected by?
```
drug preparation
intestinal motility,
food (lipid-soluble or water-soluble),
age,
first-pass metabolism.
```
therefore it varies between patients
33
What factors affect the distribution of a drug through the body?
lipophilic/hydrophilic
protein binding
also:
disease states
regional blood flow
specific receptor sites in tissues
34
If a drug is lipophilic, how does this affect it's distribution?
it will move out of the plasma into tissues with a higher lipid content
reaches all body compartments and accumulate in fat
35
If a drug is lipid-insoluble, how does this affect it's distribution?
the drug is mainly confined to the plasma an interstitial fluid
36
If a drug is not lipid soluble or is highly plasma bound, what does this mean for it's volume of distribution and plasma concentration?
low Vd
therefore plasma concentration remains high
37
If the drug can diffuse out of the plasma compartments and pass into other fluid compartments, what does this mean for it's volume of distribution and plasma concentration?
high Vd
plasma conc falls
38
If a drug is highly bound by tissue proteins, what does this mean for it's volume of distribution and plasma concentration?
Vd becomes very high
large proportion of drug removed from fluid compartments
low plasma conc
39
Why are acute increases in Vd seen in sepsis?
increased vascular permeability
40
Describe Phase 1 drug metabolism in the liver
dependent on CYP450
catabolic
produces products that are chemically active
41
Describe Phase 2 drug metabolism in the liver
anabolic
involve conjugation
less pharmacologically active and less lipid-soluble products
42
What factors determine the rate of renal excretion of drugs?
GFR
passive tubular secretion
active tubular secretion
renal blood flow
plasma protein binding
tubular urinary pH
43
Why would a drug need to be monitored?
* Zero-order kinetics
* Long half life
* Narrow therapeutic window
* High risk of drug-drug interactions
* Known toxic effects
44
How can steady state (CpSS) be calculated?
CpSS = dose rate / clearance
45
How can a loading dose be calculated?
Loading Dose (DoseL) = Vd x CpSS
46
How are acidic drugs actively secreted in the proximal tubule?
OAT
transports in negatively charged anionic form
can transport against electrochemical gradient
47
How are basic drugs actively secreted in the proximal tubule?
OCT
in their protonated cationic form
only down a electrochemical gradient
48
State some of the actions of insulin
- Activates GLUT4 to relocate to the cell membrane, to increase uptake of glucose into cells
- Inhibits glycogen breakdown and enhances uptake by liver and adipose tissue
- Stimulates fatty acid synthesis for transport as lipoproteins and inhibits lipolysis in adipocytes
- Inhibits proteolysis to reduce amino acid levels in the blood
49
What is the difference between type 1 and type 2 diabetes?
Type 1 = absolute insulin deficiency from destruction of β-cells in the pancreas; = “insulin-dependent diabetes”
Type 2 diabetes is due to insulin resistance and progressive insulin deficiency
50
What lifestyle changes can act to control diabetes a first?
```
limiting fat intake
increasing proportion of complex carbohydrates
reduction in alcohol
smoking cessation
increase exercise
```
51
Give the name of a biguanide drug
metformin
52
Describe the mechanism of action of metformin
* increasing cells sensitivity to insulin
* reduces hepatic gluconeogenesis – primary effect
* increased glucose intake and utilisation in skeletal muscle
* reduced carbohydrate absorption from the intestine
* increased fa oxidation
* reduced circulating LDLs and VLDLs
53
Describe the pharmacokinetics of metformin
```
oral administration
half-life 2-3 hours
no binding to plasma proteins
no metabolism
renal elimination
```
54
Why is metformin the first line therapy for type 2 diabetes?
can reduce HbA1c by 2%
does not stimulate appetite
weight neutral
55
What are metformin's ADRs?
Gi disturbances
| interferes with absorption of vitamin B12 in long term
56
Why I smetformin contraindicated in patients with compromised HRH function or respiratory disease?
risk of lactic acidosis
| reduced tissue perfusion
57
Give an example of a sulphonylurea
gliclazide
58
Describe the mechanism of action of sulphonylureas
bind to and antagonise β-cells' K+-ATP channel activity,
increases K+ concentration within the cell
leads to depolarisation.
increases Ca2+ ion entry into the cell
increases insulin release from β-cells.
59
Describe the pharmacokinetics of sulphonylureas
oral
bind to albumin - 99% affinity
metabolised in liver
excreted by kidneys
60
Why are sulphonylureas contraindicated in pregnancy?
can cross placenta and enter breast milk
61
Describe the ADRs of sulphonyureas
hypoglycaemia
stimulate appetite
weight gain
62
Give the names of two thiazolidinediones
Rosiglatazone
| pioglatizone
63
Describe the mechanism of action of thiazolidinediones
agonistically bind to nuclear hormone receptor site the peroxisome proliferator-activated receptor-γ or PPAR- γ (mainly found in adipose tissue, but also in muscle and liver)
Activation of PPARγ regulates the transcription of several insulin responsive genes
results in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle
There is differentiation of adipocytes, increased lipogenesis and increased uptake of fatty acids and glucose. It also promotes amiloride sensitive sodium ion reabsorption, which leads to fluid retention.
64
Describe the pharmacokinetics of thiazolidinediones
```
oral
rapidly absorbed
99% albumin affinity
metabolised by CYP450
pioglatizone eliminated in bile
rosiglatoazobe renal elimination
```
65
Describe the ADRs of thiazolidinediones
liver toxicity
weight gain - increase in subcutaneous fat
fluid retention
osteopenia and increased fracture risk
66
State the mechanism of action of acarbose
reversibly Inhibits intestinal α glucosidase.
delays carbohydrate absorption from gut
reducing increase in blood glucose after a meal.
67
Describe the pharmacokinetics of acarbose
oral
poorly absorbed
metabolised by intestinal bacteria
some of the metabolites are absorbed and excreted into the urine
68
Describe the ADRs of acarbose
flatulence, loose stools and diarrhoea, abdominal pain and bloating
69
Describe the mechanism of action of Glucagon-like Peptide 1 (GLP1) Analogues
lowers blood glucose after a meal by:
increasing insulin secretion, -> increases peripheral glucose uptake
supressing glucagon secretion -> reduced hepatic glucose output
slowing gastric emptying.
So:
They reduce food intake and are associated with weight loss. They reduce hepatic fat accumulation.
70
Describe the pharmacokinetics of Glucagon-like Peptide 1 (GLP1) Analogues
SC twice daily
71
Describe the ADRs of Glucagon-like Peptide 1 (GLP1) Analogues
hypoglycaemia
| gastrointestinal effects
72
Describe the mechanism of action of Dipeptyl-peptidase 4 (DPP4) Inhibitors
competitively inhibit DPP-4 - normally responsible for breakinf down GLP-1
increases endogenous GLP-1 concentration after eating.
GLP-1 stimulates insulin secretion
weight neutral
73
Describe the pharmacokinetics of Dipeptyl-peptidase 4 (DPP4) Inhibitors
oral
well absorbed
Saxagliptin metabolised by CYP450 to active metabolite
renal excretion
74
Describe the ADRs of Dipeptyl-peptidase 4 (DPP4) Inhibitors
nasopharyngitis
headache
Although infrequent, pancreatitis
75
How is gradation of glycaemic control achieved using exogenous insulins?
variation in pharmaceutical preparation
| single amino acid substitutions
76
Describe a 'pre-mixed' insulin regime
injected twice a day, with morning and evening meals
| mixture of short and long acting insulin
77
Describe a Basal Bolus insulin Regimen
intermediate/long lasting insulin to provide a basal level that extends overnight.
supplemented with short acting insulin injected with meals to provide acute response,
This involves injecting around 5 times a day yet does provide good flexibility and better control
78
Describe the action of short-acting insulin
onsets around 30min after injected
peak around 2-5h after injections
can be given just before a meal.
79
Describe the action of intermediate-acting insulin
onsets around 2h after injected
peak around 4-10h after injection
can be given as basal control
80
Describe the action of long-acting insulin
onsets around 5h after injected
peak around 8-30h after injection
can be given as basal control
81
Describe the treatment steps in type 2 diabetes
lifestyle
metformin
HbA1c >7% = sulphonylureas
HbA1c >7.5% = TZDs/insulin
82
What needs to be monitored during diabetes treatment?
