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Integrative physiology and pharmacology > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

How might dysrhythmias occurs?

A

Automaticity- ectopic pacemakers
Re-entry- damage to muscle could result in unidirectional conduction
Accessory pathway re-entry- bridges between atrial and ventricles other than the AV node
Transient depolarisations during repolarisation resulting in AP outside of the SA node control
Dysfunctional AV node- uncouples ventricles from atria and increases time from P to QRS and stops some QRS

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2
Q

Describe class 1 antiarhythmic drugs

A

Lignocaine, flecainide, lidocaine

Voltage-gated Na channel blockers

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3
Q

Describe class 2 antiarhythmic drugs

A

Beta blockers
Propranolol
Decreases sympathetic effects in the heart
Decreases the slope of the pacemaker potential

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4
Q

Describe class 3 antiarhythmic drugs

A

Amiodarone (Ca), sotalol (beta blocker function)
Prolongs the cardiac action potential
Via K channel block?

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5
Q

Describe class 4 antiarhythmic drugs

A

Verapamil, diltiazem

L type Ca channel blockers

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6
Q

Describe adenosine as an antiarhythmic drug

A

Non-classified

Receptors in SA/AV- K channels open and Ca channels close to delay pacemaker potential

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7
Q

Describe digoxin as an antiarhythmic

A

Cardiac glycosides

Increases vagal activity to the heart, decreases AV conduction rate and ventricular rate

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8
Q

What is dysrhythmias?

A

Disorders of rate or rhythm of the heart
Can be atrial, junctional or ventricular
Tachycardia or bradycardia

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9
Q

What are inotropic drugs?

A

Increase or decrease contractility of the heart muscle

+he inotropic drugs increase intracellular Ca to increase contractility and therefore cardiac output

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10
Q

Describe cardiac glycosides

A

Eg. Digoxin
Partial inhibition of Na/K ATPase
Loss of the Na conc grad so the Na/Ca antiporter cannot work and Ca is no longer transported out of the cell
Side effects:
Increase the resting membrane potential, increases excitability and can lead to dysrhythmias
GIT, neurological disturbances, gynecomastia
Low therapeutic index
Used in CHF (and dysrhythmias)
Affected by diuretics- hypokalaemia- less competition for Na/K ATPase
Toxicity treyted with increase K, and antibodies

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11
Q

Describe sympathomimetic inotropes

A

Beta receptor agonist
Mixed beta1&2- isoprenaline
Beta1- dobutamine
Increase intracellular cAMP to open Ca channels
Used in emergencies
Has short half-life and problems with desensitisation

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12
Q

Describe phosphodiesterase inhibitors

A 
Stops cAMP breakdown
Eg. Milrinone, enoximone
PDE type 3 heart specific
No desensitisation
Increases excitability 
Used in emergencies only
Has short half-life
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13
Q

Desceoibe the concept of cellular homoeostasis in drug desensitisation

A

Increased stimulation leads to decreased responsiveness and vice versa
Occurs in response to drugs, agonist or antagonists but also to physiological and pathological changes- denervation and chronic heart failure

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14
Q

Describe the mechanisms of drug induced desensitisation

A

Pharmacokinetic changes- eg. Barbiturates: induce cytochrome p450 and markedly increase elimination so addicts can take many times the normal lethal dose
Receptor changes- rapid and reversible inactivation eg. Suxamethonium produces depolarising block and beta-adrenoceptors uncouple from G protein
Or changes in receptor number eg. Theophylline leads to upregulation of A1/A2 receptors in the brain
Post-receptor changes- eg. Amphetamines depletes NA/DA levels in nerve terminals, or changed in signalling molecules, adaptive reflexes eg. Baroreceptor response to antihypertensive drugs

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15
Q

What is the difference between homologous and heterologous desensitisation?

A

Homologous- loss of responsiveness only to the desentising agent or agents acting at the same receptor
Heterologous- loss of responsiveness to agents that do not act at the same site as the desentising agent

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16
Q

Describe short term beta2 receptor desentitisation

A

2-20min exposure too agonist
Uncoupling from GS
Loss of response with no change in channel number due to phosphorylation of the receptor reversed by phosphatases

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17
Q

Describe long term beta2 receptor desensitisation

A

Hours of exposure to agonist
Receptor down regulation- receptor internalisation and lysosomal breakdown and decreased transcription
Reversed slowly

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18
Q

Does desensitisation occur during the use of beta2 agonist in asthma?

