Pharmacology Flashcards
1
Q
In terms of errors, what’s the difference between a slip and a lapse?
A
A slip is an action that involves recognition or selection failure, whereas a lapse, is a failure of memory or attention
2
Q
What factors can increase the rate of medication errors?
A
Increasing number of elderly patients with comorbidities, polypharmacy and increased risk of ADRs
Doctors with little experience
Vast number of new drugs
Clinical evidence for drugs is usually only for drug used in isolation in healthy patients
Many ADRs only come to light in post-marketing surveillance
On-call prescribing can mean that doctor doesn’t know the patient
Blind following of guidelines can lead to prescription where serious ADRs/DDIs exist
Doctors working shift work with reduced total hours - less experience/more tired
3
Q
What are the two different approaches within Reason’s model of accident causation?
A
Person approach - Accidents occur due to aberrant mental processes so counter measures are centered on the person
System approach - Errors are seen as a consequence of the system that they occur within. Countermeasures are centered on barriers and safeguards
4
Q
What do Black Triangle drugs indicate?
A
Drugs that are intensively monitored. Generally been newly released, or have changed indications, formulations or is a combination product. Any side effect, even if thought to be unrelated must be reported.
5
Q
What is meant by a serious reaction to a drug?
A
Any reaction that results in or prolongs hospitalisation
6
Q
What is pharmacogenetics?
A
How genetic variability affects the pharmacokinetics or pharmacodynamics of a drug in an individual
7
Q
Why is understanding of pharmacokinetics important in everyday practice?
A
Knowledge of bioavailability impacts on formulation used
Knowledge of half lives impact on dosing regimen
Understanding of intra-subject variability allows for correct dosing within special groups
8
Q
What are the main passive factors affecting the systemic entry of a drug?
A
pH
Lipophilicity
Molecular size
9
Q
What are the main active factors affecting the systemic entry of a drug?
A
Active transport
Splanchnic blood flow
Destruction by gut and bacterial enzymes
10
Q
What are the main factors affecting the peak plasma concentration of a drug and how long it spends in the body?
A
First pass metabolism
Rate of uptake
11
Q
What is bioavailability?
A
The fraction of a drug that finds its way into a specific compartment
12
Q
How is bioavailability calculated?
A
Amount of drug reaching systemic circulation/total amount of drug administered
13
Q
What kind of graph can be used to express bioavailability?
A
Time (x) vs plasma concentration (y) graph
14
Q
How can bioavailability be calculated clinically using AUCs?
A
= AUC oral/AUC IV - shows total exposure with oral route compared to total exposure in optimal IV route
15
Q
What are the two main factors that affect the bioavailability of a drug?
A
Absorption and first pass metabolism
16
Q
What factors can affect absorption and so affect bioavailability?
A
Formulation
Age
Food (if lipid/water soluble)
Vomiting
17
Q
What are three possible sites of first pass metabolism?
A
In gut lumen by substances such as gastric acid, proteolytic enzymes, and grapefruit juice, or by drugs such as ciclosporin, insulin and benzopenicllin
At gut wall as p-glycoprotein efflux pumps can remove drugs from enterocytes, back into the gut lumen
In the liver (hepatic first pass)
18
Q
What are the main factors affecting the distribution of a drug in the body?
A
Lipophilicity - if lipophilic, will exit plasma and enter other tissues
Plasma protein binding - if high, there’s less freely available
Tissue protein binding - if high, there’s less freely available
Mass of volume of target tissue and the density of binding sites within that tissue
19
Q
When are protein binding drug interactions particularly important?
A
If there’s high protein binding, if there’s a low volume of distribution or if there’s a narrow therapeutic ratio
20
Q
What factors affect protein binding of a drug?
A
Hypoalbuminaemia
Pregnancy
Renal failure
Displacement by other drugs
21
Q
What factors affect tissue distribution of a drug?
A
Disease states Regional blood flow Active transport Lipophilicity Specific receptor sites in tissues Drug interactions
22
Q
What is volume of distribution?
A
A measure of how widely a drug is distributed in tissues
23
Q
How is volume of distribution calculated?
A
Total amount of drug in the body/Plasma concentration of a drug at time=0
24
Q
Roughly, what will the volume of distribution be in a very lipophobic drug that doesn’t exit the plasma?
A
Roughly equal to plasma volume of 5 litres
25
Roughly, what will the Vd be in a drug that can exit the plasma and enter other fluid compartments?
Between volumes of ECF and ICF so between 10 and 40 litres
26
Roughly what will the Vd be in a drug that's very lipophilic and enters various tissues?
Extremely high - in the hundreds
27
What is the main purpose of metabolism of drugs prior to excretion?
To increase their ionic charge so they're excreted more easily. Eg in very lipophilic drugs, would otherwise diffuse back along their concentration gradient through renal cell membranes
28
What are the main reactions involved in phase 1 metabolism?
Oxidation and reduction, mainly carried out by cytochrome P450 system
29
What is the CYP450 system affected by?
```
Inducing and inhibiting drugs
Alcohol/smoking
Age
Liver disease
Hepatic blood flow
```
30
What are the main reactions of phase 2 metabolism?
Conjugation with glucuronide, sulphates, glutathione, N-acetylw
31
What are the main inducers of the CYP 450 system?
```
Phenytoin
Carbamazepine
Barbiturates
Rifampicin
Alcohol
Sulphonylureas
St Johns Wort
```
32
What are the main inhibitors of the CYP 450 system?
```
Omeprazole
Disulfiram
Erythromycin
Valproate
Isoniazid
Cimetidine/Ciprofloxacin
Ethanol intoxication
Sulphonamides
+grapefruit juice
```
33
What is clearance?
The volume of plasma that is completely cleared of a drug per unit time
34
How is half life calculated using Vd and clearance?
= (0.693 x Vd)/Clearance
35
What are the main factors affecting renal elimination of a drug?
Glomerular filtration
Active tubular secretion (eg of penicillin)
Passive tubular absorption
36
What is passive tubular absorption of a drug affected by?
pH
| Urine flow rate
37
What channels are important in renal elimination?
Organic Anion Transporters
| Organic Cation Transporters
38
When is drug monitoring necessary?
In drugs with zero order kinetics
In drug with long half lives
In drugs with known toxic effects
In drugs with a narrow therapeutic window
To monitor the therapeutic effects of a drug
When there's a high risk of DDIs
39
What is meant by first order/linear kinetics?
That the rate of elimination of a drug is proportional to the drug level so a constant fraction is eliminated. (straight line on a log graph)
40
What is meant by zero order/non-linear kinetics?
That the rate of elimination of a drug is constant (curved line on a log graph)
41
What are some drugs with zero order kinetics?
Phenytoin
Fluoxetine
Verapamil
High dose aspirin
42
How is a loading dose calculated?
= Vd x desired therapeutic concentration
43
What are the main, usual sites of action for drugs?
Receptors
Enzymes
Ion Channels
Substance transport
44
What are some unconventional modes of action for drugs?
```
Acting as an enzyme
Chemically reactive with small molecules
Covalently linking to macromolecules
Disruption of structural proteins
Binding of free molecules of atoms
```
45
What is meant by affinity?
The tendency of a drug to bind to a specific receptor type
46
How can affinity be expressed?
Kd or Ki
| Concentration at which half of receptors are bound
47
What is meant by efficacy?
Maximal effect of a drug when bound to a receptor, so when no increase in drug concentration will cause a further increase in response
48
What is meant by potency?
The dose required to produce the desired biological response?
49
How is potency expressed?
In agonists, as concentration at which there's 50% of the maximal response = EC50
In antagonists, is the concentration that reduces the maximal response by 50%
50
Give some examples of drugs with narrow therapeutic ranges
Warfarin
Digoxin
Aminoglycoside antibiotics
Aminophylline
51
How can drugs have pharmacokinetic reactions in terms of absorption?
If drugs affect gut motility, can affect time available for absorption. eg metoclopramide increases rate of gastric emptying
52
How can drugs have pharmacokinetic reactions in terms of distribution?
If drugs compete for binding sites eg on plasma/tissue proteins, can affect free plasma concentrations
53
How can drugs have pharmacokinetic reactions in terms of metabolism?
Many drugs can alter their own metabolism or that of other drugs, by interacting with the CYP450 system
54
What are some common drug classes that commonly lead to DDIs?
```
Anticonvulsants
Anticoagulants
Antidepressants
Antibiotics
Antarrhythmics
```
55
How can drugs have pharmacokinetic reactions in terms of elimination?
If a drug affects protein binding, tubular secretion, urine flow or pH, it can affect a drug's elimination
56
How can cardiac diseases alter a drug's pharmacodynamics?
If there's reduced cardiac output, there's reduced organ perfusion so reduced hepatic and renal clearance. This can increase risk of toxicity.
Will also mean there will be an excessive response to hypotensive agents
57
How can renal diseases alter a drug's pharmacodynamics?
If there's a reduced GFR, there's reduced clearance so increased risk of toxicity. Any electrolyte disturbances also increase risk of toxicity.
58
How can hepatic diseases alter a drug's pharmacodynamics?
If there's disease, there will be reduced hepatic clearance and reduced CYP450 activity so increased drug levels in the body so risk of toxicity.
Also, if there's hypoalbuminaemia there will be increased free plasma concentrations
59
What are Type A ADRs?
Those that are on target so either due to an exaggerated immune response or an effect on the same receptor or non-target tissue
60
What are Type B ADRs?
Those that are off target so due to interaction with different receptor sub-types or because of metabolites causing toxicity. May be due to an individual's disposition or an inappropriate immune response.
61
What are some causes of variability in response to drugs?
Can be related to biological system, so due to age, weight, sex, pharmacogenetics, a person's condition of health or due to a placebo effect
Can also be related to drug adminisration so because of the dose, formulation or route of administration, due to DDIs or in repeat administration, leading to tolerance, resistance or allergy
62
What are the actions of oestrogens?
```
Mildly anabolic
Reduces LDL levels and increases HDL levels
Increases sodium and water retention
Reduces glucose tolerance
Reduces bone resorption
Increases blood coagulability
Improves mood and concentration
```
63
What are some unwanted effects of oestrogens?
```
Breast tenderness
Nausea and vomiting
Water retention
Impaired glucose tolerance
Hypercoagulability and thromboembolism
Endometrial hyperplasia and malignancy
```
64
What are some indications of oestrogen therapy?
In primary hypogonadism to stimulate development of secondary sexual characteristics
In primary amenorrhoea, with progesterone, to stimulate an artificial cycle
At sexual maturity for contraception
At or after menopause to reduce menopausal symptoms and to reduce bone loss
65
What's the effect on congenital adrenal hyperplasia on sex steroid production?
Involves a deficiency in 21-hydroxylase enzyme which is normally responsible for conversion of progesterone into aldosterone and 17 alpha-OH progesterone into cortisol.
As it's deficient, there's a build up of progesterone and 17 alpha-OH progesterone pathway moves in direction of testosterone and oestrogen production so there's precocious puberty
66
What are the actions of progesterone?
```
Anabolic
Secretory endothelium
Mood changes
Increased bone mineral density
Water retention
```
67
What are some unwanted effects of progesterone therapy?
```
Weight gain
Fluid retention
Acne
Irritability
Depression and PMS
Nausea and vomiting
Lack of concentration
```
68
What are the actions of testosterone?
```
Anabolic
Acne
Voice changes
Aggression
Adverse metabolic effects on lipids
Male secondary sexual characteristics
```
69
How can oestrogen therapy be administered?
Can be given orally but is rapidly metabolised by the liver. Can instead be given as pessary or intravaginal cream for local effect as it's well absorbed by skin and mucous membranes. This way, it enters the blood stream directly, avoiding the first pass effect
70
How can progesterone therapy be administered?
Can be given orally but is extensively metabolised by the liver. Can instead be given by IM depot injection, as a subcutaneous implant or as a vaginal ring
71
How can testosterone therapy be administered?
Can be given orally but is rapidly metabolised by the liver. Can instead be given as a subcutaneous implant, as an IM depot injection or as a transdermal patch.
72
What is hormone replacement therapy?
The continuous or cyclical administration of at least one oestrogen, with or without a progesterone. It aims to improve menopausal symptoms and helps prevent and treat post-menopausal osteoporosis.
73
How can HRT be administered?
```
Orally
Transvaginally
Nasally
Subcutaneously
Transdermally
```
74
What are some risks of HRT?
Cyclical withdrawal bleeding
Increased risk of endometrial, breast and ovarian cancers
Increased risk of thromboembolism
Increased risk of ischaemic heart disease and stroke
75
What are some examples of anti-oestrogens?
Clomiphene
| Tamoxifen
76
What kind of drug is clomiphene?
Is an antioestrogen
77
What's the mechanism of action of Clomiphene (antioestrogen)
It prevents oestrogen binding at the anterior pituitary so reduces negative feedback, increasing secretion of GnRH, LH and FSH. This causes ovary enlargement and increased oestrogen secretion
78
What is the general action of anti-oestrogens?
Weak oestrogens that compete with natural oestrogens for receptor binding sites
79
What is clomiphene used for?
To treat infertility if the problem is lack of ovulation
80
What is tamoxifen used for?
To treat oestrogen sensitive breast cancer
81
What is an example of an anti-progestogen?
Mifepristone
82
What kind of agent in mifepristone?
An anti-progestogen
83
How does mifepristone work?
Is a partial agonist at progesterone receptors to reduce progesterone action
It makes the uterus more sensitive to prostaglandins and when given with prostoglandins, can be used for medical termination of pregnancy or can be used to induce labour
84
What is an example of an antiandrogen?
Cyproterone
85
What kind of agent is cyproterone?
An antiandrogen
86
How do antiandrogens work?
Progesterone derivatives that exert a weak progestogenic effect. They're partial agonists at progesterone receptors and can be used in COCPs
87
What is an example of a selective oestrogen receptor modulator?
Raloxifene?
88
What kind of agent is raloxifene?
A selective oestrogen receptor modulator
89
How do selective oestrogen receptor modulators work?
These have antioestrogenic effects on the breast and endometrium to prevent proliferation, but have oestrogenic effects on blood coagulation, lipid metabolism and bone
90
What can raloxifene (selective oestrogen receptor modulator) be used to treat?
To help prevent and treat post-menopausal osteoporosis.
| Slightly reduces risk of invasive breast cancer
91
How do the effects of more recent preparations of the COCP compare to earlier preparations?
New generation (3/4) exert less androgenic effects and have less of an affect on lipoprotein metabolism, however they carry a higher risk of thromboembolism
92
How does the COCP work?
Oestrogen acts to reduce FSH secretion and so prevent follicular development. Progesterone acts to reduce LH secretion and so prevent ovulation. It also thickens cervical mucus
Both act to alter the endometrium to discourage implantation and can interfere with coordinated contraction of fallopian tubes, uterus and cervix that normally aid fertilisation and implantation.
93
What are some benefits of the COCP?
```
Reduces menstrual symptoms
Reduces iron deficiency
Reduces PMT
Reduces risk of benign breast disease
Reduces risk of fibroids
Reduces risk of functional ovarian cysts
```
94
What are some ADRs of the COCP?
```
Venous thromboembolism
Myocardial infarction
Reduced glucose tolerance
Hypertension
Increased risk of stroke, especially if focal migraines are present
Headaches
Mood swings
Cholestatic jaundice
Increased gallstone risk
Precipitates porphyria
Weight gain
Nausea, flushing, dizziness, irritability and depression
Amenorrhoea on cessation of variable length
```
95
How does the POP work?
Thickens cervical mucus, impairing sperm transport
Alters endometrium
Affects motility and secretions of the fallopian tubes
96
What are some disadvantages of the POP?
Less reliable contraceptive effect compared to the COCP
| Causes disturbances to menstruation
97
What are some benefits of the POP?
Suitable alternative is oestrogen therapy is contraindicated
| Suitable if marked increase in BP is found with COCP
98
What are some important drug interactions with the COCP?
Metabolised by CYP450 system. Oestrogen used at minimum effective dose so any induction of this system and so increased clearance can lead to contraceptive failure.