```
glycaemic levels
dietary habit
HbA1c
renal function
hepatic function
neurological function
cardiovascular function
```
83
State an anti-obesity lipase inhibitor drug
Orlistat
84
Describe the mechanism of action of orlistat
inhibits gastric and pancreatic lipase
decreases the breakdown of dietary fat
decreases fat absorption by about 30%. T
The loss of calories from decreased absorption of fat is the main cause of weight loss.
85
Describe the pharmacokinetics of orlistat
oral
minimal systemic absorption
mainly excreted in the faeces
86
Describe the ADRs of orlistat
```
oily spotting,
flatulence with discharge,
fecal urgency,
increased defecation
Pancreatitis
liver injury
interferes with the absorption of fat-soluble vitamins and β-carotene, as well as some drugs
```
87
State the names of some short-acting insulin drugs
Actrapid,
Humulin S,
Novorapid
88
State the names of some intermediate-acting and long-acting insulin drugs
Insulin Glargine,
| Isophane insulin
89
What is the method of administration of insulin?
Subcutaneous injection
90
What levels should cholesterol, LDLs and HDLs be at?
Total cholesterol 5.0mmol/L or below
Fasting LDL 3mmol/L or below
HDL 1.2mmol/L or above
91
Give two examples of a statins
Simvastatin
| Atorvastain
92
What is the mechanism of action of statins?
Inhibit HMG-CoA reductase in hepatocytes
Decreases hepatic cholesterol synthesis
Up regulates LDL receptor synthesis
Increases LDL clearance from plasma into hepatocytes
Reduce LDL
93
Give an example of a cholesterol lipase inhibitor
Ezetimibe
94
Describe the mechanism of action of ezetimibe
Blocks cholesterol transport protein NPC1L1 in brush border of intestine
Inhibits intestinal cholesterol uptake
Reduces dietary cholesterol reaching liver
Up regulates LDL transporter expression
Reduces circulating Cholesterol levels
NB does not affect absorption of fat soluble vitamins, TAGs or bile acids
95
Describe the pharmacokinetics of cholesterol lipase inhibitors
Metabolised in brush border to active metabolite
Repeated enterohepatic circulation
Slowly eliminated
96
Describe ADRs of cholesterol lipase inhibitors
Abdominal pain
Diarrhoea
Head aches
97
Give an example of a fibrate
Bezafibrate
98
Describe the mechanism of action of fibrates
Stimulate PPAR-alpha (Peroxisome proliferator-activated receptor-alpha)
Increases production of lipoprotein lipase
Increases hepatic LDL uptake
Lowers TAGs
Slightly Lowers LDL and raises HDL
99
Give examples of the ADRs of fibrates
Rhabdomyolysis resulting in AKI
GI upsets
Rash
Pruritis
100
What is the mechanism of action of nicotinic acid?
Inhibits hepatic VLDL secretion
Reduces circulating triglyceride and LDL
Raises HDL
101
What are the ADRs of nicotinic acid?
Flushing
Palpitations
GI disturbance
102
What levels should cholesterol, LDLs and HDLs be at?
Total cholesterol 5.0mmol/L or below
Fasting LDL 3mmol/L or below
HDL 1.2mmol/L or above
103
Give two examples of a statins
Simvastatin
| Atorvastain
104
What is the mechanism of action of statins?
Inhibit HMG-CoA reductase in hepatocytes
Decreases hepatic cholesterol synthesis
Up regulates LDL receptor synthesis
Increases LDL clearance from plasma into hepatocytes
Reduce LDL
105
Give an example of a cholesterol lipase inhibitor
Ezetimibe
106
Describe the mechanism of action of ezetimibe
Blocks cholesterol transport protein NPC1L1 in brush border of intestine
Inhibits intestinal cholesterol uptake
Reduces dietary cholesterol reaching liver
Up regulates LDL transporter expression
Reduces circulating Cholesterol levels
NB does not affect absorption of fat soluble vitamins, TAGs or bile acids
107
Describe the pharmacokinetics of cholesterol lipase inhibitors
Metabolised in brush border to active metabolite
Repeated enterohepatic circulation
Slowly eliminated
108
Describe ADRs of cholesterol lipase inhibitors
Abdominal pain
Diarrhoea
Head aches
109
Give an example of a fibrate
Bezafibrate
110
Describe the mechanism of action of fibrates
Stimulate PPAR-alpha (Peroxisome proliferator-activated receptor-alpha)
Increases production of lipoprotein lipase
Increases hepatic LDL uptake
Lowers TAGs
Slightly Lowers LDL and raises HDL
111
Give examples of the ADRs of fibrates
Rhabdomyolysis resulting in AKI
GI upsets
Rash
Pruritis
112
What is the mechanism of action of nicotinic acid?
Inhibits hepatic VLDL secretion
Reduces circulating triglyceride and LDL
Raises HDL
113
What are the ADRs of nicotinic acid?
Flushing
Palpitations
GI disturbance
114
What serum levels need to be checked when taking statins and why?
transaminase - risk of liver failure
| creatine kinase - risk of Myopathy and rhabdomyolysis
115
Describe the effects of drug interactions between statins and CYP inducers
decrease the plasma levels of statin
116
Describe the effects of drug interactions between statins and CYP inhibitors
increase the risk of myopathy and other side effects
117
How are statin used in primary prevention?
primary prevention of arterial disease in patients who are at high risk because of elevated serum cholesterol.
118
How are statin used in secondary prevention?
secondary prevention of MI and stroke in those who already have symptomatic atherosclerosis.
119
Describe the transport of oestrogens in the blood
most bound to albumin or sex-hormone binding globulin
| 2% travels as free hormone
120
How does oestrogen bind ot oestrogen receptors?
travels across cell membranes
| binds to nuclear receptors - ERα and ERβ
121
What effect does oestrogen binding to its receptor cause?
the oestrogen receptors form dimers once oestrogen binds
activated steroid-receptor complex interacts with nuclear chromatin
initiates hormone-specific RNA synthesis.
results in the synthesis of specific proteins that mediate physiologic functions.
122
what effect does oestrogen have on progesterone?
Oestrogens induce PR expression in endometrial cells, so act to condition the endometrium
123
Describe the ligand-receptor interactions of progesterone
Progesterone binds to the dimeric progesterone receptor, PR,
| induces secretory changes the endometrium
124
What are the effects of progesterone in females?
promotes the development of a secretory endometrium
high levels of progesterone inhibit the production of gonadotropin and, therefore, prevent further ovulation.
If conception takes place, progesterone continues to be secreted, maintaining the endometrium and reducing uterine contractions.
increases bone density
fluid retention
125
What are the side effects of progesterone?
- Weight gain
- Fluid retention
- Acne
- Nausea and vomiting
- Irritability
- Lack of concentration
headache
depression
increased risk breast cancer
126
What are the systemic effects of oestrogen in females?
- Mild anabolic
- Sodium and water retention
- Raise HDL, lower LDL
- Decrease bone reabsorption
- Improve blood coagulability
127
What are the side effects of oestrogen?
- Nausea and vomiting
- Water retention and peripheral oedema
- Risk of thromboembolism and MI
- Impaired glucose tolerance
- Endometrial hyperplasia and cancer
breast tenderness
128
Describe the pharmacokinetics of oestrogen
low oral bioavailability due to first pass metabolism
hydroxylated in liver by CYP450 , then subsequently glucuronidated or sulfated.
excreted into bile and then reabsorbed through the enterohepatic circulation
Inactive products are excreted in urine
129
Describe the pharmacokinetics of progesterone
rapid absorption orally
metabolised in liver by CYP450 - glucaronidation
short half life
excreted primarily by the kidney
130
What is the COCP?
oestrogens in combination with progesterone
131
Describe the mechanism of action of the COCP
Oestrogen inhibits secretion of FSH by –ve feedback at the anterior pituitary.
This supresses follicular development in the ovary.
Progesterone inhibits secretion of LH and therefore prevents ovulation.
132
What is the difference between monophasic and triphasic COCP?
mono = dose of oestrogen and progesterone is constant in the active tablets
tri = attempt to mimic the natural female cycle and most contain a constant dose of estrogen with increasing doses of progestin given over three successive 7-day periods
133
How should COCP be taken?
The combined pill is usually taken for 21 days followed by 7 placebo pill days. This causes a withdrawal bleed.
134
What is the POP?
progesterone only pill
135
what is the mechanism of action of POP?
cause cervical mucus thickening
| preventing sperm movement into uterus
136
In which patients is POP commonly used?
offered to women for whom the COCP is contraindicated
| e.g. risk factors for venous thromboemboli, smokers, or hypertensive.