A

Sporadic use- none decernable
Moderate use- decreases side effects, decreased beta2 receptors okn lymphocytes but no change in bronchodilator response? Spare receptors?
Abuse- decreased bronchodilator response associated with increased mortality
Treatment with a short course of high dose steroids or a drug holiday

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19
Q

Describe drug dependence?

A

Usually occurs over days or weeks
Usually requires a drug that gives a reward
Leads to tolerance and dependence
Via: change in central reward pathways (mesolimbic, dopaminergic)
Same receptor changes seen in desensitisation
Psychological dependence
Characterized by withdrawal with adverse physiological effects over days and weeks
Treated by alleviating symptoms eg. Benzodiazepines for alcohol withdrawal
Long-term substitution eg. Method one for heroin
Blocking response eg. Immunization for cocaine
Averse therapies eg. Disulfiram for alcohol
Reducing craving eg. Bupropion to reduce tobacco use

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20
Q

Describe lipid transport

A

Via lipoproteins
Non-polar core of cholesterol esters and/or triglycerides
Polar coat of apoproteins
Chylomicrons, VLDL, LDL, HDL
Can be transported endogenously or exogenously

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21
Q

Describe atherosclerosis

A

Atheromas in large and medium arteries AMD underlies the commonest cause of death
Evolves over decades
-endothelial dysfunction (⬇NO)
-injury (adhesion molecules)
-LDLs accumulate AMD get oxidised by monocytes/macrophages)
-ox LDL taken up by macrophages form foam cells
-foam cells AMD lymphocytes lead to fatty streaks
-macrophages, platelets and endothelial cells release growth factors and cytokines
-proliferation of smooth muscle and connective tissue lead to a fibrous cap overflying the lipid core
-this atheromatous plaque can rupture leading to thrombosis

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22
Q

Describe the exogenous lipid pathway

A

Lipid emulsified by bile acids in the GIT
Absorbed as chylomicrons (more triglycerides than cholesterol esters)
Triglycerides hydrolysed by lipoprotein lipase associated with the endothelial cells in the liver
The chylomicron remnants (more cholesterol esters than triglycerides) go to liver amd are recycled as bile acids)

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23
Q

Describe the endogenous lipid pathway

A

Hepatic Cholesterol and triglycerides synthesised in the liver (+cholesterol from the exogenous pathway)
VLDL secreted (CE+TG)
TG removed to give LDL (CE)
Extra-hepatic- reverse cholesterol transport
C from dead cells and plaques form HDL
CE from HDL given to LDL and is sent to the liver
More HDL promotes LDL removal

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24
Q

Describe LDLs

A

60-70% of circulating cholesterol- used ikn membranes, steroids amd bile acids
Normal lipid- C=

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25
Q

Describe hyperlipidaemia

A

Primary (genetic)- 6 phenotypes depending on the lipoprotein affected
2a- increase LDL
2b- increase LDL and VLDL
Increase risk of atherosclerosis as LDL contains a protwi. So I!as to plasminogen which leads to competition and decreased plasmin so more thrombosis
Secondary- due to metabolic disorders eg. Diabetes, hypothyroidism, renal disease, alcoholism

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26
Q

Describe the use of HMG CoA reductase inhibitors

A

Statins- pravastatin, simvastatin
Potent competitive inhibitors to decrease cholesterol synthesis in the liver
Leads to increased transcription of enzyme and receptor which means that there is a partial increase in cholesterol synthesis and increased receptor leads to decreased plasma cholesterol amd decreased heart disease
Used if lipid conc is normal
Se- myositis, hepatitis, contraindicated in pregnancy (germ cell migration)

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27
Q

Describe the use of fibrates

A

Bezafibrate, gemfibrozil
Activate nuclear receptos to increase lipoprotein lipase amd decrease VLDL production
Decreases triglycerides, increases liver uptake of LDL and increases HDL
Used In a case of increased TG (stations first), maybe for decreased HDL patients
Decreases heart disease
SE- myostitis