Phenytoin, Carbamazepine, Barbiturates, Rifampicin, Alcohol, Sulphonylureas
COCP enters enterohepatic circulation so broad spectrum antibiotics that affect gut flora and so absorption could lead to contraceptive failure
99
What are three different methods of emergency contraception?
Levonorgestrel used up to 3 days after intercourse
Copper bearing intrauterine device used up to 5 days after sex
Ullipristal diacetate used up to 5 days after sex
100
How can levonorgestrel be used as emergency contraception?
Is a high dose progestogen. Alters cervical mucus and delays ovulation
101
How do copper IUDs work as emergency contraception?
Prevent fertilisation by damaging the sperm and egg before they meet
102
How is ullipristal diacetate used as an emergency contraceptive?
In a selective progesterone receptor modulator
103
What is atherosclerosis?
A thickening of arterial walls due to the invasion and accumulation of white blood cells
104
How do atheromas form?
Endothelial dysfunction and endothelial injury lead to the attraction of monocytes. LDLs adhere to the vessel wall and are oxidised by monocytes. When oxidised, they're taken up by monocytes to form foam cells, which then join with T cells to form fatty streaks. Platelets, macrophages and endothelial cells release cytokines and growth factors that cause smooth muscle cell proliferation and fibrous cap formation, which leads to atheromatous plaque forming.
105
What effect does the oxidisation of LDLs by monocytes have, leading to propagation of atheroma formation?
Oxidised LDLs act to reduce motility of macrophages and stimulate the activation of T cells. Also stimulate the division and differentiation of vascular smooth muscle cells.
The LDLs are toxic to endothelial cells and promote aggregation of platelets
106
What effect do statins have on lipid profiles?
Reduce LDLs by 5-15%
Slightly increase HDLs by 5%
Reduce triglycerides by 10-35%
Reduce vLDLs
107
How do statins work?
Inhibits the HMG CoA Reductase enzyme which is involved in cholesterol synthesis. Also increase uptake of LDLs hepatically by increasing receptor number so there's an increase in their clearance from the plasma
108
What are some side effects of statins?
```
Myopathy
Increased transaminase levels but no evidence on liver disease
GI disturbances
Arthralgia
Headaches
```
109
What are some secondary benefits of statin use?
Anti-inflammatory
Plaque reduction
Increase function of endothelial cells
Reduce thrombotic risk
110
What are some important drug reactions of statins?
Risk of rhabomyolysis with combination therapy with fibrates or niacin
Metabolised by CYP enzymes
111
What are some examples of fibrates?
Bezafibrate
| Ciprofibrate
112
What kind of agent is bezafibrate?
Fibrate - Lipid lowering drug
113
What effects do fibrates have?
Slightly reduce LDLs
Increase HDLs by 15-25%
Reduce triglycerides by 25-50%
114
How do fibrates act?
Act on the peroxisome proliferator activated receptor.
| Increase hepatic LDL uptake and increase glucose tolerance and reduce smooth muscle proliferation
115
When are fibrates used?
First line in many triglyceridaemias
| Used in conjunction with dietary changes and statins in high cholesterol
116
What are some ADRs of fibrates?
```
Myositis
Pruritis and itching
GI upset
Cholelithiasis
AKI in toxicity
```
117
When are fibrates contraindicated?
In renal and hepatic disease
| In preexisting gallbladder disease
118
Give an example of a cholesterol absorption inhibitor?
Ezetimibe
119
What kind of agent is ezetimibe?
Cholesterol absorption inhibitor
120
How to cholesterol absorption inhibitors, eg ezetimibe work?
Selectively inhibit intestinal cholesterol absorption by blocking the transport protein for cholesterol at the brush border of enterocytes. This means that less dietary cholesterol reaches the liver so there's an upregulation of LDL receptors at the liver, so increasing its clearance from the plasma
121
How is ezetimibe (cholesterol absorption inhibitor) targeted for its action?
Circulates enterohepatically so limits its systemic exposure and ensures that it reaches its target
122
When are cholesterol absorption inhibitors (ezetimibe) used?
Either as an adjunct alongside diet and statin therapy, or alone if statins aren't tolerated
123
What are some side effects of cholesterol absorption inhibitors (ezetimibe)?
```
Headache
Abdominal pain
Diarrhoea
Rash
Angioedema
```
124
What dietary changes can be made to help improve lipid profile?
Increase intake of fish oils, fibre and vitamin C
125
What is niacin?
A nicotinic acid derivative used to improve lipid profile
126
How to nicotinic acid derivatives work?
Convert to nicotinamid which reduces the hepatic secretion of vLDLs there's reduction in LDL and triglyceride levels. Also the best agents for increasing HDL levels and they inhibit lipoprotein synthesis
127
What are some side effects of nicotinic acid derivatives?
```
Headache
Itching
Flushing
Precipitates gout
Hepatotoxicity
Activates peptic ulcer
Impairs glucose tolerance
```
128
When are nicotinic acid derivatives contraindicated?
In those with active liver disease, unexplained raised LFTs or with peptic ulcer disease
129
What can happen if statins are used in conjunction with fibrates?
Normally fine but if used with gemfibrozil, it acts to reduce the glucuronidation of statins and inhibits the organic anion transporters in the kidney, thereby inhibiting its metabolism and its clearance so there's increased risk of toxicity and rhabdomyolysis
130
How does the type of statin given affect dosing regime?
Some statins, eg simvastatin, have a short half life of 1-4 hours so are taken at night in order to coincide with peak cholesterol production in the morning
However, some statins, eg rosuvastatin, have a longer half life of around 20 hrs and so can be given at any time
131
What lifestyle changes should be made on diagnosis with diabetes?
Reduce fat intake and increase relative calorie intake from complex carbohydrates, combined will aid with weight loss
Stop smoking
Limit alcohol intake
Increase exercise
132
What kind of agent is metformin?
A biguanide
133
Give an example of a biguanide?
Metformin
134
What are the actions of metformin?
```
Reduces hepatic glucose production
Increases glucose uptake and utilisation by skeletal muscle
Increases fatty acid oxidation
Reduces carbohydrate absorption
Reduces frequency of cardiac events
```
135
What are some ADRs of metformin?
GI disturbances that are dose related
| Lactic acidosis
136
When is metformin contraindicated?
```
Renal disease
Liver disease
Shock
Hypoxic pulmonar disease
Because of risk of lactic acidosis
```
137
Other than diabetes, when else can metformin be used?
In Polycystic Ovarian Syndrome
Non-alcoholic fatty liver disease
Some forms of precocious puberty
138
What are the main types of insulin release stimulants?
Sulphonylureas
Glitazones
Meglitidines
139
Give some examples of sulphonylureas?
Gliclazide
| Tolbutamide
140
What kind of agent is tolbutamide?
A sulphonylurea used in diabetes
141
How do sulphonylureas work?
Antagonise K+/ATP channel on Beta cells in pancreas so that they depolarise, increasing intracellular calcium and so stimulating release of insulin containing vesicles.
142
How do the half lives and so dosages of sulphonylureas differ?
Some eg tolbutamide have short half life of 4 hours so offers good coverage of meals and is given 2/3 times a day
Glibencamide has a half life of 10 hours so in given once a day
143
What are some ADRs of sulphonylureas?
```
Weight gain
Hypoglycaemia, especially in the elderly and renal impairment
Skin rashes
GI disturbances
Bone marrow toxicity
```
144
What are some important drug reactions of sulphonylureas?
Agents such as NSAIDs and CYP450 inhibitors increase risk of hypoglycaemia
Agents such as corticosteroids, contraceptive pill and thiazide diuretics reduce glycaemic control
145
When are sulphonylureas contraindicated?
In type 1 or late stage type 2 diabetes as they require functioning beta cells to exert an effect
146
Give some examples of meglatidines?
Repaglinide
| Nateglinide
147
What kind of agent is repaglinide?
A meglatidine for diabetes controle
148
How do meglatidines work?
Inhibit K+/ATP channel on beta cells of pancreas so depolarise cells, increase intracellular calcium and stimulate insulin release
149
When may meglatidines be used instead of sulphonylureas?
In obese patients as meglatidines don't cause weight gain like sulphonylureas
150
What are some ADRs of meglatidines?
Flatulence
Loose stools
Diarrhoea
Abdominal pail
151
Give some examples of glitazones?
Rosiglitazone
| Pioglitazone
152
What kind of agent is pioglitazone?
Glitazone used in diabetes control
153
How do glitazones work?
```
Bind to peroxisome proliferato activated receptor found on liver, adipose tissue and muscle.
Acts to increase lipogenesis
Reduce hepatic glucose production
Increase fatty acid uptake
Increase glucose uptake
Increased Na retention
```
154
What are some ADRs of glitazones?
```
Weight gain
Hepatotoxicity
Fluid retention
Fatigue
Headache
Increased bone metabolism
GI disturbances
```
155
When are glitazones contraindicated?
Heart failure
Pregnancy
Breast feeding
Children
156
What are the main incretin based therapies for diabetes?
GLP-1 receptor agonists
| DPP-4 inhibitors/gliptins
157
Give an example of a GLP-1 inhibitor?
Exenatide
158
What kind of agent is exenatide?
GLP-1 inhibitor used in diabetes
159
How do GLP-1 agonists work?
Mimic effects of Glucagon Like Peptide so increase insulin, reduce glucagon, reduce glucose production, reduce gastric emptying and reduce appetie.
Promote weight loss
160
What's an ADR of GLP-1 agonists?
Pancreatitis
161
Give an example of a DPP-4 inhibitor/gliptin?
Sitagliptin
162
How do DPP-4 inhibitors/gliptins work?
Inhibit DPP-4 which normally acts to break down GLP-1
Act to increase isulin release, reduce glucagon release, increase peripheral glucose uptake and reduce hepatic glucose output
163
What are some ADRs of gliptins?
Nasopharyngitis
Headache
Nausea
164
How do sodium-glucose contransporter 2 inhibitors work?
Inhibit to SGLT2 transporter in the PCT so reduce glucose reabsorption
165
Give an example of a sodium-glucose contransporter 2 inhibitor
Dapagliflozin
166
What are some ADRs of sodium-glucose cotransporter 2 agents?
Increase risk of UTI
Polyuria
Hypoglycaemia
167
What are the two main antiobesity agents?
Orlistat
| Sibutramine
168
What is sibutramine?
Antiobesity agent
169
How does sibutramine work?
Inhibits NA and 5HT at sites in hypothalamus that control appetite. It increases energy expenditure through thermogenesis so can reduce hyperglycaemia
170
What are some ADRs of sibutramine?
```
Dry mouth
Increased heart rate
Increased blood pressure
Constipation
Insomnia
```
171
How does orlistat work?
Inhibits gastric and pancreatic lipases so there's reduced conversion of dietary fat into fatty acids and glycerol so reduced fat absorption
172
What are some ADRs of orlistat?
Faecal incontinence
Abdominal cramps
Flatus with discharge
173
How do DNA viruses replicate?
Viral DNA enters the host nucleus and is transcribed into mRNA by reverse transcriptase. mRNA is then translated into specific viral proteins. These can go on to make more viral DNA or structural proteins to make viral coat and envelope
Completed virion is then released either by budding or on host cell lysis
174
How do RNA viruses replicate?
Enzymes within the virion make their own mRNA which is then translated by the host cell into structural proteins and RNA polymerase
175
How do retroviruses replicate?
Virion contains reverse transcriptase which transcribes viral RNA into DNA, which then integrates into the host cell genome, forming a provirus. DNA can then be transcribed into viral RNA and mRNA to form structural proteins. Completed virion is released by budding, without damage to host cell
176
What needs to happen before a virus can enter a host cell and exert an effect?
It needs to attach to a neuraminc or sialic acid residue on the membrane of a glycoprotein. The complex can then enter by endocytosis.
Their then needs to be ATP driven H+ entry into the endosome so that the viral membrane can fuse with the internal endosomal membrane.
Finally, there needs to be proton entry into the virus itself via an M2 receptor. This reduces the pH within the virus so the viral coat breaks down and the viral RNA can be released into the cytoplasm
177
Give an example of an M2 ion channel blocker
Amantadine
178
What kind of agent is amantadine?
M2 ion channel blocker antiviral
179
How do M2 ion channel blockers work?
Inhibit proton entry into the virus and so inhibit the release of viral genetic information into the host cell cytoplasm
180
What are some ADRs of M2 ion channel blockers?
```
Dizziness
COnfusion
Hallucination
Slurred speech
Insomnia
```
181
How do neuramidase inhibitors work?
Inhibit neuramidase enzyme which is needed to break bond between new virion and neuraminic acid residue on cells. This means that virion can't be released to infect more cells and so halts progression.
182
Give an example of a neuramidase inhibitor
Osteltamivir
183
What kind of agent is osteltamivir?
Neuramidase inhibitor antiviral
184
Give some ADRs of neuramidase inhibitors
```
GI disturbance
Nose bleeds
Headache
Respiratory depression
Bronchospasm
```
185
What are the three main ways by which antibiotics can exert their effects?
Affecting cell wall synthesis
Affecting DNA synthesis
Affecting protein synthesis
186
What are the main antibiotic classes that affect bacterial DNA synthesis?
Quinolones
| Folic acid antagonists
187
Give an example of a quinolone
Ciprofloxacin
188
What kind of agent is ciprofloxacin?
Quinolone antibiotic
189
How do quinolones work?
Inhibit topoisomerase II enzymes which is needed for DNA synthesis and replication
190
What kind of bacteria are quinolones effective against?
Broad spectrum so gram positive and negative, and enterbacteriaceae
191
What are some ADRs of quinolones?
GI upset
headache
Nausea
Prolonged QT interval
192
Give some examples of folic acid antagonist antibiotics
Trimethoprim
| Sulphonamides
193
How do sulphonamides work?
Act as analogues to precursors to folic acid synthesis and so prevent synthesis and prevent DNA synthesis
194
How does trimethoprim work (antibiotic)?
Inhibits dihydrofolate reductase enzyme and so inhibits folate and DNA synthesis
195
What are some dangers of folic acid antagonist antibiotics?
Can cross placenta and exert a teratogenic effect as affect folic acid synthesis
196
What are some ADRs of trimethoprim? (folic acid antagonist)
Thrombocytopenia
| Hyperkalaemia
197
What classes of antibiotics affect protein synthesis?
Macrolides
Tetracyclines
Aminoglycosides
198
Give an example of an aminoglycoside antibiotic
Gentamycin
199
What kind of agent is gentamycin?
AN aminoglycoside antibiotic
200
How do aminoglycosides work?
Block action of 30S ribosomal subunit
201
What kind of agents are aminoglycosides effective against?
Gram negative, predominantly aerobic
202
What are some ADRs of aminoglycosides?
Ototoxicity
Nephrotoxicity
Anorexia
Confusion
203
Give an example of a macrolide?
Erythromycin
204
What kind of agent is erythromycin?
Macrolide antibiotic
205
How do macrolides work?
Bind to 50s ribosomal subunit and prevent elongation
206
What kind of agents are macrolide antibiotics good for?
Gram positive organisms
207
Why should macrolide antibiotics be used with caution?
Inhibitors of the CYP450 system so can increase risk of toxicity in some drugs, including statins where there's an increased risk of myopathy
208
What are some ADRs of macrolide antibiotics?
Nausea
| Prolonged QT interval
209
How do tetracyclines work?
Bind to 30s ribosomal subunit and prevent aminoacylt tRNA from binding
210
What are some ADRs of tetracyclines?
Phototoxicity
| GI upsets
211
What are some contraindications of tetracyclines?
Shouldn't be given to pregnant women, breastfeeding women or children under 8 as cause teeth discolouration
Also shouldn't be used in liver failure
212
What antibiotic classes affect cell wall synthesis?
Beta lactams
| Glycopeptides
213
Give some examples of beta-lactam antibiotics?
Penicillins
Carbapenems
Cephalosporins
214
How do beta lactam antibiotics work?
Inhibit cross linked of peptides in formation to peptidoglycan cell wall
215
What kind of agents are beta lactams good for?