137
How is POP taken?
at the same time each day, every day
138
What are the problems with POP?
less effective than COCP
| may produce irregular menstrual cycles and spotting more frequently
139
What are the ADRs of COCP?
```
increased risk of DVT
raising blood pressure
increased risk of gall stones,
decrease glucose tolerance,
nausea,
weight gain (due to anabolic state or fluid retention)
increased risk of breast cancer
```
140
Describe the Drug interactions of COCP
CYP450 inducers (increase plasma clearance) and inhibitors (decrease plasma clearance)
141
Name some CYP450 inducers
```
PCBRAS
Phenytoin,
Carbamazapine,
Barbiturates,
Rifampicin/rifabutin,
Alcohol,
Sulphonylureas/St John’s Wort
```
142
why is the dose of oestrogen kept to a minimum?
avoid excess risk of thromboembolism
143
How do broad-spectrum antibiotics affect plasma concentration of the COCP?
reduce efficacy of COCP
the effect they have on intestinal flora will reduce their re-uptake into the circulation (by lowering enterohepatic recycling)
144
What is the menopause?
cessation of menstrual periods
145
What is the perimenopause?
time shortly before the occurrence of the menopause
146
Why are sex steroids given in menopause?
to reduce the symptoms of the menopause
| and to prevent osteoporosis
147
What is ERT?
just oestrogen given in menopause
148
what is HRT?
| Why could this be better than ERT?
oestrogen + progesterone.
Reduces risk of endometrial carcinoma
149
Why is history of a hysterectomy important when prescribing HRT?
For women who have an intact uterus, a progestogen is always included with the estrogen therapy, because the combination reduces the risk of endometrial carcinoma associated with unopposed estrogen.
For women who have undergone a hysterectomy, unopposed estrogen therapy is recommended because progestins may unfavourably alter the beneficial effects of estrogen on lipid parameters
150
Describe the side-effects of HRT
increased risk of stroke
increases HDLs
increased risk venous thromboembolism
decreased resorption of bone
151
What is the difference between bacteriostatic and bacteriacidal drugs?
Bacteriostatic drugs arrest the growth and replication of bacteria, limiting the spread of infection
Bactericidal drugs kill bacteria
152
What is an MIC?
Minimum inhibitory concentration
| lowest concentration of antibiotic that inhibits bacterial growth
153
What is MBC?
Minimum bactericidal concentration
lowest concentration of antimicrobial agent that results in a 99.9 percent decline in colony count after overnight broth dilution incubations
154
Which antibiotics affect DNA synthesis?
quinolones
| folic acid antagonists
155
Which antibiotics affect protein synthesis?
aminoglycosides
macrolides
tetracyclines
156
Which antibiotics affect cell wall synthesis?
beta-lactams - (penicillins and cephalosporins)
| glycopeptides
157
Give some examples of penicillins
Penicillin,
Amoxicillin,
Flucloxacillin,
Co-amoxiclav
158
Describe the mechanism of action of penicillins
bind to penicillin binding proteins in peptidoglycan cell wall
inhibit transpeptidation enzyme that cross-links peptidoglycan chains
inactivates inhibitor of autolytic enzymes
cell lysis occurs
bacteriacidal
159
Describe the antibacterial spectrum of penicillins
gram positive microorganisms have cell walls that are easily traversed by penicillins so are susceptible
Gram-negative microorganisms have an outer LPS envelope surrounding the cell wall that acts as a barrier to the water-soluble penicillins.
BUT gram-negative bacteria have proteins inserted in the lipopolysaccharide layer that act as water-filled channels (called porins) to permit transmembrane entry
160
How is the GI absorption of penicillins affected by food?
most incompletely absorebed
BUT amoxicillin almost completely absorbed
absorption decreased by food in the stomach, because gastric emptying time is lengthened, and the drugs are destroyed in the acidic environment
administered 30 to 60 minutes before meals or 2 to 3 hours postprandial.
161
How are penicillins excreted?
```
organic acid (tubular) secretory system
glomerular filtration.
```
162
State the ADRs of penicillins
hypersensitivity
diarrhoea
nephritis
neurotoxicity
163
Name some cephalosporins
Cefaclor,
Cefotaxime,
Aztreonam
164
Describe the mechanism of action of cephalosporins
bind to penicillin binding proteins in peptidoglycan cell wall
inhibit transpeptidation enzyme that cross-links peptidoglycan chains
inactivates inhibitor of autolytic enzymes
cell lysis occurs
bacteriacidal
165
How are cephalosporins administered?
most IV or IM
| poor oral absorption
166
Which cephalosporins are readily able to cross the BBB?
ceftriaxone
cefotaxime
therefore used in meningitis
167
How are cephalosporins excreted?
tubular secretion and/or glomerular filtration
168
Describe the ADRs of cephalosporins
hypersensitivity reactions.
Nephrotoxicity
Diarrhoea common, leading to C. diff.
169
Name some tetracyclines
Tetracycline,
Doxycycline,
Oxytetracycline
170
Describe the mechanism of action of tetracyclines
enter into organisms by passive diffusion or energy dependant transport
organism accumulates drug
binds to 30S subunit of bacterial ribosome, blocking accses of amino-acyl tRNA
prevents translation
protein synthesis inhibited
bacteriostatic
171
Describe the antibacterial spectrum of tetracyclines
broad spectrum
gram +ve
gram -ve
Mycoplasma
Chlamydia
172
Describe the pharmacokinetics of tetracyclines
```
oral
well absorbed (especially doxycycline)
cross placental barrier
metabolised in liver
excreted in bile
enterohepatic circulation
enter urine by glomerular filtration
```
173
What affects the absorption of tetracyclines in the gut?
```
form complexes with metal ions,
so absorption decreased in presence of:
dairy products
iron preparations
antacids
```
174
Can tetracyclines be given to pregnant or breast feeding women?
no
cross placenta and enter breast milk
deposited in fetal bone and teeth
175
Describe the ADRs of tetracyclines
```
irritation gastric mucosa
depostioni n frug and bones
liver failure
phototoxicity - increased risk of burning in sunlight
vertigo
```
176
Name some aminoglycosides
gentamicin
| neomycin
177
Describe the mechanism of action of aminoglycosides
orgs allow drug to enter cell
binds to 30S subunit before ribosome formation
interferes with assembly of functional ribosome
protein synthesis cannot be initiated
bactericidal
178
Describe the antibacterial spectrum of aminoglycosides
broad spectrum
some gram +ve
aerobic gram –ve
179
Describe the pharmacokinetics of aminoglycosides
IV or intrathecally
high conc in renal cortec and endolymph and perilymph of inner ear
no metabolism in host
excreted in urine by glomerular filtration
180
Describe the ADRs of aminoglycosides
ototoxicity
nephrotoxicity
paralysis
181
Can aminoglycosides be given to pregnant women?
no
crosses placenta
accumulates in fetal plasma and amniotic fluid
182
What needs to be monitored when taking aminoglycosides?
plasma concentration
183
Name some macrolides
Erythromycin,
| Clarithromycin
184
Describe the mechanism of action of macrolides
irreversibly bind to 50s subunit
inhibiting translocation in protein synthesis
bacteriostatic
185
Describe the antibacterial spectrum of macrolides
erythromycin = similar to penicillins (gram +ve and gram -ve)
clarithromycin = similar to erythromycin, but also H influenae, Chlamydia and H pylori
186
Describe the pharmacokinetics of macrolides
oral or IV
good GI absorption
erythromycin = excreted in active form in bile and partial enterohepatic circulation. inactive form by kidneys
clarithromycin eliminated by kidneys
187
Describe the drug interactions of macrolides
inhibit CYP450
188
Describe the ADRs of macrolides
GI disturbance
jaundice
ototoxicity
189
Describe the mechanism of action of vancomycin
inhibits synthesis bacterial cell wall phospholipids and peptidoglycan polymerisation
190
Describe the antibacterial spectrum of vancomycin
gram +ve orgs
MRSA
Enterococci
191
Describe the pharmacokinetics of vancomycin
IV infusion
(oral in C. diff)
eliminated by glomerular filtration
192
Describe the ADRs of vancomycin
```
fever
rashes
chills
phlebitis
ototoxicity
nephrotoxicity
```
193
What determines bacterial killing?
time
| concentration above the MIC
194
What is time-dependant killing?
major killing affect of an antibiotic depends on how long the drug is bound to the receptor
195
What is concentration-dependant killing?
major killing affect of an antibiotic depends on their concentration
196
Describe the steps of Influenza virus replication?