28
Q

Describe the use of bile acid-binding resins

A

Cholestryramine and colestipol
Resins are not absorbed so you lose C and bile acids which increases bile acis synthesis and decreases liver cholesterol which increases LDL receptors and decreases LDL smnd heart disease- not as much as statins
Increases triglycerides
Unpleasant GI side effects

29
Q

Describe the use of ezetimibe

A

Inhibits intestinal absorption of cholesterol by blocking transport protein NPC1L1
But no evidence of decrease atherosclerosis
No effect on the absorption of fat soluble vitamins and have a much higher potentcy than resins

30
Q

Describe the use of nicotinic acid

A

Decreases TG synthesis, VLDL and LDL
Increases HDL
Combined with stations (+-resins)
SE- Common- flush and pruritis duer to prostaglandins amd GI upset amd jaundice in high doses

31
Q

Describe the use of fish oil in hyperlipidaemia

A

Omega-3 triglycerides
Improve survival after myocardial infarction
Decreases TG(not relevant)
Increases Cholesrerol so not used in type 2a
Maybe decreases clotting by altering the structure of eicosanoids (thromboxane, leukotrienes- less active forms, prostaglandins- more active)

32
Q

Outline the prescribing guidelines for hyperlipidaemia

A

Primary prevention- statins in diabetics >40yr old, can combine with ezetimibe
Secondary prevention- stations or vibrates/resins
Nicotinic acid

33
Q

Describe blood pressure maintenance

A

Baroreceptor reflex
Autonomic nervous system
RAAS- kidneys alter blood volume, angiotensin 2 vasoconstricts

34
Q

Describe beta adrenoceptor antagonists as antihypertensives

A

Act on the periphery
Propranolol (beta1&2) and atenalol (beta1) decreases HR and contractility
Decrease renin secretion which decreases angiotensin 2 and therefore TPR
SE- bronchospasm on beta2 receptors amd exercise intolerance
Used in mild hypertension
Other side effects in some patients after decades of use

35
Q

Describe alpha1 adrenoceptor antagonists as antihypertensives

A

Act on the periphery
Prazosin and doxazosin
Blocks vasoconstriction
SE- postural hypotension- no Baroreceptor reflex

36
Q

Describe alpha 2 adrenoceptor agonists as antihypertensives

A

Act centrally
Clonidine amd methyldopa
Bind presynaptically and give negative feedback to reduce NA release
Decrease sympathetic outflow and vascular tone
SE- postural hypotension, increased secretion because of unopposed parasympathetic action
Drowsiness and depression
Largely obsolete

37
Q

Describe ACE inhibitors as antihypertensives

A 
Targets RAAS
Angiotensin-converting enzyme inhibitors
Captopril, enalapril
Decreases angiotensin 2
Decreases degradation of vasodilator kinins
SE- dry coughs- kinins irrate neurones in the respiratory system
First dose hypotension
Used in mild hypertension
38
Q

Describe the use of angiotensin 2 receptor antagonists

A 
Targets RAAS
Losartan and irbesartan
Blocks AT1 receptors decreases action of angiotensin 2 to decrease TPR
No major side effects
Used in mild hypertension
39
Q

Describe the use of direct vasodilators as antihypertensives

A

Bind selectively to vascular smooth muscle

Minoxidil- severe, nitrates- severe, DHPs- mild

40
Q

Describe the use of diuretics as antihypertensives

A

Thiazides, fursemide, spironolactone
Initially increase water excretion from kidney and decreases blood volume
Long term effects area atrial dilation
Na depletion- decreases intracellular Ca in vascular smooth muscle
SE- hypokalaemia
Used in mild hypertension

41
Q

How would you treat hypotension?

A

Only if life threatening

Sympathomimetics- adrenaline to increase TPR/CO

42
Q

Describe drug elimination

A

The irreversible removal of a drug from the body

Metabolism primarily by the liver and excretion primarily by the kidney but also through expiration or through the gut

43
Q

Describe metabolism of drugs

A

Phase 1- modification
Cytochrome P450 dependent mixed-function oxidase
Causes oxidation, reduction or hydrolysis, creates highly reactive compounds
Eg. Amiodarone (class 3 antidysrhythmic) causes substrate inhibition of CYP1A2 for caffeine
Non-substraye inhibition by quinidine
Induction by barbiturates, rifampicin, phenytoin- CYP2C9- ibuprofen
Phase 2- conjugation
Joins the reactive phase 1 metabolite with molecule to make it charged eg. Glutathione, sulfate, glucuronic acid too aid renal clearance

44
Q

What are active metabolites?