Particularly gram positive.
| Carbapenems and cephalosporins have increasing activity against gram negatives
216
What are some ADRs of penicillins?
GI upset
| Allergic reactions
217
What are some ADRs of cephalosporins?
Nephrotoxicity
GI upset
Rash
218
Give an example of a glycopeptide
Vancomycin
219
What kind of agent is vancomycin?
A glycopeptide antibiotic
220
How do glycopeptide antibiotics work?
Bind to amino acids in bacterial cell wall and prevent addition of new units
221
What kind of bacteria are glycopeptides effective against?
Gram positive organisms
| Those resistant to beta lactam antibiotics
222
What are some ADRs of glycopeptides?
Phlebitis
Nephrotoxicity
Neutropenia
223
How are glycopeptides administered?
Not absorbed in GI tract so can be taken orally if for GI infection, ie in treating Clostridium difficile
If systemic, given IV but risk of necrosis and phlebitis
224
How can bacteria confer intrinsic resistance to antibiotics?
By genetic mutations in bacterial chromosomes
225
How can bacteria confer extrinsic resistance to antibiotics?
By transformation as DNA is taken up from environment and incorporated
Conjugation as plasmid DNA is taken up
Transduction as plasmid DNA is transferred between bacteria of the same species
226
What is the minimum inhibitory concentration of an antibiotic?
The lowest concentration of an antimicrobial needed to inhibit visible growth of a microorganism after overnight incubation
227
What is time dependent killing?
Killing of an antimicrobial will depend on how long they're active for. Potency not increased with increased dose
228
What is concentration dependent killing?
When killing of antimicrobial depends on its concentration at infection site. Killing is optimal when concentration is at least ten times the minimum inhibitory concentration at the infection site
229
What are some effects of rheumatoid arthritis, not involving joints?
```
Lung fibrosis
Renal amyloidosis
Skin changes
Atherosclerosis
Pericarditis
Episcleritis
Anaemia
```
230
How is rheumatoid arthritis diagnosed?
```
With morning joint stiffness lasting at least one hour
Arthritis of hand joints
Arthritis in at least 3 joints
Symmetrical arthritis
Presence of rheumatoid nodules
Presence of serum rheumatoid factor
X-ray changes
```
231
What are the aims of treatment in rheumatoid arthritis?
Give symptom relief
| Prevent joint destruction
232
What is systemic lupus erythematosus?
A multi system autoimmune condition where there's immune mediated apoptosis in healthy tissue
233
What are some symptoms of lupus?
```
Recurrent miscarriages
Fever
Headaches
Ulcers
Reynaud's
Depression
Nausea and vomiting
Butterfly rash
Oedema
Hypertension
Fatigue
Anaemia
Photosensitivity
```
234
What is vasculitis?
An auto-immune inflammation of blood vessels that can occur on it's own or secondary to another condition eg RA
235
What are some symptoms of vasculitis?
```
Headaches
Glomerulonephritis
Palpable purpura
Fever
Weightloss
Haemoptysis
Headache
MI
Hypertension
Blood in stool
Abdominal pain
Joint and muscle pain
```
236
What are the treatment goals of SLE and vasculitis?
Give symptomatic relief
Reduce mortality
Prevent organ damage
Reduce long term morbidity
237
Give an example of a corticosteroid
Prednisolone
238
How do steroids work?
Enter cells, binding to cytosolic receptors and then entering the nucleus to alter gene expression
239
How do steroids have an anti-inflammatory effects?
Reduce gene expression of inflammatory mediators and inhibit all stages of T cell activation
240
What autoimmune conditions can corticosteroids be used to treat?
SLE
RA
IBD
Vasculitis
241
What are some ADRs of corticosteroids?
```
Steroid psychosis
Weight gain
Increased risk of infections
Glucose intolerance
Increased risk of osteoporosis
```
242
Why shouldn't steroid use be stopped suddenly?
Chronic use or high doses suppress to hypothalamic pituitary axis and so rapid removal could precipitate an addisonian crisis
243
How does azothioprine work?
Is a prodrug, converted to an analogue of purine synthesis so inhibits purine synthesis, reducing DNA, RNA and immune mediator synthesis
244
What needs considering before prescribing azothioprine?
TPMT levels. Azothioprine is converted into 6-MP which is then metabolised by TPMT, however TPMT levels vary greatly between different people so if levels are low, there may be toxicity and myelosuppression.
Therefore, TPMT levels need to be measured before prescribing
245
What are some ADRs of azothioprine?
```
Bone marrow suppression
Increased malignancy risk
Increased infection risk
hepatitis
Nausea and vomiting
Skin erruptions
```
246
What autoimmune conditions is azothioprine used in?
```
RA
IBD
SLE
Vasculitis
Leukaemia
```
247
How does cyclophosphamide work?
Is a pro-drug, metabolised by CYP 450 system. It is metabolised into cytotoxic substances that alkylate DNA irreversibly, causing apoptosis. It suppressed B cell proliferation
248
What conditions is cyclophosphamide used in?
```
Leukaemia
Lymphoma
Solid cancers
Vasculitis
SLE
```
249
What are some ADRs of cyclophosphamide?
```
Haemorrhagic cystitis as one of its metabolites is toxic to bladder epithelium but can be reduced by aggressive hydration
Increased bladder cancer risk
Infertility
Nausea and vomiting
Bone marrow suppression
Lethargy
FBCs and kidney function need monitoring
```
250
How does mycophenolate mofetil work?
Prodrug metabolised to mycophenolic acid which inhibits guanosine and so purine synthesis so reduces T and B cell proliferation
251
Why are only T and B cells affected by mycophenolate mofetil?
Other rapidly producing cells have other ways of synthesising guanosine
252
What are some ADRs of mycophenolate mofetil?
```
Nausea and vomiting
Myelosuppression
Leukopenia
Neutropenia
Increased risk of infection
```
253
What conditions is mycophenolate mofetil used for?
Transplantation
| SLE
254
How does methotrexate work?
Binds to dihydrofolate reductase with a much greater affinity than folic acid, and inhibits it. This reduces DNA, RNA and protein synthesis.
255
What are some ADRs of methotrexate?
```
Mucositis
Bone marrow suppression
Hepatitis
Cirrhosis
Pneumonitis
Increased infection risk
Teratogenesis
```
256
Why does dosing of methotrexate need to be done very carefully?
Excreted by the liver but accumulates in cells and can remain for weeks/months so dosing needs to be altered.
Is only given weekly
257
What conditions is Methotrexate used for?
RA
Malignancy
Psoriasis
Crohn's
258
Give examples of calcineurin inhibitors
Tacrolimus
| Ciclosporin
259
How do calcineurin inhibitors work?
Normally when antigens meet T helper cells, calcineurin is activated which stimulates transcription of IL-2. Ciclosporin and tacrolimus bind to cyclophillin and tacrolimus binding protein respectively. These complexes then bind to calcineurin and inhibit it and so inhibit T cell mediated immunity
260
What conditions are calcineurin inhibitors used for?
Transplantation
| Inflammatory skin conditions
261
What are some ADRs of calcineurin inhibitors?
```
Nephrotoxicity
Hepatotoxicity
Neurotoxicity
Hypertension
Anorexia
Lethargy
Paraesthesia
Gingival hyperplasia
Hirsuitism
Thrombocytopenia
Hyperglycaemia
```
262
What are some important reactions of methotrexate?
```
As it's excreted renally, anything that affects renal blood flow, renal elimination or protein binding
Especially:
Phenytoin
Tetracyclines
Penicillin
```
263
How may methotrexate act as a disease modifying anti-rheumatic drug?
May act to increase adenosine levels which is then generated in cellular injury or stress to regulate and reduce inflammatory cell function
264
What inflammatory condition can methotrexate be used to treat?
RA
265
What immune effects does sulphasalazine have?
Inhibits T cell proliferation
Reduces T cell IL-2 production
Reduces chemotaxis of neutrophils
Reduces neutrophil degranulation
266
What are some ADRs of sulphasalazine?
Myelosuppression
Hepatitis
Rash
Nausea, abdominal pain, vomiting
267
What inflammatory conditions is sulphasalazine used for?
IBD
| RA
268
Give an example of an anti-TNF alpha drug?
Infliximab
269
What are the effects of anti-TNF alpha agents?
Reduce inflammation by impairing cytokine cascade and reducing recruitment of leukocytes
Reduce angiogensis by affecting VEGF levels
Reduce joint destruction
270
What are some ADRs of anti-TNF alpha agents?
```
Activation of latent TB
Increased infection risk
Hepatic and renal impairment
Mild heart failure or worsening of existing heart failure
May be risk of demyelinating disease
```
271
What are the main principles of asthma treatment?
Bronchodilators or relievers to give symptomatic relief
| Anti-inflammatories to reduce inflammatory mechanism behind disease
272
How do beta 2 agonists work in treating asthma?
Act on beta 2 receptors present in bronchial smooth muscle to increase intracellular cAMP, reduce intracellular Ca2+ and so reduce myosin binding of calcium and increase K+ entry and so bring about bronchodilation
Also reduce release of inflammatory mediators from mast cells
Reduce TNF-alpha release from monocytes
Increase mucus clearance
273
How do the different half lives of beta 2 agonists impact on asthma therapy?
Shorted acting beta agonists, such as salbutamol, last for 3-5 hours and so are given for acute symptomatic relief
Longer acting agents such as salmeterol that last for 12 hours can be given twice a day if control isn't achieved with corticosteroids, or to treat nocturnal asthma
274
What are some ADRs of beta 2 agonists?
Skeletal muscle tremor
Tachycardia
Dysrhythmia
275
What are some contraindications of Beta 2 agonists?
Shouldn't be used in cardiac ischaemia or in arrythmias as can worsen effects
276
Give an example of a muscarinic receptor antagonist used in asthma treatment?
Ipatropium
277
How do muscarinic receptor antagonists contribute to treatment of asthma?
Act on M3 receptors in bronchial smooth muscle to block constricting effects of ACh and to reduce mucus secretion
278
When are muscarinic receptor antagonists used in asthma?
To augment beta 2 agonists in acute exacerbations
If Beta 2 agonists aren't tolerated/ are contraindicated
Treat COPD
279
What are some ADRs of muscarinic receptor antagonists?
Dry mouth
Urinary retention
Glaucoma
280
Give an example of a methylxanthine
Aminophylline
281
How do methylxanthines treat asthma?
Mechanism not understood but bring about relaxation of smooth muscle and stimulate the CNS and respiratory system
282
What should be considered when prescribing methylxanthines?
Have a narrow therapeutic window and so require therapeutic drug monitoring
Also metabolised by the CYP 450 system so careful drug history is needed
283
What are some ADRs of methylxanthines?
```
Nausea
Gastric reflux
Headache
Tachycardia
Dysrhythmia
Psychomotor agitation
Seizures
```
284
When are methylxanthines used?
Severe asthma
| COPD
285
What is transrepression and transactivation?
Action of steroids to either down or upregulate genetic expression
286
How do corticosteroids work in asthma?
Transrepress inflammatory mediators
Transactivate anti-inflammatory mediators that cause apoptosis in inflammatory cells and reduce mast cell numbers in mucus
Also transactivate Beta 2 receptors on bronchial smooth muscle
287
When are corticosteroids used in asthma?
As inhaler for regular use to reduce inflammation
Orally in acute exacerbations
IV in severe asthma
288
What are some ADRs of inhaled corticosteroids in asthma?
Oropharyngeal candidiasis
Sore throat
Croaky voice
Adrenal suppression
289
Describe the stepwise management of asthma
If mild and intermittent, manage with short acting beta 2 agonist as needed
If regular preventer therapy is needed, add on inhaled steroid
If control is not achieved and add on therapy is needed, give a long acting beta 2 agonist
If there's persistent poor control, can give a daily oral dose of steroids alongside the inhaled and consider adding leukotriene receptor antagonist
290
What is involved in the immediate phase of asthma?
If atopic, is immediate response to an allergen but may be a response to a non-specific stimulus. There's increased levels of mast cells and monocytes which react with the allergen to produce histamine, leukotrienes and prostaglandins which are spasmogens, causing bronchospasm
Mast cells also produce chemokines and chemotaxins which activate the late phase
291
What's involved in the late phase of asthma?
Activated by the immediate phase, there's infiltration of Th2 cells which release cytokines and activate inflammatory cells, particularly eosinophils. Eosinophils release toxic proteins which cause endothelial damage, as well as mediators such as IL-3 and IL-5. Also release growth factors, causing hypertrophy of smooth muscle.
Endothelial damage contributes to hyperreactivity, along with inflammatory cells.
All this causes bronchiospasm, wheezing and coughing
292
What changes occur in the airways in asthma?
```
Hyperplasia
Inflammation
Mucous gland hyperplasia
Airway wall thickening
Increase mass of smooth muscle
Subepithelial fibrosis
Sesquamation of epithelium
```
293
What are the signs signalling asthma that is well controlled?
```
Minimal symptoms at day and night
Normal lung function
Minimal need of reliever medication
No exacerbations
No limitation of physical activity
```
294
What are the signs of a severe acute asthma attack?
```
Any one of:
Inability to complete sentences
Pulse at least 110 bpm
Resp rate at leas 25 breaths per min
Peak flow 33-50% of best or predicted
```
295
How are severe acute asthma exacerbations treated?
```
High flow oxygen, aiming for sats to be 94-98%
Nebulised salbutamol
Oral prednisolone
Nebulised ipratropium bromide
Consider IV aminophylline
```
296
What are the signs of life threatening asthma?
```
PEF 4.5kPa
Silent chest
Cyanosis
Feeble respiratory effort
Bradycardia
Hypotension
Arrythmia
Exhaustion
Confusion
Coma
```
297
What are the features of COPD?
Chronic cough that's worse in the morning, particularly in winter and with purulent sputum
Progressive breathlessness
Airflow obstruction, improved by bronchodilator
Pulmonary hypertension
298
How are prostaglandins synthesised?
Arachidonic acid is formed from cell membrance phospholipids. Arachidonic acid then forms prostaglandins, stimulated by COX-1 and COX-2 enzymes
299
Other than prostaglandins, what other substances does arachidonic acid form?
Thromboxanes
Leukotrienes
Prostacyclins
300
What are the differences in expression of COX-1 and COX-2?
COX-1 is constantly expressed and its prostaglandins have cytoprotective role at gastric mucosa, renal parenchyma, myocardium and ensures optimal perfusion and reduces ischaemia
COX-2 expression is stimulated by injurious stimuli and inflammatory mediators
301
How do NSAIDs work?
Inhibit COX-1 and COX-2 enzymes to inhibit prostaglandin synthesis. Mainly exert therapeutic effect by COX-2 inhibition but aspirin irreversibly inhibits COX-1
302
Explain the anti-inflammatory effects of NSAIDs?
Inflammation involes a range of local mediators that induce COX-2 expression and so prostaglandin synthesis. Prostaglandins increase the permeating effects of bradykinin and histamine and so indirectly increase vascular permeability. They also increase peripheral nociception
Effect of NSAIDs is proportionate to effects of prostaglandins in inflammation (reduce erythema and swelling)
303
Explain the anti-pyretic effects of NSAIDs
Bacterial endotoxins stimulate IL-1 release from macrophages which increases prostaglandin synthesis at the hypothalamus. Prostaglandins act to increase Ca2+ concentrations inside neurons which regulate temperature and so increase heat production and reduce heat loss. They also elevate the set point of the central thermostat.
NSAIDs reduce prostaglandin levels and so reduce temperature
304
Explain the analgesic effects of NSAIDs
After injury, prostaglandin is released which binds to GPCRs on nociceptive pain fibres which sensitises them by increasing their sensitivity to bradykinin, inhibits K+ channels and increases sensitivity of Na+ channels so C fibres are hyperactive. There's also increased Ca2+ concentrations so there's increase in release of neurotransmitters.
If increased pain signalling is sustained then there's increase in prostaglandin synthesis in the dorsal horn.
NSAIDs act to reduce this effect of sensitisation and reduce headache pain by reducing cerebral vasodilation
305
What are the main DDIs of NSAIDs?