- Binding and adsorption, facilitated by haemagglutinin glycoprotein surface molecule
- endocytosis into the cell. ATP-driven entry into the endosome. Protons gain entry into the virus via an M2-ion channel. The fall in pH within the virus allows for the viral coat of the nucleocapsid to breakdown.
- The viral RNA is synthesised and replicated to form viral proteins. The virus is then assembled within the cell
- virus is released from the cell via budding. Neuraminidase is a glycoprotein antigen found in the viral membrane and enables the virus to leave the host cell.
197
What is the role of the Influenza protein haemagglutinin?
facilitates adhesion of virus to host cell
198
What is the role of the Influenza protein Neuraminidase?
Neuraminidase is a transmembrane viral protein which enables newly formed virions to escape from their host cell.
As the newly formed virus egresses from its host cell many re-attach to the sialic acid membrane glycoprotein residues on the cell membrane.
To get released and infect other host cells they need to break this bond. This is carried out by the viral neuraminidase.
199
What is the role of the Influenza M2 ion channel??
allows H+ ions to enter the endosome, causing the viral coat of the nucleocapsid to break down
200
Describe the differences between the Influenza virus classes
A - multiple host species, greatest severity, undergoes antigenic drift and shift
B - no animal host, low severity
C - common cold like
201
Name some M2 ion channel blockers
amantadine
| rimantadine
202
Describe the mechanism of action of M2 channel blockers
blocking the M2 channels
prevents entry of H+ into endosome
inhibits viral uncoating,
inhibits of viral replication
203
Which classes of influenza are M2 channel blockers effective in treating?
A
204
Describe the ADRs of M2 channel blockers
dizziness,
GI disturbances
hypotension,
more serious complications include confusion, insomnia and dizziness
Rimantadine causes less CNS side effects as it does not cross BBB
205
Name some neuraminidase inhibitors
zanamivir
| ostelamivir
206
Describe the mechanism of action of neuraminidase inhibitors
Neuraminidase inhibitors bind to neuraminidase and prevent newly formed virions detaching from the host cell.
207
Which classes of influenza are neuraminidase inhibitors effective in treating?
A
| B
208
Can neuraminidase inhibitors be used for prophylaxis?
Zanamivir is given as an aerosol and has low bioavailability and can only be used for treatment of an already infected patient.
Oseltamivir is a prodrug and by contrast is well absorbed, with 80% bioavailability This enables it to be given orally for both treatment and prophylaxis.
209
Describe the ADRs of neuraminidase inhibitors
GI disturbance (not zanamivir as administered orally)
headaches
nose bleed
irritation of airways - zanamivir
210
what is inflamed in RA?
synovium
211
what causes the inflammation in RA?
TH1 cells release rheumatic factor
stimulates macrophages to release I:-1 and TNFalpha
stimulates fibroblasts and osteoblasts to damage cartilage and bone by releasing metalloproteinases
212
What is the purpose of DMARDs?
to halt and reverse the underlying processes of RA
213
What is the mechanism of action of methotrexate in RA?
folic acid antagonist
inhibition of enzymes involved in purine metabolism
accumulation of adenosine within the cell.
Adenosine is released following cell injury
acts on GPCRs of inflammatory and immune cells
reduced activity of T-cells
214
how is methotrexate administered?
oral, IV or IM
215
describe the pharmacokinetics of methotrexate
50% protein bound
hepatic metabolism
renal excretion
216
Describe the ADRs of methotrexate
* Mucositis - pain and inflammation of the body's mucous membrane.
* bone marrow suppression,
* hepatitis,
* cirrhosis,
* increased infection risk
* acts as teratogenic and abortifactant
217
Describe the mechanism of action of sulfasalazine
combination of 5-aminosalicylate acid (5-ASA) and sulfapyridine
The 5-ASA is the active component in treating IBD. The sulfapyridine allows the 5-ASA to reach the intended area
inhibits T cell proliferation
inhibits IL2 productions
reduces chemotaxis and degranulation of neutrophils
218
how is sulfasalazine administered?
oral
219
Describe the ADRs of sulfasalazine
* nausea,
* fatigue,
* headaches.
* myelosuppression,
* hepatitis
* allergic rash
220
What is the mechanism of action of rituximab?
anti-lymphocyte monoclonal antibodies that cause lysis of B lymphocytes
prevents stimulation of T lymphocytes by B lymphocytes
221
What is the mechanism of action of infliximab?
antibody that binds to human TNF-α, and inhibits binding with its receptors
prevents stimulation of synovial cells to proliferate and synthesize collagenase
222
What is the mechanism of action of adalimumab?
monoclonal antibody that binds to TNF-α, blocking its binding to the surface receptors
223
How are biological DMARDs administered?
IV
adalimumab = SC
224
What are the ADRs of biological DMARDs?
hypersensitivity
infections
injection site reactions
225
How do corticosteroids affect the immune system?
IMMUNOSUPRESSION
redistribution of leukocytes to other body compartments
increase in the concentration of neutrophils
decrease in the concentration of lymphocytes (T and B cells), basophils, eosinophils, and monocytes;
inhibition of the ability of leukocytes and macrophages to respond to antigens
decreased production of prostaglandins and leukotrienes
226
Describe the pharmacokinetics of corticosteroids
90% protein bound
metabolised in liver
excreted by kidney
227
Describe the ADRs of corticosteroids
* glucose intolerance
* hypercholesterolemia,
* cataracts,
* osteoporosis
* hypertension with prolonged use
* infection risk
228
Describe the mechanism of action of azathioprine
prodrug which is metabolised to 6-mercaptopurine (6-MP) which inhibits purine synthesis
reduces DNA and RNA synthesis
lymphocytes affected as high mitotic rate
229
What are the ADRs of azathioprine?
* bone marrow suppression,
* increased risk of infection,
* emergence of malignant cell lines.
* Nausea and vomiting
230
describe the mechanism of action of Mycophenolate mofetil
potent, reversible, uncompetitive inhibitor of inosine monophosphate dehydrogenase,
blocks formation of guanosine phosphate.
deprives the rapidly proliferating T and B cells of a key component of nucleic acids
231
What is the mechanism of action of cyclophosphamide?
prodrug
metabolised by CYP450 to active form
prevents DNA replication
acts on cells with high mitotic rates
232
What are the ADRs of cyclophosphamide?
* Alopecia
* Nausea, vomiting and diarrhoea
* increased risk of bladder cancer (due to toxic metabolite to bladder epithelium produced),
* lymphoma
* leukaemia,
* infertility
* teratogenesis
233
Name some IV anaesthetic agents
Propofol
| Ketamine
234
Name some inhalational anaesthetic agents
Nitrous oxide
Isoflurane
Sevoflurane
235
What are the effects of anaesthesia?
```
Sedation
Reduction in anxiety
Lack of awareness
Amnesia
Skeletal muscle relaxation
Suppression reflexes
Analgesia
```
236
Describe the agents used and the effects of general anaesthesia
Affect whole body
Uses IV and inhalational with adjuvants
Act reversibly
Inhibits sensory, motor and sympathetic transmission
Unconsciousness
Absence of sensation
237
Describe the process of and effects of regional anaesthesia
Stops sensation in specific regions of the body
Transmission block between body part and spinal cord
Patient it conscious
Spinal and epidural anaesthesia
238
Describe the effects of local anaesthesia
Defined peripheral nerve block
Injection of anaesthetic
239
Describe dissociative anaesthesia
Inhibition of transmission of nerve impulses between higher and lower centres of brain
240
Which area of the Brain is involved in mediating unconsciousness in anaesthesia?
Thalamus
241
How is anaesthetic potency predicted?
Lipid solubility - abide it to dissolve and enter cell membranes
242
Define potency
Concentration of drug needed to give 50% maximal therapeutic effect
243
How do anaesthetics mediate their effects?
Affect post synaptic transmission at ligand gated ion channels
244
Describe the effect of anaesthetics at GABAA LGICs
Increase sensitivity to GABA
increases chloride currents
Hyperpolarises cell
Decreases excitability
245
Which channel does propofol act at?