A

Metabolites may be Active giving either a toxic or therapeutic effect
Eg. Morphine- converted to morphine-6-glucuronide another analgesic
Pethidine- converted to norpethidine which is epileptogenic
Prodrugs- inactive drugs administered to be converted to the active form

45
Q

Briefly describe paracetamol metabolism

A

Phase 1- N-hydroxylation by CYP2E1 or CYP1A2 or CYP2D6 to form NAPQI
Phase 2- conjugation to glutathione
In overdose conjugation cannot proceed quickly enough and NAPQI accumulates

46
Q

Describe drug elimination from the kidney

A

Charged molecules tend to be trapped in the tubules and are then excreted in the urine
Some transporters eg. Acid transporters- penicillin, uric acid
Organic base transporters- pethidine and quinine
Can be competition between drugs for transporters slowing clearance
Ion trapping in acidic urine

47
Q

How can you calculate renal clearance of drug X?

A

Clearance= [X]u x Urine flow rate/ [X]p

48
Q

List causes of emesis

A

Disease associated- uraemia, gastroduodenal, hepatic, infection
Drug induced- cancer chemo and radiotherapy- cisplatin, dopamine agonists- L-Dopa, opiates, Ipecacuanha (Road side plant that makes you sick), alcohol
Anticipatory
Post operative emesis (PONV)- due to general anaesthetic- location- abdominal and gynaecological
Motion sickness
Pregnancy- 1st trimester due to increase hCG

49
Q

Describe the control for emesis

A

Higher centers- mood
Brain stem- floor of the fourth ventricle- the vomiting centre; lateral reticular formation- not a discrete nucleus, similar neurones for cardiovascular and respiration so no universal target for anti-emetics
Chemoreceptor outside the BBB

50
Q

List some antiemetics that are neuroleptics

A 
Chlorpromazine
Haloperidol
Domperidone- does not cross BBB
Metoclopramide- high dose- extra efficacy with genuine antiemetic effects- decrease vomiting episodes- weak 5-HT3 receptor antagonist- need high dose for effect
SE- have extrapyramidal side effects
True antiemetics- just sedation?
51
Q

List antiemetics that are selective 5-HT3 receptor antagonists

A

Highest level 5-HT3 receptor in whole body
1st gen setrons- ondansetron, granisetron, tropisetron
attenuate cisplatin induced emesis with extra-pyramidal side effects
2nd gen- Palonosetron- long half life with 5-HT3 receptor internalisation

52
Q

How does cisplatin have it’s emetic effects?

A

Thins the GI mucous

Local inflammation activates enterchromaffin cells (mast cells) degranulates and releases 5-HT

53
Q

How does aprepitant have anti-emetic effect?

A

Substance P receptor antagonist- vagal neurotransmitter

used fro ciplatin induced emesis and postoperative emesis, combined with a 5-HT3 receptor anatagonist

54
Q

List antiemetics that are steroids

A

Dexamethosone- reduce inflammation

Additive with 5-HT and substance P antagonists

55
Q

List antiemetics that are benzodiazepines

A

Diazepam- neuronal suppression

Metaclopramide + Dexamethosone + diazepam

56
Q

List antiemetics that are cannabinoids

A

Cannabis sativa- Nabilone

Euphoria and sedation

57
Q

How would you treat motion sickness?

A

Anti-muscarinics- Scopolamine (+/-hyoscine)- via the cholinergic labyrinthine-vestibular-cerebellar pathway
Anti-histamines- Dimenhydinate- H1 antagonist on presynaptic membrane of neurones in the LVC pathway
Cinnarizine, cycizine, promethazine
Also useful in vertigo and tinnitus

58
Q

Briefly describe chemotherapy

A

Attacks tumours at the cellular level by interfering with processes or substances needed for cellular replication
Goals- cure, prolonged survival, palliation, radiosensitive
Can be cell cycle specific- schedule dependent
Cell cycle non-specifc- dose dependent
Classes:
1. Alkylating agent
2. Platinum based
3. Antimetabolites
4. Mitotic inhibitors
5. Anti-tumour antibiotics
6. Topoisomerase inhibitors
When in combo each drug should be active individually, different mechanisms of action, minimal cross-resistance and different toxicities
Common toxicities occur because because they target cells that are fast multiplying including normal cells- neutropenia, anaemia, thrombocytopenia- collectively myelosuppression, nausea and vomiting, mucosistis and diarrhoea, alopecia, sterility and infertility