Are highly protein bound and so can affect the protein binding of other drugs, especially warfarin, sulphonylureas and methotrexate. This causes increased bleeding, hypoglycaemia and wide ranging serious ADRs due to increased free concentrations
When used with opiate they extend the therapeutic range and so reduce ADR profile of opiods compared to if opiates are used alone
306
What are some ADRs of NSAIDs?
```
Increased risk of gastric ulceration, perforation and haemorrhage
Stomach pain
Nausea
Heartburn
Hypertension
Increased bleeding time
Increased bruising
Skin rashes
Asthmatic bronchospasm
Stevens Johnson syndrome
```
307
What are the signs of aspirin overdose?
```
Vomiting
Dehydration
Hyperventilation
Tinnitus
Vertigo
Sweating
There's respiratory alkalosis that develops into metabolic acidosis
```
308
How does aspirin affect platelets?
It irreversibly inhibits COX-1 that normally has a pro-aggregative effect on platelets and the vessel wall, so it's inhibition reduces thrombotic formations.
309
What is the neurotransmitter of pain perception?
Substance P
310
What are the main types of endogenous opioid and what is there precursor?
Endorphins from POMC
Enkephalins from proenkephalin
Dynorphins from prodynorphin
311
What is the difference in distribution of opioid receptors?
Delta are widely distributed.
Mu are mainly supraspinal
Kappa are mainly in spinal cord
312
Where are endogenous opioids found?
CNS and peripheral nervous system structures involved in processing of pain. ie thalamus, limbic system, spinal cord, primary afferents
313
What is the response to binding of opioid receptors?
There's reduced efflux of K+ so reduced excitability of neurons
There's reduced synthesis of cAMP so reduced intracellular Ca2+ so reduced release of neurotransmitters (Substance P)
314
What are some ADRs of opiates?
```
Nausea and vomiting
Diarrhoea
Drowsiness
Miosis
Respiratory depression
Hypotension
Euphoria
Confusion
Anaphylaxis
Overdose, tolerance and dependence
```
315
Give some examples of full opioid agonists?
Morphine
Codeine
Methadone
316
Give some examples of partial agonist/antagonist opiates
Bupranorphine
| Nalbuphine
317
What's the advantage of partial opioid agonist/antagonist?
Give good anaesthesia without the euphoria
318
Give an example of a full opioid antagonist
Naloxone
319
When are IV opiates used?
In severe pain (can also give intrathecally) and patient can control levels themselves
320
Why do people's responses to codeine vary greatly?
Is metabolised by CYP450 system to morphine, when it becomes active. Great genetic variation in activity of CYP 450 so some people have very little pain relief and some have a lot
321
Why is slow release morphine sometimes necessary?
One of it's metabolites is also pharmacologically active so overall, it's half life is quite long
322
When is pethidine used?
As IM analgesic in labour
323
What are some issues with giving pethidine in labour?
Can cross placental barrier. As it's an opiate, depresses respiratory system so baby may be born with low O2 levels and may also have some degree of opiate dependence.
For this reason, frequent repeated doses should not be given.
324
How does displacement of hair cells cause stimulation of CNVIII?
Displacement opens mechanotransducer K+ channels, which causes depolarisation and opening of VOCCs so there's increased intracellular Ca2+ which stimulates neurotransmitter release. This activates the spiral ganglia which are afferent axons for CNVIII with each hair cell responsible for a different frequency and thereby a different CNVIII fibre
325
How does basement membrane of cochlea relate to frequency of sound?
The basement membrane of the cochlea increases in width from the oval window to the apical end and also reduces in stiffness. This means that high frequency sounds optimally displace hair cells at stapedial end and lower frequency sounds optimally displace hair cells at the apical end
326
What is the role of the medial superior olive in perception of sound?
Localises sound. It detects difference in timings for when the same stimulus reaches different ears. It responds more strongly when stimuli occur close together
327
What is the role of the lateral superior olive in perception of sound?
Localise sound based on intensity.
LSO on one side is excited by a stimulus and Media Nucleus of Trapezioid Body is activated contralaterally and so gives an inhibitory signal to that side. Therefore, excitation from side of stimulus outweighs any inhibition on that side and so there;s excitation of auditory centres in the midbrain on that side.
On the contralateral side, inhibition outweighs any excitation so there's no signal.
328
What is cortical deafness?
Where caise of deafness is only in the auditory centres of the brain. Sound is heard at normal threshold but perception and processing is so poor that they're not understood.
Usually caused by embolic stroke at temporal lobe bilaterally
329
How are arterial clots treated?
Antiplatelets and thromolysis treatment
| Eg in stroke/MI
330
What are the two main mechanisms of anti platelet therapy?
Inhibition of thromboxane A2
| Antagonists of platelet ADP receptors
331
How do thromboxane A2 inhibitors work?
Aspirin and dipyradimole inhibit different steps in thromboxane synthesis pathway (COX1 and platelet phosphodiesterase respectively)
Thromboxane is usually made from arachidonic acid and released by activated platelets to give further platelet aggregation and increased vasoconstriction
332
How do platelet ADP receptor antagonists work?
Platelet ADP receptors usually stimulate crosslinking of platelets by fibrinogen but antagonists inhibit this step
333
Give examples of platelet ADP receptor antagonists
Clopidogrel
| Triclopidine
334
What kind of agent is clopidogrel?
Platelet ADP receptor antagonist
335
What conditions is thrombolysis used is?
Acute MI
Pulmonary embolism
Ischaemic stroke
Major venous thrombus
336
What are the general mechanisms of thrombolytic drugs?
Drugs such as alteplase and tPA generate their own plasmin
Wherease drugs such as streptokinase activate endogenous plasminogen which is bound to fibrin.
Alteplase preferentially works in presence of fibrin so is clot specific. Streptokinase causes degree of thrombolysis in general circulation
337
Why can streptokinase be problematic?
It's a bacteral protein so is antigenic and can cause allergic reactions. It can also only be used once as body produces antibodies against it.
It can cause transient hypotension whilst it's being infused.
338
What are some ADRs of thrombolysis?
Transient hypotension
Allergic reaction
Haemorrhage
Cerebrovascular event
339
What are some contraindications for thrombolysis use?
```
Active peptic ulcer
Other potential bleeding source
Recent trauma or surgery
History of cerebral haemorrhage or stroke of uncertainaetiology
Uncontrolled hypertension
Coagulation defect
Previous streptokinase use
```
340
When is thrombolysis ok to be used?
If quickly enough so that effects of occlusion aren't irreversible. Thrombi also become more resistant to lysis with time
341
What are the criteria for thrombolysis in pulmonary embolism?
Clear diagnosis
Evidence of significant haemodynamic compromise
No contraindications
342
What are the criteria for thrombolysis use in MI?
Clear evidence from history and ECG of an acute MI
Within 12 hours of onset
No contraindications
343
What are the criteria for thrombolysis use in stroke?
Evidence that it's not haemorrhagic
Within 3 hours from onset
No contraindications
344
What are the reversible effects of general anaesthesia?
```
Sedation up to unconsciousness
Anxiolysis
Analgesia
Amnesia
Muscle relaxation
Reflex suppression
Immobilisation
```
345
What is general anaesthesia?
Anaesthesia affecting the whole body with reversible inhibition of sensory, motor and sympathetic activity in the CNS
346
What is local anaesthesia?
A more defined peripheral nerve block
347
What is regional anaesthesia?
The rendering of larger specific regions of the body insensate. eg epidural
348
What is dissociative anaesthesia?
The inhibition of impulses between higher and lower centres of the brain
349
Inhibition of what structure in anaesthesia leads to immobilisation?
Spinal cord
350
Inhibition of what structure in anaesthesia leads to unconsciousness?
Thalamus
351
Inhibition of what structure in anaesthesia leads to amnesia?
Hippocampus
352
Which inhibitory ligand gated ion channels are affected in anaesthesia?
Mostly GABA Cl- channel, as well as glycine Cl- channel. Anaesthetics act to increase sensitivity to GABA and glycine and so increase influc of Cl-, so there's hyperpolarisation and reduced excitability
353
How do anaesthetics act to increase potency and efficacy of neurotransmitters?
When bound to GABA and glycine receptor, reduce EC50 of GABA and glycine so less of the neurotransmitter is needed to produce same maximal effect (increase potency)
ALso stabilise the receptor in the open state so more Cl- flows through channel for every binding of neurotransmitter (increase efficacy)
354
Which excitatory ligand gated ion channels are affected in anaesthesia?
Nicotinic ACh receptors are inhibited to reduce influx of Na+ so reduce exciability, causing analgesia and amnesia
Also inhibit NMDA glutamate receptors so reduce Ca2+ influx and so reduce excitability
355
How do anaesthetics act to reduce efficacy of neurotransmitters?
Bind to glutamate receptors to reduce its efficacy
356
What is contained within the pre surgical review for anaesthesia?
```
Age
BMI
Prior medical and surgical history
Airway assessment
Current medication
Fasting time
History of drug and alcohol abuse
```
357
During surgery, what aspects of anaesthetic and adjuvant delivery is monitored?
Gaseous mixture calculation for partial pressures of O2, flurance, N2O and Nitrogen
Rate of mechanical ventilation
358
During surgery, what systemic physiological factors are monitored?
```
ECG
BP
Core temperature
Pulse oximetry
Expired CO2
EEG
```
359
Why is core temperature monitored during surgery?
Prolonged anaesthesia causes a drop in core temperature. This means that anaesthetist needs to be aware of any infections or fevers to detect malignant hyperthermia
360
What is malignant hyperthermia?
COndition occurring in general anaesthesia where there is excessive skeletal muscle oxidative phosphorylation so there's excessive heat production
361
Why is EEG monitored during surgery?
TO measure CNS activity and anaesthetic depth. Also helps reduce risk of over or under dosing and monitors efficacy of adjuvants.
362
What are the 3 main stages of anaesthesia?
Induction
Maintenance
Recovery
363
What is involved in induction of anaesthesia?
Administration of propofol and delivery of inhalational agents begins. There's also IV administration of adjuvants
364
What is involved in maintenance of anaesthesia?
Balance of adjuvants to maintain adequate depth and regular adjustment to keep within therapeutic window
365
What is involved in recovery from anaesthesia?
Withdrawal of agents
Close monitoring of physiological functions to make sure they can be maintained without support
Antidotes given as necessary to facilitate process
366
What are the 4 stages of anaesthetic depth?
1 - analgesia and unconsciousness with normal breathing and muscle tone and slight eye movement.
2 - excitement with unconsciousness, erratic eye movement and normal/high muscle tone. Delirium and aggressive behaviour can occur
3 - surgical anaesthesia with further 4 stages of increasing depth until breathing is weak, muscles are completely relaxed and there's no eye movement. Breathing may need to be assissted
4 - respiratory paralysis due to severe medullary depression. Can lead to death
367
What mediates stage 1 of anaesthetic depth?
Early effects on transmission of spinothalamic tracts (pain, temperature and vibration sensation)
368
What is the effective integrated MAC needed in surgical anaesthesia?
1.2-1.5
369
What is the MAC therapeutic window?
1.2-2.2
370
How are inhalation anaesthetic agents prepared and administered?
Require careful titration and vaporising as fluranes are volatile fluids at room temperature. Principal agent is then mixed with oxygen, air and nitrous oxide and fed into respiratory system by spontaneous or controlled respiration
371
What is the minimal alveolar concentration?
The percentage of inhaled anaesthetic that abolishes to response to surgical incision in 50% of patients.
372
How is Minimal Alveolar Concentration related to potency?
Higher MAC means lower potency. Also Higher MAC means lower lipid solubility.
373
What defines degree of absorption of anaesthetics across the alveoli?
Blood:gas coefficient which is volume of gas that can dissolve in one litre of blood. A higher coeffecient means drug enters blood more readily
374
What determines how readily anaesthetics are taken up into specific tissue types from blood?
The tissue:blood partition coefficient. Higher coefficient means more drug taken up by an equivalent volume of tissue than blood
375
In general, which tissues show higher blood:tissue partition coefficients?
Fat is very lipophilic, then muscle, then brain
376
How can fat solubility of a drug affect recovery from anaesthesia?
Fat acts as a very large reservoir of drug and so can redistribute the drug in recovery, prolonging it.
377
How are inhalational anaesthetic agents eliminated?
When blood concentration reduces, drug moves out of cells into veins, then back to alveoli where they're eliminated
378
What order of kinetics do inhalation anaesthetic agents follow?
First order elimination
379
What is duration of recovery from anaesthesia related to?
Length of procedure
| Degree of loading of muscle and fat.
380
How are IV anaesthetic agents distributed?
When initial induction bolus is given. it is quckly distributed to the CNS and surgical anaesthesia is maintained for abot 5 minutes until surgical depth decreases as drug redistributes to muscle and fat.
381
How is propofol metabolised?
Hepatically and extrahepatically
382
What are some ADRs of inhalational flurane anaesthetics?
Respiratory and cardiovascular depression due to reduced neuronal activity in medullary centres
Hypotension due to reduced vascular resistance
Increased cerebral blood flow causes raised intracranial pressure.
Bronchodilation and irritation so cough and laryngospasm
Muscle tetany and malignant hyperthermia due to massive sarcoplasmic release of Ca2+
383
What are some ADRs of inhalation nitrous oxide as an anaesthetic?
It causes expansion of gaseous cavities. This is dangerous in bowel obstruction, pneumothorax, intracranial air and vascular air emboli
Diffusion hypoxia as it has a low blood:gas coefficient and quickly reenters alveoli on withdrawal. Dangerous in reduced respiratory function
384
How can diffusion hypoxia be offset in nitrous oxide recovery?
By increasing the partial pressures of oxygen given at recovery onset
385
What is the function of nitrous oxide in anaesthesia?
Can't act alone as an anaesthetic but is an adjunct to more volatile anaesthetics (reduced MAC)
386
What agents can be given as pre-medication in anaesthesia?
Hypnotic benzodiazepines for anxiolysis and amnesia (GABA agonists)
387
What agents are given for intraoperative analgesia?
Opioids such as fentanyl and morphine
388
What's the benefit of giving fentanyl as an intraoperative analgesic, over morphine?
Is more potent with short hal life so allows finer control of analgesic effect
389
Why is muscle paralysis important in surgery?
Abolishes reflexes and induces muscle relaxation. THis facilitates intubation and ventilation and abolishes reflexes that occur with significantly invasive procedures that would otherwise interfere with surgery
390
What agents can be given to induce muscle relaxation in surgery?
Competitive ACh antagonists eg tubocurarine
ACh depolarising agents eg succinylcholine
Flurane
391
What's the benefit of using multiple agents in anaesthesia?
Divides the pharmacological labour so there can be finer control of anaesthetic depth
392
When are carbonic anhydrase inhibitors used?
In glaucoma and infantile epilepsy
393
How do carbonic anhydrase inhibitors work?
Act to increase HCO3- exretion and subsequent Na+, K+ and H2O excretion. This increases flow of alkaline urine and causes metabolic acidosis
394
Where do osmotic diuretics work?
PCT, descending limb and collecting tubules
395
When are osmotic diuretics used?
Acute renal failure
Rasied intracranial pressure
Raised intraocular pressure
396
Give an example of a loop diuretic
Furosemide
397
What kind of agent is furosemide?
Loop diuretic
398
How do loop diuretics act?
Inhibit Na+/K+/Cl- transporter on thick ascending limb to reduce Na+ and Cl- reabsorption and increase excretion of H+ and K+ and increase concentration of HCO3-
Also reduce excretion of uric acid
399
Give an example of a thiazide diuretic
Hydrochlorothiazide
400
How do thiazide diuretics work?
Act on Na+/Cl- transporter in DCT to increase loss of Na+, Cl-, H+ and K+. Also reduces Ca2+ excretion
401
Give an example of an aldosterone antagonist
Spironolactone
402
What kind of agent is spironolactone?
Aldosterone antagonist
403
What are some general ADRs of diuretics?
Electrolyte disturbance
Metabolic abnormalities
Anaphylaxis or rash
Hypovolaemia and hypotension
404
What are some ADRs specific to thiazide diuretics?