GABAA
increases chloride current
246
Describe the action of anaesthetics at glycine LGIC
Increases sensitivity to glycine
Increases chloride current
Hyper polarisation
Decreases excitability
247
Describe the action of anaesthetics at neuronal nicotinic ACh LGIC
Reduces Na+ currents
Contributes to analgesia and amnesia
248
Describe the effect of anaesthetics at NMDA receptors
Reduces Ca2+ currents
| Altered modulation of synaptic responses
249
Which anaesthetics Mediate their response at NMDA receptors?
Nitrous oxide
| Ketamine
250
How are inhalational anaesthetics administered?
Volatile liquids at room temp
Mixed with oxygen or nitrous oxide carrier
Fed to respiratory system via mask
251
What is the minimal alveolar concentration?
End tidal conc needed to eliminate movement in 50% of patients challenged by standardised skin incision
Expressed as percentage of gas in a mixture required to achieve the effect
252
What does a low MAC value show about an anaesthetic's potency?
Low MAC = high potency
253
What is the blood:gas coefficient?
Volume of gas in litres that can dissolve in one litre if blood
Measure degree of absorption across the alveoli into the blood
254
What does a high blood:gas coefficient mean?
High b:g c means that the gas will more readily enter the blood
255
What does the distribution of anaesthetic around the body depend on?
Relative blood supply to each tissue
| Specific tissue uptake capacity
256
What is a tissue:blood coefficient?
Shows How readily the anaesthetic will move from blood to a specific tissue type
257
Describe the elimination of anaesthetics
Anaesthetic moves out of cells into blood stream as conc anaesthetic in blood drops
Well perfume tissues first - kidney, brain, liver
Then muscle
Then fat
Can leave body via alveoli or redistribute
258
What affects the duration of recovery from anaesthesia?
length if procedure
| Degree of fat and muscle loading
259
What would be included in a pre-surgical review?
```
Age
BMI
Medical and surgical history
Medication
History of drug abuse
Fasting time
Airway assessment
```
260
What pp need to be monitored during surgery?
Oxygen
Flurane
Nitrous oxide
Nitrogen
261
What physiological monitoring is carried out during surgery?
```
ECG
BP
pulse oximetry
Expired CO2 - assess ventilation rate
Core temp
```
262
Describe the induction phase of anaesthesia
Beginning of inhalational agent delivery
| IV adjuvants also given
263
Describe the maintenance phase of anaesthesia
Maintain adequate anaesthetic depth using adjuvants
| Regular adjustments made
264
Describe the recovery of anaesthesia
Agents withdrawn
| Physiological function monitored
265
State the names of the stages of anaesthesia
Stage I analgesia
Stage II excitement
Stage III surgical anaesthesia
Stage IV Medullary paralysis
266
Describe stage I of anaesthesia
Loss of pain sensation
Progression from conscious and conversational to drowsy
Amnesia
267
Describe stage II of anaesthesia
Delirium
Combative behaviour
Rise and irregularity in blood pressure and resp rate
Moderate eye movements
268
Describe stage III of anaesthesia
Gradual loss tone and reflexes
Regular resp
Muscles relax - loss of spontaneous movement
Ideal state for surgery
Careful monitoring to check do not enter stage IV
269
Describe stage IV of anaesthesia
Severe depression resp and vasomotor centres
| Death unless resp and circulation controlled
270
Name the endogenous groups of opioids
Enkephalins
Endorphins
Dynorphins
271
Name opioids uses in clinical practice
Morphine
Diamorphine
Codeine
Tramadol
272
Name the types of Opioid receptor
MOP
KOP
DOP
273
Describe the MOP receptors location
Found supraspinally
274
Describe KOP receptors location
Found spinally
275
Describe DOP receptors location
Wide distribution
276
What happens when opioids bind to an opioid receptor?
GPCR
Increase outward efflux of K+
Decrease influx Ca2+
Reduce cAMP synthesis -> reduces influx Ca2+
Fall in [Ca2+]i
Decreased release neurotransmitter at synapse
277
Describe the ADRs of opioids
```
Respiratory depression
Constipation
Drowsiness
Miosis
Nausea and vomiting
Dysphoria
```
278
How is an opiate overdose treated?
Naloxone
279
Name some class 1a anti-arrhythmic drugs
Quinolone
| Procainamide
280
Describe the mechanism of action of class 1a anti arrhythmics
Blocks Na channels that are open or inactivated
Slows phase 0 depolarisation in myocytes
Increases AP duration
Slow conduction velocity
281
What are the ADRs of class 1a anti arrhythmics?
Prolonged QT interval
Hypotension
SA and AV block
282
Name some class 1b anti arrhythmics
Lidocaine
283
Describe the mechanism of action of class 1b AA
Blocks open or inactivated sodium channels
Shortens phase 3 repolarisation
Decreases duration AP
Shortens QT
284
What are the ADRs of class 1b AA?
Drowsiness
Slurred speech
Agitation
Short QT interval
285
Name a class 1c AA
Flecainide
286
Describe the mechanism of action of class 1c AA
Blocks open or inactivated sodium channels
Slows phase 0 depolarisation greatly
No effect on AP duration
287
Describe the effect if the different class 1 AA's on the AP duration
1a - prolongs
1b - shortens
1c - no effect
288
Describe the effect of the class 1 AAs on phase 0 of the ventricular AP
1a - slows
1b - no effect
1c - slows greatly
289
When are class 1 AA used?
1a - AF, re entrant loops, ventricular tachycardia
1b - ventricular arrhythmia after MI
1c - arrhythmia
290
Name some class II AA
Propanolol
| Sotalol
291
Describe the mechanism of action of class II AA
Slows phase 4 depolarisation at SA and AV nodes
| Slows heart rate
292
What are class II AA used to treat?
Protect ventricles in AF
293
Name some class III AA
Amiodarone
| Sotalol
294
Describe the mechanism of action of class III AA
Blocks K channels
Prolongs phase 3 repolarisation
Prolongs effective refractory period
295
When are class III AA used in treatment?
AF
296
Describe the ADRs of class III AA
```
Interstitial pulmonary fibrosis
GI tract intolerance
Corneal micro deposits
Thyroid probs
Peripheral neuropathy
Hepatotoxic
Hypokalaemia
```
297
Name some class IV AA
Diltiazem
| Verapamil
298
Describe the mechanism of action of class IV AA
```
Use dependant!
Block ca2+ channels
Slow phase 4 spontaneous depolarisation
Slow conduction in AV node
Prolongs effective refractory period in AV node
```
299
When are class IV AA used?
Re entrant tachycardia
| AF
300
What are the ADRs of class IV AA
Worsen heart failure
Hypotension
Sympathetic nervous system activation
301
What is tumour compartmentation?
A way of dividing the cells of a tumour by whether they are involved in active proliferation or not
302
Describe the activity of cells in tumour compartment A
Dividing
| Receiving adequate nutrient and vascular supply
303
Describe the activity of cells in tumour compartment B
Resting
Remind in G0
Able to join compartment A if there are changes in cell signally or the local environment
Situated in middle of tumour
304
Describe the activity of cells in tumour compartment C
No longer able to divide
| Contribute to bulk of tumour
305
Which tumour compartment is most susceptible to chemo?
Compartment A - only 5-20% of tumour cells
306
Are cells in compartment B affected by chemo?
Maybe
Some RNA and protein synthesis may be happening.
BUT
Cells in G0 are not available for attack
Low effective kill ratio
307
What is a log kill ratio?
Chemo agents kill a constant fraction of cells - first order kinetics
308
What does the kill rate for cancer cells need to be balanced against in chemotherapy?
Kill rate for healthy cells
Need to secure that the kill rate does not lead to mortality
Ensure that the rate of regrowth in healthy tissues is sufficiently faster than in tumour cells
309
Name an alkylating agent
Cisplatin
310
What is the mechanism of action of alkylating agents?
Allow covalent bonds to form between DNA strands - interstrand or intrastrand
Prevents DNA replication
Prevents tumour growth
311
Name some antimetabolite chemo drugs
6-mercaptopurine
5-fluorouracil
Methotrexate
312
Describe the mechanism of action of methotrexate in chemo
Inhibits dihydrofolate reductase
Prevents formation purines
Cells unable to form DNA
313
Describe the mechanism of action of 5-fluorouracil
Activated into 5-FdUMP
Inhibits action thymidylate synthase
Prevents formation pyramidines
Reduces DNA synthesis
314
What is the overall action of antimetabolites?
Prevent formation DNA
| Prevent cell replication
315
Name some spindle poison chemo drugs
Vincristine
Vinblastine
Paclitaxel
316
State the mechanism of action of spindle poison chemo drugs
Affects spindle fibre formation during metaphase
Damages the spindle fibres
Causes cell death
Prevents excessive growth
317
Why are most chemo drugs not given orally?