59
Q

Describe alkylating agents

A

Attach an alkyl group to the guanine base in DNA and stops tumour growth by crosslinking guanine nucleobases in DNA so strands cannot separate and the cell cannot divide
Act non-specifically- mainly on synthesis, tumour cells more sensitive because of faster cycling and less DNA repair, but also works on normal cells like those in the GIT and bone marrow
Also most are carcinogenic
Types:
SN1- react directly with the biological molecules eg. nitrogen mustards (cyclophosphamide and ifosfamide) and nitrosoureas
SN2- forms a reactive intermediate that reacts with the biological molecule eg. busulfan
Toxicities of cyclophophamide and ifosfamide- nausea and vomiting, myelosuppression, alopecia, high-dose cardiotoxicity (endothelial injury–> haemorrhagic necrosis and decline left ventricular systolic failure), ifosfamide high-dose neurotoxicity (metabolite crosses BBB, encephalopathy–> cerebellar ataxia, mental confusion, complex visual hallucination), high-dose haemorrhagic cystitis (acrolein metabolite excretion into bladder)
Mesna- can prevents haemorrhagic cystitis, detoxifies metabolites by reacting with sulfhydryl group

60
Q

Describe platinum based chemotherapy

A

Cause crosslinking of DNA as a monoadduct, interstrand crosslinks, intrastrand crosslinks or DNA protein crosslinks
Eg. Cisplatin, carboplatin, oxalaplatin
Toxicities- nausea and vomiting, myelosuppression, ototoxicity (irreversible high frequency hearing loss), peripheral neuropathy, nephrotoxicity (prevention with aggressive hydration and electrolyte supplements)

61
Q

Describe antimetabolites

A

Inhibits the use of a metabolite
Eg. methotrexate (folic acid analogue) and 5-fluorouracil (uracil analogue)
Similar structure to the metabolite competitive inhibition
5-FU:
Active metabolite, FdUMP, inhibits dTMP–> increased levels of dNTP and dUTP–> cause DNA damage
Can activate p53 by incorporation of FUTP into RNA, FdUTP into DNA and the DNA damage
Up to 80% of 5-FU is broken down by DPD in the liver- bioavailibility, variation in DPD levels and function
Toxicities of 5-FU
myelosuppression, oral mucositis, GIT disturbances, hand-foot syndrome, rare cardiotoxicity, ocular toxicity, hyperbilirubinaemia

62
Q

Describe mitotic inhibitors

A

Disrupt microtubule polymerisation- usually derived from natural sources, cannot separate chromosome
Eg. vinca alkaloids (vinblastine- lymphomas and is myelosuppression, vincristine- leukaemia and is neurotoxic, and vinorelbine- lung cancer and is neurotoxic and myelosuppressive) and taxanes (paclitaxel, docetaxel)

63
Q

Describe topoisomerase inhibitors

A

Block the ligation step in the cell cycle generating SSB and DSB that harm genome integrity leading to apoptosis
Topoisomerase 1 inhibitors- irinotecan, topotecan
Topoisomerase 2 inhibitors- etoposide
May lead to secondary neoplasms

64
Q

Describe Anti-tumour antibiotics

A

Act by:
Intercalating DNA–> inhibits DNA and RNA synthesis
Triggers cleavage by topoisomerase 2
Binds to cell membranes and plasma proteins may be involved
Generates radicals- myocardial damage
Eg. Anthracyclines- adriamycin and epirubicin
life -threatening heart damage

65
Q

Describe Mitomycin

A

Aziridine-containing natural products from bacteria
SE- bone marrow suppression, nausea, vomiting, stomatitis, rash, fever and malaise
Delivered in 6-week intervals because of delayed myelosuppression
Metabolised by liver enzymes and exctreted in bile- possible enzyme abnormalities caused
rare- haemolytic uraemic syndrome, renal failure, haemolysis, neurological abnormalities and interstitial pneumonitis

Integrative physiology and pharmacology (3 decks)

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