Erectile diysfunction
405
What are some ADRs specific to loop diuretics?
Gout
Ototoxicity
Myalgia
406
What are some DDIs of K+ sparing diuretics?
When used with ACE inhibitors, increases risk of hyperkalaemia
407
What are some DDIs of loop diuretics?
When used with aminoglycoside antibiotics, risk of ototoxicity and nephrotoxicity.
When used with digoxin or steroids, increased risk of hypokalaemia.
408
What are some DDIs of thiazide diuretics?
WHen used with digoxin or steroids, increased risk of hypokalemia
When used with Beta blockers, risk of hyperglycaemia, hyperlipidaemia and hyperuricaemia
When used with carbamazepine, risk of hyponatraemia
409
When may diuretic resistance occur?
If there's incomplete treatment of the primary disorder
In non-compliance with treatment
If there's continuously high Na+ intake
In poor absorption
In volume depletion leading to reduced filtration and increased serum aldosterone so increased Na+ reabsorption
In NSAID use leading to reduced renal blood flow
410
What drugs can be used in heart failure?
Thiazide or loop diretics to reduce preload
Beta blockers to reduce work of the heart
Spironolactone
ACE inhibitors to reduce afterload
411
What drugs are used in decompensated liver disease?
Spironolactone
| Loop diuretics
412
What drugs are potentially nephrotoxic?
```
AMinoglycosides
Penicillins
Cycolsporin A
Metformin
NSAIDs
ACE inhibitors
```
413
How can ACE inhibitors be nephrotoxic?
If there's existing renal artery stenosis leading to reduced eGFR and activation of RAAS to maintain blood flow, there's vasoconstriction and further reduced eGFR.
ACE inhibitors preferentially dilate the efferent arteriole so blood accumulates in the kidney leading to reduced eGFR and acute renal failure
414
What are the different grades of hypertension?
Grade 1 mild = 140-159/90-99
Grade 2 moderate = 160-179/100-109
Grade 3 severe = >180/>110
415
What are the different grades of isolated systolic hypertension?
Grade 1 = 140-159/160/<90
416
What is the threshold for treating hypertension?
If >160/ >100 then treat straight away
If >140/>90 with diabetes then treat straight away
If 140-159/90-99 without diabetes then decision depends on overall risk profile, presence of end organ damage and if there's a >15% risk of a cardiovascular event withint ten years
417
What are the non-pharmacological aspects of hypertension therapy?
```
Patient education
Encourage optimum body weight
Limit alcohol intake
Limit salt intake
Engage in regular aerobic exercise
Consume at least 5 portions of fruit and veg a day
Reduce total and saturated fat intake
Stop smoking
Relaxation therapy
```
418
What are the treatment guidelines for pharmacological therapy of hypertension?
If less than 55 years old then treat with an ACE inhibitor initially. If 55 or older or black, then treat with either a thiazide diuretic or calcium channel blocker initially.
Progress onto an ACE inhibitor with either a calcium channel blocker or a diuretic
Then progress onto an ACE inhibitor, calcium channel blocker AND diuretic
If control still not reached, then add either another diuretic, an alpha blocker or a beta blocker
419
Give an example of an ACE inhibitor
Lisinopril
420
What kind of agent is lisinopril?
ACE inhibitor
421
How do ACE inhibitors work to treat hypertension?
Reduce levels of circulating aldosterone and cause vasodilation and increased sodium and so water excretion. Also potentiate the action of bradykinin
422
What are some ADRs of ACE inhibitors?
```
Dry cough
Angioedema
First dose hypertension
Sharp decline in renal function
Hyperkalaemia
```
423
How do angiotensin receptor blockers work to treat hypertension?
Bind to AT1 receptor to inhibit vasoconstriction and production of aldosterone
424
What are some ADRs of angiotensin receptor blockers?
Renal failure
| Hyperkalaemia
425
What are the three types of calcium channel blocker?
Dihydropyridins eg amlodipine
Phenylalkylamines eg verapamil
Benzothiazepines eg diltiazem
426
In general, how do calcium channel blockers work to treat hypertension?
Bind to L type Ca2+ channels to reduce calcium entry, causing vasodilation
427
How do dihydropyridin calcium channel blockers work?
Vasodilators causing baroreflex mediated tachycardia
428
What are some ADRs of dihydropyridin calcium channel blockers?
Tachycardia and palpitations
Flushing, sweating and headache
Oedema
Gingival hyperplasia
429
How do phenylalkylamine calcium channel blockers work?
Reduce Calcium transport across smooth muscle membrane to cause vasodilation and reduce cardiac contractility so reduce preload
430
What are some ADRs of phenylalkylamine calcium channel blockers?
Constipation
Bradycardia
Negative inotropy
431
How do benzothiazepine calcium channel blockers work?
Like phenyalkylamine class. Reduce calcium transport to reduce preload and contractility but have a smaller constipation risk and less significant effect on inotropy
432
Give an example of an alpha blocker?
Doxasin
433
What kind of agent is doxasosin?
Alpha blocker
434
How do alpha blockers act to treat hypertension?
Selectively antagonise post synaptic alpha1 receptors to antagonise contractile effects of NA on vascular smooth muscle to reduce vascular resistance
435
What are some ADRs of alpha blockers?
Postural hypotension
Dizziness
Headache and fatigue
Oedema
436
What are some ADRs of beta blockers?
```
Lethargy and impaired concentration
Bradycardia
REduced exercise tolerance
Impaired glucose tolerance
Cold hands
```
437
Give an example of a direct renin inhibitor
Aliskirin
438
What kind of agent is aliskirin?
Direct renin inhibitor
439
How do direct renin inhibitors act to treat hypertension?
Bind to renin and so block cleavage of angiotensinogen
440
How are direct renin inhibitors excreted?
In faeces
441
When are direct renin inhibitors contraindicated?
```
Pregnancy
Risk of hyperkalaemia
Sodium or volume depletion
Heart failure
Severe renal impairment
Renal artery stenosis
```
442
How can centrally acting agents treat hypertension?
Agonise central alpha2 receptors to cause vasodilation
443
What are some ADRs of centrally acting agents in hypertension?
Tiredness and lethargy
| Depression
444
Give some examples of centrally acting agents used in hypertension
Methyldopa
| Clonidine
445
What are the aims of treatment of heart failure?
Find and treat underlying cause if present
symptom control
Reduced mortality
Lifestyle changes
Combine lifestyle, medication, devices and surgery
Delay progression
Treat complications and risk factors
446
What drugs can improve prognosis in heart failure
Beta blockers
| Drugs that antagonise RAAS
447
What classes of drugs antagonise RAAS?
ACE inhibitors
Angiotensin receptor blockers
Aldosterone antagonists
448
What are some ADRs of aldosterone antagonists?
```
GI disturbance
Hair loss or overgrowth
Gynaecomastia
Breast pain
Kidney problems
```
449
How do beta blockers work to treat heart failure?
Inhibit sympathetic activity to the heart to reduce heart rate and cardiac output reduce oxygen demand
450
How can Nitrates and hydralazine work to treat heart failure?
Glyceryl trinitrate causes venodilation so reduces preload. Hydralazine causes vasodilation so reduces afterload.
451
What are some ADRs of glyceryl trinitrate?
Severe headache
Tolerance
Hypotension
Bradycardia
452
What are some ADRs of hydralazine?
Tachycardia
Headache
Palpitations
453
How can cardia glycosides be used in heart failure?
Inhibit Na+/K+ pumps to increase intracellular Na and inhibit NCX to increase intracellular Ca2+ so there's increased force of contraction
454
What are some ADRs of cardiac glycosides?
```
Nausea and vomiting
Diarrhoea
Dyspnoea
Confusion
Dizziness and headache
Blurred vision and diplopia
```
455
Give an example of a potassium sparing diuretic
Amiloride
456
How do potassium sparing diuretics work to treat heart failure?
Block ENaC to increase sodium and water release
457
What are the four main phenomena that underly cardiac arrhythmias?
Abnormal impulse generation with triggered rhythms
Abnormal impulse generation with automatic rhythms
Abnormal conduction with block
Abnormal conduction with re-entry
458
What is an after-depolarisation?
An abnormal depolarisation of myocytes that interrupts phase 2-4 of the cardiac action potential
459
What are the subtypes of abnormal impulse generation with triggered rhythms, underlying arrhythmia?
Delayed after depolarisation
| Early after depolarisation
460
What is a delayed after depolarisation and why do they happen?
After depolarisation that occurs after repolarisation has finished but before another depolarisation would normally occur. Usually due to raised calcium activating the 3Na+/Ca2+ channel so there's depolarisation.
461
What is an early afterdepolarisation and why do they happen?
After-depolarisation that is an abortive action potential occurring before normal repolarisation has completed. May be because of altered opening of sodium and calcium channels. Happens in torsades de pointes and tachycardia
462
What are the subtypes of abnormal impulse generation with automatic rhythms, underlying arrhythmia?
Enhance normal automaticity
| Ectopic focus
463
What is meant by enhanced normal automaticity in arrhythmia?
There's accelerated generation of an action potential by normal pacemaker tissue leading to sinus tachycardia
464
What happens in ectopic foci in arrythmia?
Action potentials arise from a site other than the sinoatrial node. Normally the SA node can suppress this activity but if it's malfunctioning or the ectopic focus has a superior intrinsic rate then the ectopic focus can take over the natural rhythm.
465
What are the different types of ectopic beats and what do they indicate?
Premature ectopic beats give a reduced R-R interval and indicate increased excitability of myocytes or conducting tissue
Late ectopic beats give an increased R-R interval and indicate proximal pacemaker or conduction failure
466
Whatis involved in first degree heart block?
Impulses from atria to ventricles are slowed so there's an increased P-R interval
467
What is involved in second degree heart block?
Impulses from atria to ventricles are significantly slowed and some don't reach the ventricles at all
468
What are the two different types of second degree heart block?
Mobitz type 1 is where there's progressive slowing of impulse transmission until a beat is skipped
Mobitz type 2 is where there's a less regular pattern with a normal P-Q interval but some QRS waves are missing
469
What is involved in third degree heart block?
No impulses reach the ventricles. There's an increased rate of P waves and QRS complexes occur at slower rate than usual and aren't coordinated with the atrial contractions.
470
What is a re-entry leading to arrhythmia?
Occurs when instead of an action potential dying out after activating the ventricles, the impulse re-excites areas of myocardium when refractory period subsides so there's continuous circulation of action potentials.
471
What are the different causes of a re-entry arrhythmia?
Can occur because of an anatomical abnormality or aberrant conduction pathway eg in Wolff-Parkinson-WHite
Or because of heterogeneous conduction because of myocardial damage, eg after an MI
472
What are the different classes of anti-arrhythmics?
Class 1 - sodium channel blockers
Class 2 - Beta blockers
Class 3 - drugs that prolong action potential
Class 4 - Calcium chanell blockers
473
Give an example of a class 1a anti-arrhythmic
Quinidine
474
How do class 1a anti-arrhythmics work?
Are use dependent and act to reduce conduction in phase 0 (make initial upslope less steep). Also increase length of refractory period and threshold.
Overall act to increase duration of action potential.
475
When are class 1a anti-arrhythmics used?
TO convert atrial fibrillation and flutter to normal sinus rhythm
Prevent recurrent tachycardia and fibrillation
476
What are some ADRs of class 1a anti-arrhythmics?
```
Dizziness, confusion, insomnia and seizure
Hypotension
Reduced cardiac output
GI disturbance
Proarrythmic
Lupus like syndrome
```
477
Give an example of a class 1b anti-arrythmic
Lidocaine
478
How do class 1b anti-arrythmics work?
Block sodium channels to reduce action potential duration and increase threshold. Most effective in fast-beating tissue
479
When are class 1b anti-arrhythmics used?
In ventricular tachycardia and fibrillation
480
What are some ADRs of class 1b anti-arrhythmics?
Dizziness
Drowsiness
Some pro-arrythmic but less so than class 1a
481
How do class 1c anti-arrhythmics work?
Depresses depolarisation of phase 0 (less steep slope) and increases the threshold. Acts to increase duration of refractory period with small increase in action potential length.
482
When are class 1c anti-arrhythmics used?
In supraventricular fibrillation and flutter
Premature ventricular contractions
Wolff Parkinson White
483
What are some ADRs of class 1c anti-arrhythmics?
Pro-arrhythmic with risk of sudden death
Increase ventricular response to supraventricular arrhythmias
CNS and GI effects
484
How do beta blockers work as anti-arrhythmics?
Increase duration of action potential and refractory period to slow conduction at AV node and reduce conduction at phase 4. Reduce heart rate.
485
What arrhythmias are beta blockers used for?
Tachyarrhythmias
Conversion of reentrant arrhythmias at AV node to sinus rhythm
Protection of ventricles from high atrial contraction rates
486
Give examples of two class 3 anti-arrhythmics
Amiodarone
| Sotalol
487
How does amiodarone act as an anti-arrhythmic?
Acts to increase duration of action potential and refractory period. Reduces conduction in phase 0 and increases the threshold. Also reduces phase 4 and slows AV conduction
488
What are some ADRs of amiodarone?
```
Photosensitivity
Thyroid abnormalities
Increase LDL levels
Neurological disturbance
Hepatic injury
Pulmonary fibrosis
```
489
How does sotalol act as an anti-arrhythmic?
In a non-selective beta blocker so acts to increase duration of action potential and refractory period. It slows conduction in phase 4 at AV node so there's increased QT length and reduced heart rate
490
When is sotalol used as an anti-arrhythmic?
In supraventricular and ventricular tachycardias
491
What are some ADRs of sotalol?
Proarrhythmic
Fatigue
Insomnia
492
How do calcium channel blockers act as anti-arrhythmics?
Slow conduction through the AV node and increase refractory period at AV node. Reduce heart rate.
493
WHen are calcum channel blockers used as anti-arrhythmics?
In supraventricular tachycardia
494
What are some ADRs of calcium channel blockers as anti-arrythmics?
Asystole
| GI disturbance
495
How does adenosine work as an anti-arrhythmic?
Binds to alpha 1 eceptors to increase K+ conductance at the AV and SA node so reduces length of action potential and reduces heart rate
Also reduces Ca2+ currents to increase refractory period at the AV node
496
What arrhythmia is adenosine used for?
Re-entrant supraventricular arrhythmias
497
How does digoxin work?
Is a cardiac glycoside that increases K+ and reduces Ca2+ currents to reduce conduction at AV node and reduce heart rate. Also increases force of contraction
498
What arrhythmias is digoxin used for?
Atrial fibrillation and flutter
499
What are different possible compartments for tumour cells?
Compartment A is dividing cells that have an adequate supply of blood and nutrients. They make up 5-20% of tumour cells and are the most susceptible to chemo
Compartment B is resting cells in G0 phase that can rejoin compartment A if there's change in cell signalling or in local environment ie after surgery or chemo. These have much lower effective kill ratio
COmpartment C is cells that can no longer divide but contribute to overall tumour bulk
500
What is the diagnostic threshold of cancer cell number?
10^9
501
What is the log kill ratio?
Model to show proportionate killing by a drug
502
How are log kill ratios calculated?
But power of 10 cells that are killed. ie if 10^4 cells are killed out of 10^9 this is a four log kill ratio.
Will need another dose to bring it to 10^1
503
What is the fractional cell kill hypothesis?
Theory used to ensure that bone marrow cells and other healthy tissue can recover significantly ahead of tumour cells. Allows healthy cell recovery but minimal tumour cell recovery. Done by giving repeated doses of chemotherapy drug with gaps in between doses
504
Name some tumours that are highly sensitive to chemotherapy?
```
Germ cell tumours
Small cell lung tumours
Lymphomas
Neuroblastoma
Wilm's tumour
```
505
Name some tumours that are moderately sensitive to chemotherapy
```
Breat
Bladder
Ovarian
Cervical
Colorectal
```
506
Name some tumours that are poorly sensitive to chemotherapy
Brain tumours
Prostate
Endometrial
Renal cell
507
What are some causes in variability in a person's response to chemotherapy?