Toxicity would damage GI tract
| Patient will vomit - limits practicality
318
How are most chemo drugs given?
| Why?
IV
Allows fine control
Infusion can be stopped immediately in an emergency
319
How do cells become resistant to chemotherapy?
Decreased entry of agent or increased exit
Inactivation of agents within cell
Enhanced repair of DNA lesion produced by alkylation
320
Why does acquired chemotherapy resistance happen?
Suboptimal repeat doses given
| Gives cells time to manifest response to agent
321
How can chemo resistance be prevented?
High dose
Short term Intermittent repeat
Optimal combination for tumour type
322
Why do chemo drugs cause so many ADRs
Targeted at rapidly dividing cells
| Most of GI tract, hair follicles
323
What are the common chemo ADRs
```
Nausea, vomiting, diarrhoea
Mucositis
Alopecia
Myelosupression
Impaired wound healing
Skin toxicity
```
324
Which ADR limits chemo dose?
Haematological toxicity
Most common cause of death in chemo
325
Why does acute renal failure occur during chemo?
Rapid tumour lysis releases purines into circulation
Metabolism creates urates
causes hyperuricaemia
Precipitation of urate crystals in renal tubules
326
Which chemo drugs is neuropathy seen as an ADR with?
Cisplatin
| Mitotic spindle inhibitors
327
What is monitored during chemo?
Response of the cancer
Pharmacokinetics - measuring of drug in body
Organ function deficit - heart, lungs, liver, kidney, nerves
328
What is neoadjuvant chemo?
Given before surgery
| Decrease primary tumour size
329
What is adjuvant chemo?
After surgery
| Minimises risk of relapse due to metastasis
330
What is palliative chemo?
Treat symptoms without curative intent
331
How is acid formed by the parietal cells in the stomach?
Water split to form OH- and H+
H+ enters lumen of canaliculi using H+K+ATPase
Chloride and potassium ions enter canaliculi through channels
OH- combines with CO2 to form HCO3-
HCO3- and Cl- antiporter in basolateral membrane
Creates alkaline tide
332
What stimulates the parietal cell to release more acid
Gastric distension -> Parasympathetic nervous system -> ACh
Gastrin
Histamine from enterochromaffin cells
333
What does parietal cell stimulation result in at a molecular level?
Increased intracellular calcium
Histamine activates adenylyl Cyclase, increasing cAMP
334
Describe the effect somatostatin has on parietal cells
Released from D cells in response to low pH
Bind to enterochromaffin cells
Inhibit histamine release
Decrease acid secretion from parietal cells
335
Name some H2 receptor antagonists
Ranitidine
336
Describe the mechanism of action of H2 antagonists
Block H2 histamine receptor on parietal cell
| Inhibits stimulation acid secretion
337
Describe the pharmacokinetics of H2 antagonists
Oral
| Excreted in urine
338
Describe the ADRs of H2 antagonists
Headache
Dizziness.
Diarrhoea
Muscular pain
339
Name some PPIs
Omeprazole
Lansoprazole
Esomeprazole
340
What is the mechanism of action of PPIs
Bind to H+K+ATPase of parietal cell
Irreversible inactivation
Suppress H+ secretion
341
What are the ADRs of PPI s
Vitamin B12 deficiency- acid is required for absorption
| Increased risk bone fractures - bad calcium absorption
342
What effect do PPI have on CYP450
Inhibition
343
describe the neural control of the gut motility
stimulation of post-ganglionic cholinergic enteric nerves leads to increased force of contraction
stimulation noradrenergic inhibitory nerves inhibits contractions
344
What si the enteric nervous system?
autonomic nerves within the gut wall
345
What is the intestino-intestinal inhibitory reflex?
distention of one intestinal segment causes complete intestinal inhibition
346
What is the anointestinal inhibitory reflex
distention of the anus causes itestinal inhibition
347
What is the effect of the gastrocolic and duodenocolic reflexes?
material enters stomach or duodenum
| stimulates motility
348
Describe the process of vomiting
pyloric sphincter closes
cardia and oesophagus relax
abdominal wall and diaphragm contract to propel gastric contents
glottis closes and soft palate elevate to prevent entry of vomitus into trachea and nasopharynx
349
What causes vomiting?
```
pregnancy
medications
pain
toxins
smell/touch
RICP
rotational movement
stretching of stomach
```
350
What neurotransmitters act to stimulate the vomiting centre in the medullla?
ACh
histamine -H1
dopamine - acts at postrema on floor fourth ventricle
351
Name some D2 receptor antagonists
Metoclopramide,
| Domperidone
352
Describe the mechanism of action of the D2 receptor antagonists
inhibition at postrema
353
Name a 5-HT3 antagonist
ondansetron
354
Describe the mechanism of action of 5-HT3 antagonists
5-HT released into the ut would normally ause vagal stimulation and therefore increased gut motilty
blockade decreases gut motility
355
What kind of drug is Hyoscine
ACh antagonist
| anti-emetic used in travel sickness
356
Name an H1 antagonist
cyclizine
357
How can constipation be treated non-pharmacologically?
treating underlying cause
increasing fluid intake
high fibre diet
exercise
358
Describe eh mechanism of action of bulk laxatives, such as fybogel
insoluble and non-absorbable substance
causes gut fisetion
stimulates stretch receptors
re-establish normal peristalsis
359
What is isphagula husk?
fybogel!
| bulk laxative
360
Describe the mechanism of action of senna
```
stimulant laxative
irritates mucosa
excites sensory nerve endings
decreases water and electrolyte absorption
leads to peristalsis
```
361
What are the ADRs of senna?
colonic atony
| hypokalaemia
362
Name osmotically active laxatives
Lactulose
| Macrogols - Movicol
363
Describe the mechanism of action of osmotically active laxatives
increase the amount of water in the large bowel,
| either by drawing fluid from the body into the bowel or by retaining the fluid they were administered with.
364
Describe the mechanism of action of lactulose
cannot be hydrolysed by digestive enzymes
fementation by colonic bacteria leads to acetic and lactic acid
this decreases water reabsorption
365
Name some faecal softeners
Glycerol Supps,
| Phosphate enemas
366
State the mechanism of action of glycerol suppositories
rectal stimulant
| mildly irritant
367
What type of laxative should be given if the faeces are soft?
stimulant
368
What type of laxative should be given if the faeces are hard?
osmotic laxatives
| bulk forming laxatives
369
Why does treatment of constipation with laxatives lead to hypokalaemia
```
laxatives cause enteral loss of K+
loss Of H20 and Na+ causes increased aldosterone release
increases renal loss K+
hypokalaemia causes bowel inertia
constipation
more laxatives given
```
IT'S A CYCLE!
370
What drugs can cause constipation?
```
anti-cholinergics
antidepressants
AEDs
antipsychotics
antispasmodics
calcium supplements
diuretics
opiods
verpamil
```
371
Name an antimotility drug
Loperamide
372
State the mechanism of action of loperimide
binds to opiate receptors in bowel
reduces bowel motility = more time for fluid absorption
increases anal tone
reduces sensory defecation reflex
activate presynaptic opioid receptors in the enteric nervous system to inhibit acetylcholine release and decrease peristalsis.
373
Name some anti-spasmodics
Hyoscine,
| Mebeverine
374
State the mehanism of action of antispasmodics
relieves spasm of intestinal muscle
375
What is Virchow's triad?
Hypercoaguability
Endothelial damage
Stasis
Situations that make haemostasis more likely
376
State the general mechanism of thrombus formation
```
Rupture endothelial wall
Adhesion, activation and aggregation of platelets
Secretion of mediators
Further aggregation of platelets
Coagulation cascade
Thrombus formation
```
377
Describe the mechanism of action of warfarin
Prevents production of vit K dependant clotting factors - prothrombin, VII, IX and X
Competitive antagonism reduction of oxidised vit K required for clotting factor formation
378
How long does it take for warfarin to have a therapeutic effect? Why?
Days
Non-functional clotting factors are synthesised
Takes time for functional clotting factors to be broken down
379
Where in the clotting cascade does warfarin act?
Extrinsic and intrinsic pathways
380
Describe the pharmacokinetics of warfarin
```
Oral
Slow onset and offset
Heavily protein bound
Metabolism by CYP450
Crosses placenta
Excreted in urine and faeces
```
381
Why are patients given heparin cover initially when prescribed warfarin?
Takes a few days for warfarin to become effective - clotting factor turnover
382
What effects does warfarin have when it crossed the placenta?
First trimester - teratogenic
| Third trimester - fetal brain haemorrhage
383
How is the effect of warfarin measured?
Checking extrinsic pathway
Prothrombin time = Time taken for blood to clot after tissue factor and calcium added
Converted to INR
384
What is the INR?
International normalised ratio
Time taken for blood to clot compared to average for age and gender
High INR means poor blood clotting
385
What is the target INRs in warfarin use?
2-3 in DVT, PE, AF
| 2.5-4.5 in prosthetic valves, recurrent thrombosis on warfarin of inherited thrombophilia
386
Why drugs potentiate the effects of warfarin by inhibiting hepatic metabolism?
Drugs that inhibit CYP450
387
How does aspirin affect the action of warfarin?
Inhibits platelet function
| Potentiates warfarin action
388
How do cephalosporins affect the action of warfarin?
Reduce vit K uptake from gut bacteria
| Increases effects of warfarin
389
What are the ADRs of warfarin?
GI haemorrhage
Epistaxis
Intracranial haemorrhage
Excessive bruising
390
How is reversal of warfarin therapy achieved?
Minor bleeding - withdrawal of warfarin and oral Vit K
| Severe bleeding - IV vit K, blood products
391
Describe the mechanism of action of heparin
Activates anti-thrombin III which inhibits thrombin and factor Xa
392
What is the difference in action of unfractionated and LMWH?
Unfractionated binds to ATIII and inhibits thrombin and Xa
LMWH binds to ATIII and inhibits factor Xa only
Due to being too short polysaccharide sequence to bind to both ATIII and thrombin
393
What are LMWH used in the treatment of?
```
VTE prophylaxis
DVT
PE
MI
CHD
during surgery - quick offset if haemmorhage occurs
```
394
How is heparin administered?
IV (unfractionated)
| SC (LMWH)
395
Why does unfractionated heparin have unpredictable pharmacokinetics?
Binds to proteins in blood that neutralise its activity
396
Can heparin cross the placenta?
No
397
How is heparin activity monitored?
Measures intrinsic pathway
| APTT - activated partial thromboplastin time
398
How is APTT measured?
Time taken for blood to clot after addition Ca2+, partial thromboplastin and activator
399
What are the ADRs of heparin?
Haemorrhage- intracranial, at injection sites, GI, epistaxis
Thrombocytopenia - autoimmune.
Osteoporosis in long term use
400
Why does heparin induce thrombocytopenia?
Heparin bind to PF4 on platelet surface
| Stimulates autoimmune response
401
How is heparin treatment reversed?
Protamine sulphate
Dissociates heparin from ATIII
Binds to heparin irreversibly
402
Why are anti platelet medications used?
Prophylaxis for problems with clotting
403
Describe the mechanism of action of aspirin
Inhibits COX-1
Prevents thromboxane A2 production
Prevents platelet aggregation
404
Describe the mechanism of action of dipyridamole
Inhibits cyclic nucleotide phosphodiesterase enzymes
Decreased thromboxane A2 production
Prevention platelet aggregation
405
Describe the mechanism of action of clopidogrel
Inhibits binding of ADP to ADP receptor on platelets
Inhibits GL IIb/IIa receptors needed for fibrinogen to bind together
Inhibits ADP dependant platelet aggregation
406
Describe the formation of prostaglandins
Phospholipase A2 catalyses change of phospholipids to arachidonic acid
COX1 and CLX2 catalyse change of arachidonic acid to prostaglandins (PGH2)
407
What is the difference in function between cox1 and cox2?
COX1 - physiologic production prostaglandins
| COX2 - elevated production prostaglandins in sites of chronic disease and inflammation
408
Where and when are COX1 and COX2 expressed?
COX1 - constitutive. Ensures local perfusion. Constant synthesis
COX2 - always in brain, kidney and bone. Increased in chronic inflammation due to TNFalpha and IL-1
409
Describe the difference in binding sites in the COX enzymes
COX1 - narrow substrate binding site
| COX2 - larger more flexible substrate channel. Large space for inhibitors to bind to
410
How do prostaglandins mediate their effects?
Bind to GPCRs - EP1, EP2 and EP3
411
What is the effect of PGE2 at EP1?
How is this experienced by the patient?
```
Bind to Gq GPCR in C fibres (unmyelinated pain fibres)
Inhibit K+ channels,
increase Na+ channel expression
Increases sensitivity to bradykinin
Increased C-fibre activity
```
Allodynia and hyperalgesia
412
What is Allodynia?
Pain caused by something that wouldn't normally cause pain
413
What is hyperalgesia?
Increased sensitivity to pain
414
What is the effect of PGE2 at EP2 receptors
```
Found in dorsal horn spinal cord
Gs GPCR
increased cAMP, activation PKA
Reduced glycine receptor binding affinity
Increased pain reception
```
415
What does PGE2 binding to EP3 receptors cause?
```
Receptors on neurones regulating temp
Gi GPCR
Fall in cAMP
Increase in intracellular Ca2+
Increased heat production
Reduced heat loss
```
416
How can the actions of PGE2 at prostaglandin receptors be summarised?
EP1 - peripheral sensetisation
EP2 - central sensetisation
EL3 - pyrexia
417
Name some NSAIDs
Ibuprofen
Naproxen
Diclofenac
Celecoxib
418
What is the mechanism of action of NSAIDs
Inhibition COX2
Decreased production prostaglandins
Analgesia, anti-inflammation, anti-pyrexia
419
Describe the time frame of COX1 and COX2 inhibition
COX 1 - rapid and competitive
| COX 2 - slower and irreversible
420
How do NSAIDs cause analgesia?
Reduction prostaglandins
Decreased sensitisation of nociceptors
Decreased central sensitisation
421
How do NSAIDs lead to anti-inflammation
Reduction in prostaglandins
| Effect proportionate to PG involvement (there are other inflammatory mediators!)
422
How do NSAIDs decrease pyrexia?
Bacterial endotoxins trigger macrophages to release IL1 which stimulates hypothalamus to release PGE
NSAIDs inhibit PGE synthesis
423
Describe the pharmacokinetics of NSAIDs
Oral or topical
Heavily protein bound
First order elimination
424
What is the cause of most of the ADRs of NSAIDs?
Inhibition of COX1 - reduction in constitutive prostaglandin expression
425
State the ADRs of NSAIDs
GI ulceration, haemorrhage and perforation
Reduced GFR
Increased brushing
Increased risk of haemorrhage
Hypersensitivity - rashes and bronchospasm
426
Why do NSAIDs cause GI problems?
Prostaglandins would normally stimulate mucus production and inhibit acid production
Decreased prostaglandins increases mucosal permeability and decreased mucosal blood flow and protection
427
Why do NSAIDs cause kidney problems?
Prostaglandins normally maintain adequate blood flow to kidney
428
Why do NSAIDs increase the risk of bleeding?
NSAIDs inhibit thromboxane A2 synthesis by COX1
| Reduces platelet aggregation
429
Which drugs are commonly displaced from protein biding sites by NSAIDs?
Sulphonylureas
Warfarin
Methotrexate
430
Describe the metabolism of paracetemol
90% directly enters phase 2 metabolism - glucaronidation and sulphation
10% enters phase 1 to produce NAPQI
Both have linear PKs
431
What happens to the toxic metabolite NAPQI?
Detoxified using phase 2 conjugation with glutathione
| Limited by glutathione availability
432
What happens to the PK of paracetemol metabolism at high doses?
Turn form linear to non-linear PKs
| Both phase 1 and 2
433
How is paracetemol metabolised at high doses?
Phase II becomes saturated
Increase in phase I production NAPQI
Depletes glutathione
Increased unconjugated NAPQI
434
What is the result of NAPQI's toxicity
Highly nucelophilic
Binds with cellular macromolecules or mitochondria
Loss hepatic cell function and cell death
Renal failure
435
Why are the elderly and young even more at risk of NAPQI toxicity?
Have less glutathione
436
What are the signs and symptoms of paracetamol toxicity?
```
Nausea and vomiting in first 24hrs
RUQ pain and tenderness - hepatic necrosis
Encephalopathy
Haemorrhage
Hypoglycaemia
Cerebral oedema
Death
```
437
What is the treatment for paracetamol overdose?