Abnormalities in absorption, eg nausea and vomiting, gut problems or compliance
Abnormalities in distribution eg in ascites, weight loss and reduction in body fate
Abnormalities in elimination due to liver and renal dysfunction and other medications
Abnormalities in protein binding eg due to low albumin and other medication
508
What are some different routes of administration for chemotherapy drugs?
```
IV
Subcutaneous
Oral
Intrathecal
Intralesional
Into a body cavity
Topical
```
509
In dosing chemotherapy, why is it difficult to make assumptions on body cavities?
Plasma is proportionally larger than normal due to weight loss and decreased body fat.
Agents can be highly protein bound and there may be significant compromise in function of heart, liver and kidneys
510
How should dosing of chemotherapy be done?
Based on body surface area and BMI with measures of renal function and drug levels to normalise any variations, establish clearance and approximate total drug exposure
511
How can cancer cells acquire resistance to chemotherapy?
Upregulation of Multi Drug Resistant Protein due to repeated drug exposure and so increase non-specific removal of drugs from cells
Reduce rate of active uptake of drug eg by downregulation of carrier
Upregulate target enzyme to compensate for reduction in metabolite production
Increase expression of repair enzymes and so increase rate of repair of drug induced lesions
512
What is Multi Drug Resistant Protein?
A p-glycoprotein found in most healthy cells but particularly expressed in cells of liver, kidney adn GI tract. Acts to remove large, hydrophobic xenobiotics in a non-specific way so can be effective against various structurally dissimilar molecules
513
When might acquired resistance to chemotherapy arise?
If there's repeated suboptimal doses given that allow time for cells to manifest resistant responses
514
How can clinicians counter effects of chemotherapy resistance?
Use doses that are high, short term, intermittent and repeated in optimal combinations for a specific tumour type
515
How do alkylating agents work in chemotherapy?
Contain two highly labile groups that when in the cell can detach, leaving binding site available to form covalent bonds with nucleophilic parts of DNA bases. Two separate sites mean that inter-and intra-strand crosslinks can form which interferes with DNA replication and RNA transcription
516
Give some examples of alkyating agents
Cis-platin
| Cyclophosphamide
517
At what point in the cell cycle are alkylating agents most effective?
Interact at any point but are most effective in S phase with higher rates of DNA replicationg and large sections of exposed, unpaired DNA
Also effective in G1 where it can interfere with transcription of DNA synthesis enzyme synthesis
518
What are some specific ADRs of cis-platin (alkylating agent)?
High frequency ototoxicity
| Peripheral neuropathy
519
How does methotrexate work in chemotherapy?
Acts to inhibit dihydrofolate reductase (DHFR) enzyme which is needed for folate synthesis which is needed for purine synthesis.
It's structurally similar to folic acid but binds to DHFR with a much higher affinity. Inhibiting purine synthesis means there's reduced DNA synthesis (especially affects thymidine.)
520
How does 5-fluorouracil work in chemotherapy?
Is a uracil analogue and Converts to F-dUMP which competes with dUMP for active site of thymidylate synthase. Once bound, it forms a stable complex that can't form any product so enzyme is irreversibly inhibited.
Cell eventually undergoes thymidine-less cell death
521
What are the two main types of anti-metabolite chemotherapy agents?
Methotrexate and 5-Fluorouracil
522
What are some specific ADRs of methotrexate?
Renal failure
| Myelosuppression
523
When are antimetabolite chemotherapy agents most effective?
In S phase. Not effective in malignancies with a low growth fraction
524
What are the two main type of spindle poison chemotherapy agents?
Vinca alkaloids eg vincristine
| Taxanes eg paclitaxel
525
What is the principal of action of spindle poison chemotherapy agents?
Interfere with microtubule formation from alpha and beta tubulin proteins which go on to form mitotic spindle, needed for alignment of chromosomes in mitosis
526
How do vinca alkaloids work in chemotherapy?
Bind to beta tubulin and prevent it from polymerising to form microtubules. This arrests the cell in metaphase of mitosis, stimulating apoptotic cell death
527
How do taxanes work in chemotherapy?
Bind to beta tubulin and let it polymerise but then stabilise the microtubule so that it can't disassemble to pull the chromosomes apart.
This arrests the cell in metaphase and triggers apoptotic cell death
528
When are spindle poison alkylating agents most effective?
In M phase
529
What is a specific ADR of spindle poison chemotherapy agents?
Stocking and glove peripheral neuropathy
530
Give an example of an intercalating chemotherapy agent?
Doxorubicin
531
How do intercalating chemotherapy agents work?
Have discrete molecular ring structure that can intercalate between DNA base pairs to impair DNA transcription and replication and affect topoisomerase that normally enables replication and repair.
Main mechanism of killing is their generation of free radicals that cause DNA damage which is then detected and apoptosis is triggered.
532
What's a specific ADR of intercalating chemotherapy agents?
Cardiotoxicity
533
Give an example of a DNA scission chemotherapy agent
Bleomycin
534
How does DNA scission chemotherapy agent Bleomycin work?
Can bind with DNA and chelate with free Fe2+ ions producing free radicals which attack DNA phosphodiester bonds and so cut DNA strands.
535
When is DNA scission chemotherapy agent bleomycin most effective?
In G2 with some action in G0
536
What is a specific ADR of DNA scission chemotherapy agent bleomycin?
Pulmonary toxicity with risk of pulmonary fibrosis
537
What are the common ADRs of chemotherapy?
```
Nausea and vomiting
Alopecia
Mucositis
Skin toxicity
Cardiotoxicity
Haematological toxicity
Acute renal failure
```
538
What underlies nausea and vomiting in chemotherapy and what are its different phases?
Action of agents of central chemoreceptor trigger zones.
Acute phase occurs 4-12 hours after treatment
Delayed onset can occur 2-5 days later
Chronic phase occurs within 14 days
Can be anticipatory due to hospital environment
539
What are the different types of skin toxicity that can occur in chemotherapy?
Local toxicity with irritation and thrombophlebitis. If there's extravasation of agents into surrounding tissue, there can be tissue necrosis
General toxicity. Some alkylating and intercalating agents can cause hyperpigmentation/ Bleomycin can cause hyperkeratosis, hyperpigmentation and ulcerated pressure sores
540
How can mucositis in chemotherapy present?
Sore mouth and throat
Diarrhoea
GI bleeding
541
What is the mechanism of acute renal failure in chemotherapy?
Rapid tumour lysis means that there's rapid release of purines into circulation. These produce urates and if there's urate crystal deposition in renal tubules, can be renal failure
542
What is the benefit of therapeutic DDIs in chemotherapy?
Reduce overlap of shared toxicity whilst delivering all agents at the highest dose for the shortest time with gaps in treatment for recovery.
This reduces the risk of irreversible ADRs, increases kill ratio and offsets risk of drug resistance
543
How can response of cancer to treatment be monitored?
Radiological imaging
| Testing of tumour markers and bone marrow function
544
How is potential organ functional deficit be monitored in chemotherapy>
```
EEG/ECG for cardia function
FEV1/FVC for pulmonary function
Hepatic enzymes in plasma
Creatinine clearance for renal function
Evoked neural responses
Audiogram in cis-platin treatment
```
545
How is pharmacokinetics of chemotherapy monitored?
Estimate half life and clearance by sampling blood/urine/CSF/tissue
Estimate area under curve to estimate patient's handling of chemotherapy and to maximise benefit whilst minimising toxicity
546
What is epilepsy?
An episodic discharge of abnormal high frequency electrical activity in the brain leading to seizure
547
What evidence is required for diagnosis of epilepsy?
Evidence of recurrent seizures which are unprovoked by other identifiable causes
548
What are the two main types of epilepsy?
Focal
| Generalised
549
What are focal seizures?
Where discharges begin in a localised area of the brain with symptoms reflecting the area that is affected. There's loss of local excitatory and inhibitory homeostasis and an increase in focal discharges in the focal cortical area
550
What are some common symptoms of focal seizures?
Involuntary motor disturbance
Behavioural change
Abnormal sensations
Impending focal spread accompanied by aura of unusual smell, taste, deja vu or jamais vu
551
What are the different types of focal seizures?
Simple where consciousness is retained
Complex where consciousness is lost
Can spread through corpus callosum to give a secondary generalised seizure
552
What's the difference between primary and secondary epilepsy?
Primary epilepsy is where there's no identifiable cause and individual has inherent tendency towards seizures
Secondary epilpsy occurs as result of a medical condition affecting the brain
553
What is the general process behind epilepsy?
There's increased excitatory activity and reduced inhibitory activity with loss of homeostatic control and spread of neuronal hyperactivity
554
What are generalised seizures?
Where whole brain is affected, including the reticular system so there's immediate loss of consciousness. They're generated centrally and spread through both hemispheres
555
What are the different types of generalised seizures?
Tonic clonic with tension and rigidity of muscles giving rise to convulsions
Absence of seizures where individual loses consciousness but remains upright
556
What are some possible precipitants to a seizure?
Sensory stimuli
Brain disease or trauma such as injury, stroke, haemorrhage, drugs, alcohol, structural abnormality or lesion
Metabolic disturbance such as hypo - glycaemia, calcaemia or natraemia
Infections
Therapeutics
557
What are some possible consequences of uncontrolled epilepsy?
```
Physical injury through seizure
Hypoxia
Sudden death in epilepsy
Varying degrees of brain dysfunction
Cognitive impairment
Increased risk of serious psychiatric disease
Significant adverse reactions to medication
Stigma and loss of livelihood
Status epilepticus
```
558
What is status epilepticus?
Prolonged seizure of any type lasting longer than 30 minutes of convulsions occurring back to back with no recovery in between. Can be convulsive or non-convulsive
559
What are the dangers of status epilepticus?
Hypoxia
Brain damage
Sudden death in epilepsy
Mortality rate of 20%
560
How is status epilepticus treated?
Protect airway and give oxygen
Identify cause by doing bedisde glucose, lab U+Es and calcium, and blood gases and reverse if possible.
Give benzodiazepines first line, preferably lorazepam IV or rectally. If this isn't possible/doesn't work then give phenytoin IV but monitor for arrhythmias and hypotension
If necessary transfer to ITU for paralysis and ventilation
561
What factors should be considered when prescribing anti-epileptics in pregnancy or woman of child bearing age?
Risk to moher and fetus of a seizure if treatment stops by taking a detailed history of a person's fit frequency and severity
AED association with congential deformity
562
How can risk of congential malformations in anti-epileptic drug use be minimised?
Risk increases with multiple use so use single agent at lowest dose possible. Preferably use lamotrigine as has lowest risk and avoid valproate as has highest risk of neural tube defects and learning difficulties.
Take folate supplements to reduce risk of neural tube defects
Take vitamin K supplements in last trimester to reduce risk of vitamin K deficiency and subsequent coagulopathy and cerebral haemorrhage
563
What are the two main classes of anti-epileptic drugs?
Voltage gated sodium channel blockers
| Enhancers of inhibitory action of GABA
564
What are the 3 main voltage gated sodium channel blockers?
Carbamazepine
Phenytoin
Lamotrigine
565
How to voltage gated sodium channel blockers work to treat epilepsy?
Bind to VGSC inactivation gate on heavy depolarisation (use dependent) to prolong the inactivation state and bring firing rate back to normal when seizure involves loss of membrane potential homeostasis and spread of hyperactivity.
Detach again when membrane potential normalises
566
What are the main pharmacokinetic characteristics of carbamazepine?
```
75% protein bound
Well absorbed
Linear pharmacokinetics
Half life of 30hrs intially and reduces to 15 hours wih chronic use
Inducer of CYP 450 system
Requires monitoring
```
567
What are some ADRs of carbamazepine?
```
Dizziness
Ataxia
Drowsiness
Motor disturbnace
Numbness/tingling
Gi upset and vomiting
Blood pressure variations
Rashes
Hyponatraemia
Bone marrow suppression and neutropenia
```
568
What is a DDI of carbamazepine?
Is inhibited by antidepressants, ie SSRIs, MAOIs, TCAs
569
What kind of seizures should carbamazepine be used for?
First line in focal seizures.
| Generalised tonic clonic
570
What are the main pharmacokinetic and dynmic properties of phenytoin?
Is well absorbed and 90% protein bound so drugs competing for proteins can raise its free concentration which exacerbates it's non-linear pharmacokinetics at therapeutic doses.
Half life = 6-24 hours
Metabolised hepatically and is an inducer of CYP 450 system
Needs monitoring
571
What are some ADRs of phenytoin?
```
Dizziness
Ataxia
Nystagmus
Nervousness
Gingival hyperplasia
Headache
Rashes
Hypersensitivity, including stevens-johnson
```
572
What kind of seizures is phenytoin used for?
Focal
| Generalised tonic clonic
573
In addition to being a VGSC blocker, what other action does lamotrigine have?
Blocks Ca2+ channels on Glutamate receptor to inhibit its excitation and so reduce excitatory effects of glutamate
574
What is the half life of lamotrigine?
24 hours at linear pharmacokinetics
575
What are some ADRs of lamotrigine?
```
Dizziness
Ataxia
Somnolence
Nausea
Rashes
```
576
What are some DDIs of lamotrigine?
Levels are reduced by the ral contraceptive pill and are increased by valproate as it is heavily protein bound
577
What kind of seizures is lamotrigine used for?
Absence
Focal
Generalised tonic-clonic
First line treatment in pregnancy/women of child bearing age
578
What are the 3 main anti-epileptic drugs that act by enhancing GABA activity?
Benzodiazepines
Valproate
Vigabatrin
579
How do some antiepileptics enhance GABA action?
Can increase Cl- influx to increase threshold of action potentials to reduce likelihood of neuronal activity. Can enhance GABA by inhibiting its inactivation, inhibiting its reuptake or increasing its rate of synthesis
580
How does valproate work to treat epilepsy?
Weakly inhibits enzymes that inhibit GABA and weakly stimulate enzymes that synthesise GABA. Block VGSCs and Ca2+ channels so overall reduce excitability of neurones
581
What are the main pharmacodynamic and pharmacokinetic characteristics of valproate?
Is highly protein bound (90%)
Linear pharmacokinetics
Half life =15 hours
582
What are some ADRs of valproate?
```
Weight gain
Hair loss
Sedation
Tremor
Ataxia
Increased transaminase levels
Rarely hepatic failure
```
583
What are some DDIs of valproate?
Can increase free levels of phenytoin and lamotrigine by affecting their protein binding.
Is inhibited by antidepressants
Action is antagonised by antipsychotics which act to lower the convulsive threshold
Levels are increased by aspirin which affects its protein binding
Plasma levels, blood, metabolic and liver functions all need monitoring
584
What kind of seizures is valproate used for?
Absence
Focal
Generalised tonic-clonic
585
How do benzodiazepines work to treat epilepsy?
Increase Cl- influx at distinct GABA receptors and increase GABA's affinity for its receptor. This suppresses the seizure focus and strengthens the surrounding inhibition.
586
What are the main pharmacokinetic and pharmacodynamic characteristics of benzodiazepines?
Are well absorbed and highly protein bound
Linear pharmacokinetics
Half life = 15-45 hours
587
What are some ADRs of benzodiazepines?
```
Sedation
Confusion
Aggression
Impaired coordination
Respiratory and CNS depression
Dry mouth
Blurred vision
GI upset
Headache
Reduced bloop pressure
Amnesia
Restlessness
Chronic use causes tolerance, dependence and withdrawal effects
```
588
How can benzodiazepine overdose be reversed and what are the dangers of this?
Use IV flumazenil but this is pro-arrhythmic and can be a seizure precipitant
589
What kind of seizures are benzodiazepines used for?
Lorazepam/diazepam are used in status epilepticus
| Clonazepam can be used short term in absence seizures
590
How does vigabatrin work to treat epilepsy?
Structural GABA analogue that inhibits GABA transaminase to increase GABA levels
591
What is an ADR of vigabatrin?
Peripheral visual field defects
592
What kind of epilepsy is vigabatrin used for?
Infantile spasms
| Focal epilepsy
593
What is parkinsonism characterised by?