0-4 hours after overdose = oral activated charcoal. Reduced uptake
0-36 hours after overdose = IV N-acetylcysteine. Increases glutathione levels. Protects liver. Most effective if given within 8 hours
438
What classes of drugs are used as AEDs
Voltage gated sodium channel blockers
| Enhancers of GABA mediated inhibition
439
Name some voltage gated sodium channel blockers used in epilepsy
Carbemezepine
Lamotrigine
Phenytoin
440
State the mechanism of action on VGSC blockers used in epilepsy
Bind to internal face inactivated sodium channel
Act at neurones with high frequency discharge
Prevent return of channel to resting state
Reduce number of functional channels
441
What types of seizures are the VGSC blockers used to treat?
Carbamezepine - tonic clonic, partial
Lamotrigine - tonic clonic, partial, absence
Phenytoin - tonic clonic, partial
442
What affect does carbamezepine have on CYP450?
Inducer
443
What are the ADRs of carbamezepine
```
Drowsiness
Dizziness
Ataxia
Paraesthesia
Anaesthesia
Bone marrow suppression
Neutropenia
```
444
What affect do oral contraceptives have on lamtorigine?
Reduce plasma levels
445
What effect does phenytoin have on CYP450
Induction
446
What ADRs are seen with phenytoin?
Ataxia
Nystagmus
Gingival hyperplasia
Hypersensitivity - Stevens-Johnson
447
Which VGSC blockers competitively bind with sodium valproate?
Phenytoin
| Lamotrigine
448
What effect does phenytoin have on the OCP?
Decreased plasma concentrations
449
Name some drugs that enhance GABA mediated inhibition in epilepsy
Sodium valproate
Diazepam
Lorazepam
450
State the mechanism of action of sodium valproate
STimualtes GABA synthesising enzymes
| Inhibits GABA inactivating enzymes
451
What is sodium valproate used for?
Adjunct therapy in partial and generalised seizures
452
What are the ADRs of sodium valproate
Ataxia
Tremor
Increases transaminase levels in blood
Teratogenic
453
What interactions occur with antidepressants, antipsychotics and sodium valproate?
Antidepressant and antipsychotic antagonise sodium valproate
454
State the mechanism of action of benzodiazepines
Bind to BZD binding site on GABAA
Enhances GABA binding
Increases Cl- into neurone
Increases threshold for AP
455
What are benzodiazepines used to treat?
Status epilepticus
456
What are the ADRs of benzodiazepines
```
Sedation
Confusion
Impaired coordination
Aggression
Tolerance and dependance
Resp and CNS depression
```
457
What is the first line therapy for primary generalised seizures?
Sodium valproate
458
What is the first line therapy for partial seizures?
Carbamezepine
459
What AED drug is used in women of child bearing age?
Lamotrigine
460
What are the diagnostic symptoms of depression?
Two out of three of:
Low mood
Anhedonia
Decreased energy
Other symptoms are loss of concentration, decreased appetite, sleep disturbance, irritability
461
What are the theories behind the development of depression?
Monoamine hypothesis - deficient monoamine neurotransmitter
Neurotransmitter receptor hypothesis - abnormality in receptors for monoamines
Monoamine hypothesis of gene expression
462
Name some SSRIs
Citalopram
Fluoxetine
Sertraline
463
State the mechanism of action of SSRIs
Prevent reuptake of serotonin at ore synaptic membrane
| Increases concentration in the synaptic cleft
464
Describe the pharmacokinetics of SSRIs
Oral
Long half life
Metabolised by CYP450
465
State the ADRs of SSRIs
```
Nausea
Diarrhoea
Anorexia
Mania
Extrapyramidal syndromes
```
Citalopram can prolong QTc
466
Name some tricyclic antidepressants
Imipramine
| Lofepramine
467
State the mechanism of action of TCAs
Inhibition reuptake of serotonin and noradrenaline at pre synaptic membrane, increasing concentration
Block serotonin, alpha adrenergic, histamine and muscarinic receptors - responsible for side-effects
468
Describe the pharmacokinetics of TCAs
Oral
Lipid soluble
Long half life
469
State the ADRs of TCAs
```
Sedation
Impaired psychomotor function
Reduced glandular secretion
Tachycardia
Postural hypertension
Sudden cardiac death
Constipation
```
470
What are the effects of overdose of antidepressants?
SSRIs - very safe
| TCAs - dangerous. Short term prescriptions given
471
Name an SNRI
Venlafaxine
472
Describe the mechanism of action of SNRIs
Inhibition reuptake serotonin and noradrenaline
473
State the ADRs of SNRIs
```
Nausea
Diarrhoea
Sleep disturbance
Increased BP
dry mouth
Hyponatremia
```
474
State the order of antidepressant treatment
SSRIs first line
SNRIs
TCAs
475
What is psychosis?
Loss of contact with reality
476
State the positive symptoms of schizophrenia
Hallucination
Disturbances in thinking
Delusions
Behavioural change
477
What is a hallucination?
Perception in the absence of an external stimulus
478
What is a delusion?
Fixed false belief despite clear and obvious evidence it isn't true
479
What are the negative symptoms of schizophrenia
Social withdrawal
| Unusual speech and thought - jumbled. Difficult to understand. New words, pressure of speech
480
What are the cognitive symptoms of schizophrenia
Selective attention
Poor memory
Reduced abstract thought
Lack of insight
481
State the main dopamine pathways in the CNS and their importance
```
Meso-limbic = emotional response and behaviour
Meso-cortical = arousal and mood
Nigrostriatal = control of movement
Tubero-hypophyseal = pituitary and hypothalamus function
```
482
What is the main treatment of schizophrenia
Block dopaminergic pathways
| Thought to be due to increased dopamine
483
State the effects of blocking the dopamine pathways in schizophrenia
```
Meso-limbic = therapeutic action on positive symptoms
Meso-cortical = enhancement of negative and cognitive symptoms
Nigrostriatal = extra pyramidal side effects and tardive dyskinesia
Tubero-hypophyseal = hyperprolactiniaemia
```
484
What other neurotransmitters are affected inn schizophrenia
Serotonin - increased
| Glutamate - decreased in cortex
485
What are the effects of anti-psychotics?
```
Sedation
Tranquilisation
Antipsychotic effects
Activation of negative symptoms
Extra pyramidal side effects
```
486
Name some typical anti-psychotics
Haloperidol
| Chlorpromazine
487
Describe the mechanism of action of typical anti-psychotics
Competitive D2-antagonists
488
What are the ADRs of typical anti-psychotics
Extra-pyramidal effects
CNS depression
Cardiac toxicity - lengthens QT
Studen death
489
Name some atypical antipsychotics
Olanzapine
Risperidone
Quetiapine
Clozapine
490
What is the difference between typical and atypical anti-psychotics?
Atypical cause less extrapyramidal effects
More acceptable to patient
But higher risk of metabolic side effects
491
State the ADRs of atypical antipsychotics
Excessive weight gain
Increased prolactin secretion
Sedation
(Uncommon extrapyramidal)
492
What is the mechanism of action of atypical antipsychotics
Blockade of serotonin and dopamine
493
What is the first line treatment for schizophrenia?
Atypical antipsychotics
494
Why are benzodiazepines rarely prescribed as a treatment for anxiety?
Tolerance
Dependance - withdrawal
Severe side effects
495
What are the ADRs of benzodiazepines
Drowsiness
Dissidents
Psychomotor impairment
496
What effect do benzodiazepines have in pregnancy?
Cleft lip and palate
Respiratory depression in fetus
Feeding difficulties in baby
497
What are the symptoms of mania in bipolar disorder
```
Feeling unusually happy, optimistic or excited
Over activity
Poor concentration
Poor sleep
Rapid speech
Poor judgement
Increased interest in sex
Psychotic symptoms
```
498
What is bipolar disorder?
Episodes of both mania and depression
499
What drugs are used to treat bipolar disorder?
Lithium
AEDs
Antipsychotics
500
Describe the effect of lithium in bipolar disorder
Mood stabiliser
501
Describe the pharmacokinetics of lithium
Not metabolised
| Excreted renally - nephrotoxic
502
What are the ADRs of lithium
```
Nephrotoxicity
Hypothyroidism
Memory problems
Thirst
Polyuria
Tremor
Drowsiness
Weight gain
```
503
What are the symptoms of lithium toxicity
```
Vomiting
Diarrhoea
Coarse tremor
Dysarthria
Cognitive impairment
Restlessness
Agitation
```