```
Resting tremor
Bradykinesia
Postural instability
Lead pipe rigidity
Mood changes
Pain
Cognitive change
Urinary symptoms
Sleep disorder
Sweating
```
594
What are the main causes of parkinsonism?
Idiopathic parkinson's disease
Vascular parkinsonism
Dementia with Lewy bodies
Drug induced parkinsonism
595
What is idiopathic parkinson's disease?
A neurodegenerative progressive disease involving motor symptoms that improve with levodopa and non-motor symptoms that don't improve with levodopa.
596
How idiopathic parkinson's be visualised?
DAT scan using radiolabelled trace taken up by dopaminergic neurones. IPD will show loss of substantia nigra neurones
597
What drugs can cause parkinsonism?
```
Neuroleptics
Antidepressants
Valproate
Anti-vertigo drugs
Anti-emetics
Amiodarone
Ca2+ channel blockers
Lithium
```
598
What are Lewy bodies?
Abnormal deposits in neurones that cause neuronal death
599
What are the main symptoms of dementia with Lewy bodies?
```
Bradykinesia
Stiff limbs
Reduced attention
Difficulty carrying out simple actions
Speech problems
Tremor
Visual hallucinations
Sleep disturbances
Fainting
Unsteadiness
Falls
Memory and concentration problems
Reduced recognition of faces
Quick variations between alertness and drowsiness
```
600
What is vascular parkinsonism?
Progressive condition that occurs due to restricted blood supply to the brain. Occurs in eldery, diabetes and those with previous stroke.
601
What are the signs and symptoms of vascular parkinsonism?
```
Difficulty speaking, making facial expressions and swallowing
Memory changes
COnfused thought
Postural instability
Shuffling gait
Ataxia
Cognitive problems
Incontinence
Variable stride length
```
602
What symptoms are indicative of vascular parkinsonism over idiopathic parkinson's disease?
Vascular parkinsonism tends to involve more postural instability and falls early on which are quite late on in IPD. IPD tends to have greater degree of tremor and bradykinesia
603
What is seen on MRI in vascular parkinsonism?
White matter lesions
| Subcortical infarcts
604
At what point do symptoms of idiopathic parkinson's disease appear?
When there's been 50% loss of dopaminergic neurons at substantia nigra
605
What are some non-motor symptoms of idiopathic parkinson's disease?
```
Sleep problems
Orthostatic hypotension
Excessive sweating
Urinary incontinence
COnstipation
Reduced rate of blinking and drying eyes
Impaired sensation
```
606
What is multisystem atrophy?
A degenerative neurological condition with wide spread glial cytoplasmic inclusions and cell loss in the brain, especially basal ganglia, cerebellum and pons, and the spinal cord.
607
What are some symptoms of multi-system atrophy?
```
Urinary dysfunction, incontinence and retention
Impotence
Cerebellar ataxia
Postural hypotension
Impotence
Vocal cord paralysis
Loud snoring
Dry mouth and skin
Difficulty regulating body temperature
Insomnia
Restless legs
Dementia
Depression
```
608
What facotrs support diagnosis of multisystem atrophy, particularly of it over parkinson's?
Sporadic progression of disease, when over 30 years of age
Rapid progression
Poor response to levodopa
More pronounce autonomic features
Rigidity and bradykinesia out of proportion to tremor
Affected speech
Aspiration, inspiratory gasps and stridor
609
How can multisystem atrophy be treated?
Can treat symptoms with speech therapy, levodopa and growth hormone therapy to slow progression
610
What factors worsen the prognosis of multisystem atrophy?
Female gender
Increased age at diagnosis
Early autonomic involvement
Shorter intervals between clinical milestons
611
What causes myasthenia gravis?
Deposits of IgG at ACh binding sites so that ACh can't bind to cause an action potential and is degraded by acetyl cholinesterase
612
What are the symptoms of myasthenia gravis?
```
Fluctuating, fatiguable weakness of skeletal muscle
Extraocular muscle weakness
Dysphagia
Dysarthria
Dysphonia
Proximal and symmetrical weakness
Respiratory muscle involvement
```
613
What drugs can exacerbate myasthenia gravis?
```
Aminoglycosides
Chloroquines
Beta blockers
ACE inhibitors
Magnesium
Succinylcholine
```
614
What can cause an acute exacerbation of myasthenia gravis?
Emotional stress
Infection
Fever
In a person with already weakened respiratory muscles
615
What is involved in an acute exacerbation of myasthenia gravis?
Respiratory muscle weakness that's severe enough to need intubation and assisted ventilation
616
What can happen in over treatment of myasthenia gravis?
A cholinergic crisis where neuromuscular junction is over stimulated by ACh and so no longer responds to the ACh bombardment. There's flaccid paralysis, sweating, salvation and miosis
617
What are some ADRs of acetylcholinesterase inhibitors?
```
Hypersecretion so excess sweating and salivation and lacrimation
Brady cardia
Hypotension
GI hypermotility
Bronchoconstriction
Reduced intraocular pressure
```
618
How is myasthenia gravis treated?
Acetylcholinesterase inhibitors eg pyridostigmine
619
How is dopamine normally degraded?
TO 3-MT and homovanillic acid by COMT and monomaine oxidase aldehyde dehydrogenase
620
How does levodopa work to treat parkinson's?
Dopamine can't cross blood brain barrier but L-DOPA can. Once across, it is taken up by dopaminergic neurons and converted into dopamine so levodopa therapy increases levels od dopaine available for neurotransmission. However, it needs functioning neurons so as disease prgresses, it has more variable effects. Doesn't work on non-motor symptoms of parkinson's
621
What happens to levodopa in the body?
90% is inactivaed in the intestinal wall by monoamine oxidase and DOPA decarboxylase
9% is converted into dopamine in the peripheries by DOPA decarboxylase
Less than 1% enters the CNS
622
What factors need to be considered in timing dosages of levodopa?
It competes for absorption with amino acids so shouldn't be taken with high protein meals.
Has half life of 2 hours so needs repeat dosing at small intervals
623
How can amount of levodopa reaching CNS be maximised?
Take with DOPA decarboxylase inhibitor eg co-beneldopa and a COMT inhibitor eg entacapone which both act to reduce breakdown of L-DOPA
624
What are some ADRs of levodopa?
```
Dyskinesias
Dystonias
Anorexia and nausea
Psychosis
Hypotension
Tachycardia
Freezing of movements
Wearing off
On/off of symptoms
```
625
What are the main classes of drugs that can be used to treat parkinson's?
```
Levodopa
Monoamine oxidase type B inhibitors
COMT inhibitors
Anticholinergics
Dopamine receptor agonists
```
626
How do Monoamine oxidase type B inhibitors work to treat parkinson's?
MOA type B normally acts to break down dopamine, especially in areas of the brain containing dopamine. Therefore, its inhibitors will increase levels of dopamine
627
What are some advantages of monoamine oxidase inhibitors in parkinson's therapy?
Smooth out motor responses
Can be used with levodopa to prolong its action
May be neuroprotective and slow down disease progresion
628
Give an example of a monoamine oxidase type B inhibitor?
Rasagiline
629
What are some ADRs of monoamine oxidase type B inhibitors?
```
Excitement
Anxiety
Insomnia
Dry mouth
GI upset
Headache
Drowsiness
Aching joints
```
630
Give an example of a dopamine receptor agonist
Pramipexole
| Apomorphine
631
How do dopamine receptor agonists work to treat parkinson's?
Target post-synaptic dopamine receptors to increase their transmission
632
What are some advantages of dopamine receptor agonists in parkinson's treatment?
Don't compete with levodopa or amino acids for absorption
Have longer half lives than levodopa so require less frequent dosing and give a more uniform response
Can be used later on in disease course than levodopa
Are direct acting
Give less motor complications than levodopa
633
What are some ADRs of dopamine receptor agonists?
```
Nausea
Peripheral oedema
Hallucinations
Confusion
Hypotension
Sedation
Vivid dreams
Dopamine dysregulation syndrome
```
634
What occurs in dopamine dysregulation syndrome?
```
Impulse control disorders, manifesting as:
Compulsive eating
Pathological gambling
Hypersexuality
Compulsive shopping
Punding (repetitive actions)
Desire to increase dosage
```
635
Give an example of a COMT inhibitor?
Entacapone
636
How do COMT inhibitors work to treat parkinson's?
Have no therapeutic effect alone as can't cross blood brain barrier but reduce the peripheral breakdown of levodopa, normally carried out by COMT, producing 3-0 methyldopa which competes with L-DOPA for CNS entry. THis reduces symptoms of wearing off.
637
What are some ADRs of COMT inhibitors?
Enhance ADRs of levodopa eg nausea, dyskinesias, dystonia etc
638
How do anticholinergics act to treat parkinson's?
ACh antagonises effects of dopamine in the CNS so anti cholinergics reduce effects of this.
639
What are some advantages of anti-cholinergics in parkinson's treatment?
Treat tremr
| Don't affect dopamine system
640
What are some disadvantages of anticholinergics in parkinson's treatment?
Don't address bradykinesia
| May interfere with intestinal absorption of levodopa
641
What are some ADRs of anticholinergics?
COnfusion and memory loss
Dry mouth
Constipation
Blurred vision
642
What kind of people are suitable for surgery to treat parkinson's?
Those who have been shown to be responsive to levodopa but no longer tolerate it or it no longer works.
Those with no psychiatric history as surgery increases depression risk.
643
What does deep brain stimulation target in parkinson's treatment?
Subthalamic nucleus
644
What does the biopsychosocial model of psychiatric disorders involve?
Predisposing genetic vulnerability
Precipitating and perpetuating factors such as life events
Personality, coping skills and social support
Other environmental influences
645
What are the core symptoms of depression?
For every day, most of the time, for at least 2 weeks, need 2 out of:
Low mood
Anhedonia
Low energy
646
What are the secondary symptoms of depression?
```
Reduced appetite
Sleep disturbances
Reduced concentration
Irritability
Low libido
Hopelessness
Self farm or suicidal ideas or acts
Psychotic symptoms
```
647
What are the main classes of drugs used to treat depression?
Selective seratonin reuptake inhibitors
Tricyclics
Non selective seratonin/noradrenaline reuptake inhibitors
Monoamine oxidase inhibitors
648
What is the monoamine hypothesis of depression?
That depression arises because of a deficiency in serotonin and noradrenaline
649
What is the neurotransmitter receptor hypothesis of depression?
That depression occurs as a result of abnormality in receptors for monoamines
650
Give an example of a non-selective serotonin/noradrenaline reuptake inhibitor (SNRI)
Duloxetine
651
How do SNRIs work to treat depression?
Are dose dependent. Low doses tend to inhibit the reuptake of serotonin into pre-synaptic terminals and high doses tend to inhibit the reuptake of noradrenaline into pre-synaptic terminals
652
What are some ADRs of SNRIs?
```
Nausea
Anorexia
Diarrhoea
Tremor
Precipitation of mania
Increased suicidal ideation
Sleep disturbance
Increased blood pressure
Dry mouth
Hyponatraemia
```
653
When are SNRIs contraindicated?
IN hepatic failure as have been associated with hepatotoxicity
654
Give an example of a selective serotonin reuptake inhibitor (SSRI)
Citalopram
655
How do SSRIs work to treat depression?
Inhibit the reuptake of serotonin into the pre-synaptic terminal so increase the amount available for transmission at post-synaptic membrane
656
What is a DDI of SSRIs?
Inhibit metabolism of TCAs so can't be given together as can cause TCA toxicity
657
What are some benefits of using SSRIs over TCAs?
Have less anti-cholinergic effects so less side effects
| Less dangerous in overdose
658
What are some ADRs of SSRIs?
```
Anorexia
Nausea
Diarrhoea
Tremor
Extra-pyramidal signs
Precipitation of mania
Increased suicidal ideation
```
659
What happens in SNRI toxicity?
CNS depression
Serotonin toxicity with autonomic hyperactivity, neuromuscular abnormality and change in mental status
Abnormal cardia conduction
Seizure
660
Give an example of a tricyclic antidepressant (TCA)
Amytryptilline
661
How do TCAs work to treat depression?
Inhibit reuptake of serotonin
Inhibit reuptake of noradrenal (sympathomimetic)
Block muscarinin cholinoceptors (anticholinergic)
662
What are some DDIs of TCAs?
Its metabolism is inhibited by anti-psychotics, SSRIs and some steroid leading to toxicity
Can potentiate effects of alcohol and anaesthetics
Is highly protein bound
663
What are some ADRs of TCAs?
```
Sedation
Reduced psychomotor performance
Reduced seizure threshold
Reduced glandular secretions
Block of eye accommodation
Tachycardia
Postural hypotension
Prolonged QT
Impaired cardiac contractility
Constipation
```
664
What happens in TCA toxicity?
Excitement, delirium and convulsions
Come and respiratory inhibition
Cardia dysrhythmias and ventricular fibrillation
665
Give an example of a monoamine oxidase inhibitor?
Moclobemide
666
How do monoamine oxidase inhibitors work to treat depression? (MAOI)
Inhibit the enzyme that usually breaks down monoamines so there's increased levels for transmission
667
What are some ADRs of MAOIs?
```
Cheese reaction
Sleep disturbance
Nausea
Agitation and confusion
Postural hypotension
Drowsiness
Headache
```
668
What is the cheese effect found in MAOI use?
Caused by interaction between MAOI and tyramine, found in foods such as cheese and marmite. Tyramine metabolism is inhibited so levels increase and it enters neurones, displacing noradrenaline so there's a massive increase of free noradrenaline and this causes a hypertensive crisis
669
WHat is psychosis?
A loss of contact with reality
670
What is schizophrenia?
A breakdown in relations between thoughts, emotions and behaviour with psychotic symptoms
671
What is a hallucination?
Preception in the absence of an external stimulus
672
What is the most common type of hallucination in schizophrenia?
Auditory
673
What is a delusion?
A fixed false belief not in keeping with an individual's normal cultural or religious beliefs and it cannot be argued out of
674
What is the most common type of delusion in schizophrenia?
Persecutory
675
What is schizotaxia?
A predisposition to schizophrenia
676
What is a theory for the origin of schizophrenia?
Strong genetic and familial component. When exposed to early environmental insults, eg maternal gestational hypertension there are neurodevelopmental abnormalities and schizotaxia. When exposed to later environmental insults eg upbringing, there's furher brain dysfunction until there's neurodegeneration and development of chronic schizophrenia
677
What is the dopamine theory of schizophrenia?
SChizophrenia arises due to an excess of dopamine and dopamine antagonists are most effective antipsychotics and amphetamines increased dopamine and give symtpoms resembling positive symptoms of schizophrenia
However, negative symptoms are worsened by dopamine antagonists
678
What are the main dopamine pathways of the brain?
Mesolimbic, responsible for emotional response and behaviour
Mesocortical responsible for arousal and mood
Nigrostriatal affected in parkinson's
Tuberinfundigular controlling hypothalamus and pituitary gland
679
What happens if the mesolimbic dopamine pathway is blocked?
Dramatic therapeutic treatment of positive psychotic symptoms
680
What happens if the mesocortical dopamine pathway is blocked?
Enhancement of negative and cognitive psychotic symptoms
681
What happens if the nigrostriatal dopamine pathway is blocked?
Extrapyramidal side effects and tardive dyskinesias
682
What happens if the tuberoinfundibular dopamine pathway is blocked?
Hyperprolactinaemia causing lactation, infertility and sexual dysfunction
683
What is the serotonin theory of schizophrenia?
Than an increase in function of 5-HT is responsible for schizophrenia as it's implicated in a number of behaviours that are disturbed in schizophrenia eg perception, attention, aggression etc and clozapine is strongest anti-psychotic and antagonises 5-HT
684
What is the glutamate theory of schizophrenia?
THat it arises due to reduced function of glutamate as PCP antagonises glutamate and gives symptoms very similar to schizophrenia
685
What are the main positive symptoms of schizophrenia?
Hallucinations and delusions
Unusual speech and thought disorder
Lack of insight
Behavioural changes
686
What are the main negative symptoms of schizophrenia?
Blunted affect
Social withdrawal
Poverty of thought and speech
Lack of motivation
687
What are the main cognitive and affective symptoms of schizophrenia?
```
Selective attention
Lack of abstract thought
Poor memory
Depression
Anxiety
```
688
Give an example of an atypical antipsychotic?
Olanzapine
689
How do atypical antipsychotics work to treat schizophrenia?
Block D2 receptors with a low affinity
690
What are some ADRs of atypical antipsychotics?
Extrapyramidal side effects (less so than in typicals)
Sedation
Raised prolactin
Weight gain
691
Give an example of a typical anti-psychotic?
Haloperidol
692
How do typical anti-psychotics work to treat schizophrenia?
Block D2 receptors expecially in mesolimbic and mesocortical pathways so enhance negative symptoms more than atypicals. Also anticholinergics and antihistamines
693
What are some ADRs of typical antipsychotics?
```
Extrapyramidal side effects
Postural hypotension
Weight gain
Endocrine changed
Pigmentation
Toxicity
Neuroleptic malignant syndrome
```
694
What is involved in neuroleptic malignant syndrome
What happens in toxicity of typical anti-psychotics?Secere rigidity
Fluctuating hyperthermia, BP, pulse and consciousness
Autonomic lability
Increased creatine phosphokinase
695
What happens in toxicity from typical anti-psychotics?
CNS depression
Cardiac toxicity
Sudden death
696
What are the symptoms of anxiety?
```
Shortness of breath
Pins and needles
Numbness
Fear out of proportion to the situation
Avoidance
Fear of dying/going crazy
Light headedness
Hot and cold flushes
Nausea
Palpitations
```
697
Give some examples of anxiety disorders?
```
Panic disorder
Phobias
Generalised anxiety disorder
Obsessive compulsive disorder
PTSD
Social anxiety
```
698
What can happen if benzodiazepines are used in pregnancy?
Cleft lip/palate
Feeding difficulties
Respiratory depression
Dependence
699
What are the symptoms of mania?
Unusual excitement, happiness, optimism or irritability
Increased interest in sex and promiscuity
Overactivity
Poor concentration
Poor judgement
Poor sleep
Rapid speech
Recklessness
Psychotic symptoms and grandiose delusions
700
What are the symptoms of hypomania?
Persistent mild elevation of mood, alternating with irritability. There's also increased activity, energy, inability to concentrate and insomnia but don't get hallucinations or delusions
701
What drugs can be used for bipolar disorder?
Lithium
Sodium valproate or carbamazepine if it's rapidly cycling or in acute episodes of depression/mania
Lamotrigine to prevent depressive episodes
Anti-psychotics
Depression + anti-manic if episodes of depression far outweight episodes of mania
702
Why does lithium use need to be monitored?
IS excreted renally and is highly nephrotoxic and can cause hypothyroidism so renal and thyroid function need to be checked every 6 months.
Exact dose needed isn't know so levels need to be checked at least every 3 months to prevent toxicity
703
What are some ADRs of lithium?
```
Memory problems
Thirst
Polyuria
Nephrotoxicity
Hypothyroidism
Tremor
Drowsiness
Weight gain
Hair loss
Rashes
```
704
What happens in lithium toxicity?
```
Vomiting and diarrhoea
Coarse tremor
Dysarthria
CCognitive impairment
Ataxia
Confusion
Restlessness
Agitation
```
705
How is lithium toxicity treated?
Supportive measures
Anticonvulsants
Fluid
Hameodialysis
706
What are some risk factors for gastro oesophageal reflux disease?
Obesity
Smoking
Defective lower oesophageal sphincter
707
Why may acute peptic ulcers develop?
Acute gastritis
Complication of severe stress response
Extreme hyperacidity eg Zollinger Ellison syndrome
708
Where in the stomach do gastric ulcers most commonly occur?
Lesser curvature
709
What are some defensive factors of the gastric mucosa?
Mucous membrane barrier
Epithelial integrity
Cell replication and restitution
Vascular supply
710
What are some aggressive factors of the gastric mucosa?
Acid
H. Pylori
Drugs
711
What is the process behind production of gastric acid?
Water is hydrolysed to H+ and OH-. OH- combines with CO2 using carbonic anhydrase to form HCO3- which is then released into the blood in exchange for CL-, making up the alkaline tide. K+ and Cl- are then pumped out into the canaliculi of parietal cells and K+ is exchanged for H+ using H+/K+/ATPase (proton pump) so K+ is recycle and H+ accumulates in canaliculi, drawing out water to combine with Cl- to form HCL
712
Give an example of an H2 receptor antagonist
Cimetidine
713
How do H2 antagonists work in treating excess gastric acid?
Inhibit Histamine activation of gastric acid secretion so reduce acid secretion
714
What are some ADRs of H2 receptor antagonists?
```
Diarrhoea
Constipation
Headache
Muscle pain
Fatigue
Gynaecomastia
Galactorrhoea
```
715
What are some DDIs of H2 receptor antagonists?
Cimetidine is inhibitor of CYP450 system so can cause toxicity.
Compete for renal excretion with some drugs including some anti-arrhythmics
Anti fungal ketoconazole needs an acidic environment for its absorption so H2 antagonists interfere with this
716
Give an example of a proton pump inhibitor
Omeprazole
717
How do proton pump inhibitors work to reduce gastric acid secretion?
Act to inhibit the H+/K+/ATPase (proton pump) irreversibly and so reduce acid secretion. Converted into sulfenamide by acidic environment and can then accumu,late in canaliculi, affecting secretion for 2-3 days
718
What are some ADRs of proton pump inhibitors?
```
Headache
Diarrhoea
Rashes
Dizziness
Somnolence
Confusion
Impotence
Gynaecomastia
Joint and muscle pain
```
719
What lifestyle changes can be made in the treatment of gastro oesophageal reflux disease?
Raise head of the bed
Stop smoking
Lose weight
Eat small, regular meals
Avoid hot or fizzy drinks, caffeine and citrus fruits
Don't eat up to 3 hours before bed
Avoid TCAs, anticholinergics and Ca2+ channel blockers
720
What are some DDIs of proton pump inhibitors?
Omeprazole is an inhibitor of the CYP450 system
721
How does helicobacter pylori cause damage?
Releases ammonia which is toxic to cells, causing inflammation and apoptosis
Produces proteins which stimulate the immune response, leading to inflammation
THis can all cause chronic gastritis
722
How is helicobacter pylori eradicated?
Triple therapy of twice daily doses of:
Amoxicillin
Clarithromycin or metronidazole
Proton pump inhibitor
723
Describe the intrinsic neural control of gut motility
Cholinergic nerves increase force of contraction and contraction is inhibited by inhibitory nerves.
Involves a complex neuronal network of local nerves of the enteric nervous system, located within the gut wall
724
What are the different parts of the intrinsic neural control of gut motility?
Cajal's plexus liesin circular muscle, adjacent to longitudinal muscle
Meissner's plexus lies in the submucosa
Henle's plexus lies in the circular muscle, adjacent to the circular muscle
Auerbach's plexus lies between circular and longitudinal muscle
725
What are the different reflexes involved in extrinsic neural control of gut motility?
Intestino-intestinal inhibitory reflex causes complete intestinal relaation in response to distension of one segment
Ano-intestinal inhibitory reflex causes intestinal inhibition in response to anal distension
Gastrocolic and duodenocolic reflexes stimulate gut motility in response to material entering the stomach and duodenum
726
Describe the myogenic control of gut motility
Intersitial cells of Cajal act as pacemaker cells to drive electrical activity causing slow waves of depolarisation throughout smooth muscle of gut so that there's rhythmic contraction and passive spread of current through gap junctions
727
What is the function of secretin?
Is produced in the duodenum and acts to control pH. It inhibits insulin release and gastrin release so that there's reduced gastric acid secretion
728
What is the function of cholecystokinin?
Released by the duodenum and stimulates bile production and digestive enzyme release at the gall bladder and pancreas.
Also acts to suppress hunger in response to material entering duodenum
729
What is the function of motilin?
Produced in the duodenum and jejunum to stimulate motility, accelerate gastric emptying and stimulate pepsin production
730
What is the function of somatostatin?
Suppresses release of GI hormones and reduces gastric emptying and GI motility and inhibits secretory action of the pancreas
731
What is the pattern of gut motility in the fed state?
On eating, there's contraction of the circular muscle of the intestines causing segmental, non-propulsive churning of the contents to mix them with secretions.
There's also propulsion of contents through propagated peristaltic contractions causing caudal movement of contents. This involves contraction of circular muscle and relaxation of longitudinal muscle upstream and relexation of circular muscle and contraction of longitudinal muscle downstream
732
What is the pattern of gut motility in the fasting state?
Intestines are relatively quiescent apart from synchronised rhythmic contractions that occur every 90-120 minutes to clear undigested food, bacteria, cells and secretions
733
What changes are made in the GI tract prior to emesis?
There's closure of the pyloric sphincter and relaxation of lower oesophageal sphincter and cardia. COntraction of abdominal wall and diaphragm causes propulsion of contents. There's closure of glottis and elevation of soft palate to prevent vomitus entering trachea or nasopharynx
734
What can trigger emesis?
```
Pregnancy
Pain
Stretching and inflammation of the stomach
Medications
Toxins
Smell
Irradiation
Raised intracranial pressure
Rotational movement
```
735
What are some preliminary signs that someone is about to vomit?
```
Pupil dilation
Increased salivation
Paleness
Nausea
Sweating
Retching
```
736
What are some potential causes of constipation?
```
Low fibre intake
Dehydration
Diabetes
Parkinson's
Pregnancy
Mechanical obstruction
Cancer
Other drugs
```
737
What are the features of irritable bowel syndrome?
Bouts of stomach cramps, bloating, diarrhoea and constipation, usually triggered by stress and certain foods. Symptoms usually relieved by defecation
738
How can irritable bowel syndrome be treated?
With mebevarine which relieves intestinal muscle spasms
739
What is the neuronal control of emesis?
Vestibular apparatus releases histamine and ACh and postrema on floor of the fourth ventricle releases dopamine. These all act on the medullary vomiting centre which releases ACh, Histamine and 5-HT
740
What are the main classes of drugs used as anti-emetics?
```
Cannabnoids
Dopamine receptor antagonists
Histamine H1 eceptor antagonists
Anti muscarinics
5-HT receptor antagonists
```
741
How do dopamine receptor antagonists work as anti-emetics?
Act on postrema of floor of fourth ventricle and on the stomach to increase rate of gastric emptying
742
What are the two main dopamine receptor antagonist anti-emetics and when are they used?
Domperidone - used in acute nausea and vomiting, triggered by L-DOPA, dopamine agonists and chemotherapy
Metoclopramide also has anticholinergic effects and is used in GI causes of vomiting, in migraine and post-operatively
743
What are some ADRs of dopamine antagonist anti-emetics?
Extrapyramidal symptoms
Increased prolactin so galactorrhoea and menstrual dysfunction
Fatigue
Spasmodic torticollis
744
How do 5-HT receptor antagonists work as anti-emetics?
Act on postrema of floor of fourth ventricle and vagal 5-HT afferents
745
When are 5-HT antagonist anti-emetics used?
In radiation sickness, in chemotherapy and post-operatively
746
What are some ADRs of 5-HT antagonist anti-emetics?
Headache
| Constipation
747
How do anti-muscarinics work as anti-emetics?
Antagonise cholinergic receptors
748
When are anti-muscarinic anti-emetics used/
Transdermally to treat motion sickness
749
What are some ADRs of anti-muscarinc anti-emetics?
```
Tolerance
Bradycardia
Dry mouth
Constipation
Drowsiness
Blurred vision
```
750
When are histamine receptor antagonist antiemetics used?
Help post-op nausea and opiod induced nausea
751
How do cannabinoids treat sickness?
Act to reduce nausea and vomiting caused by riggering of the chemoreceptor trigger zone
752
What are some ADRs of cannabinoid anti-emetics?
```
Dry mouth
Dizziness
Drowsiness
Mood changes
Postural hypotension
Hallucinations
Psychotic reactions
```
753
What are the main classes of drugs used to treat diarrhoea?
Anti motility drugs (opioids and opioid analogues)
Bulk forming agents
Fluid adsorbents
754
Give an example of an anti motility drug used in diarrhoea
Loperamide ie immodium which is an opioid analogue
755
How do anti-motility opioid analogues work to treat diarrhoea?
Act on opioid receptors in the gut to reduce gut motility so that fluid has more time to reabsorb. Also increases anal tone and acts to reduce the sensory defecation reflex
756
When are anti-motility diarrhoea therapies contraindicated?
In inflammatory bowel disease as it can lead to toxic megacolon
757
How do bulk forming agents treat diarrhoea?
Encourage water absorption
758
How does cholestyramine work to treat diarrhoea?
Is a fluid adsorbent. Is a bile acid sequestrant so worksto treat diarrhoea that is bile salt induced eg in crohn's
759
What are the main classes of drugs used to treat constipation?
Bulk forming agents
Stool softeners
Osmotic laxatives
Irritant laxatives
760
How do bulk laxatives act to treat constipation?
They're agents that aren't broken down by normal digestive processes so they form a bulky, hydrated mass that promotes peristalsis and improves faecal consistency but need normal fluid intake for it to be effective.
761
What is an ADR of bulk laxatives?
Flatulence
762
How do faecal softeners work to treat constipation?
Given as enema or suppository to lubricate and soften the stool
763
What therapies are safe to treat constipation in those with GI ulceration/adhesions?
Faecal softeners
764
In general, how do osmotic laxatives work to treat diarrhoea?
Are poorly absorbed so sit in gut lumen and cause water retention by osmotic effect, this promotes peristalsis and so defecation
765
What are the two main different osmotic laxatives?
Magnesium/sodium salts are poorly absorbed solutes. They're used for rapid relief and in constipation that's resistant to other therapies. Act very quickly and have a marked effect due to abnormally large volume entering the colon. Can causes distension and cramp
Lactulose is fermented by colonic bacteria as it can't be digested. This process releases acetic and lactic acid which have an osmotic effect. These take around 12 days to act but are safe in liver failure as there's less ammonia. Can cause flatulence, diarrhoea, cramp, electrolyte disturbances and tolerance
766
How do irritant laxatives work?
Irritate mucosa and excite sensory nerve endings which stimulates water and electrolyte retention which causes peristalsis
767
When are irritant laxatives used?
When rapid relief is needed, ie in impaction or pre-op.
| Used if history and examination show soft faeces
768
What are some dangers of irritant laxative use?
Repeated use can cause colonic atony and hypokalameia so there's bowel inertia and constipation.
769
What are the different stages of dementia?
Early involves loss of memory for recent events, global disruption of personality and gradual development of abnormal behaviour
Intermediate stage involves loss of intellect, mood changes and blunting of emotion, cognitive impairment, and inability to learn
Late stage involves incontinence, lack of self care and restless wandering
770
What is dementia?
An acquired loss of cognitive ability that's severe enough to interfere with daily function and quality of life. It gives an untreatable deterioration of intellect, behaviour and personality
771
What are the halmarks of frontotemporal dementia?
Personality and behaviour changes (frontal)
| Reduced language proficiency or difficulty using the right words (temporal)
772
What are the hallmarks of lew body dementia?
Fluctuating cognition and alertness with visual hallucinations and motor parkinsonism
773
What are some causes of dementia?
```
Direct neuronal damage
Vascular damage of brain tissue, usually with underlying hypertension and repeated embolic strokes
Trauma
Malignancy
Infection
Metabolic
Drug induced neuronal death
Toxic poisoning of the brain
Pseudodementia
```
774
What's the difference between cortical and subcortical dementia?
Cortical dementia tends to involve global type personality changes and complex disabilities whereas subcortical dementia tends to involve slowness and forgetfullness, increased muscle tone and gross changes in movement
775
What are the different types of cortical dementia?
Anterior involves behavioural changes, reduced inhibition, antisocial behaviour and irresposibility
Posterior tends to involve reduced cognitive function with no marked behaviour or personality changes
776
What's an example of an anterior cortical dementia?
Huntington's disease
777
What's an example of a posterior cortical dementia?
Alzheimer's
