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Integrative physiology and pharmacology > Pharmacology > Flashcards

Pharmacology Flashcards

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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
Describe hyperlipidaemia
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
26
Describe the use of HMG CoA reductase inhibitors
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)
27
Describe the use of fibrates
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
Describe the use of bile acid-binding resins
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
Describe the use of ezetimibe
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
Describe the use of nicotinic acid
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
Describe the use of fish oil in hyperlipidaemia
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
Outline the prescribing guidelines for hyperlipidaemia
Primary prevention- statins in diabetics >40yr old, can combine with ezetimibe Secondary prevention- stations or vibrates/resins Nicotinic acid
33
Describe blood pressure maintenance
Baroreceptor reflex Autonomic nervous system RAAS- kidneys alter blood volume, angiotensin 2 vasoconstricts
34
Describe beta adrenoceptor antagonists as antihypertensives
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
Describe alpha1 adrenoceptor antagonists as antihypertensives
Act on the periphery Prazosin and doxazosin Blocks vasoconstriction SE- postural hypotension- no Baroreceptor reflex
36
Describe alpha 2 adrenoceptor agonists as antihypertensives
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
Describe ACE inhibitors as antihypertensives
``` 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
Describe the use of angiotensin 2 receptor antagonists
``` 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
Describe the use of direct vasodilators as antihypertensives
Bind selectively to vascular smooth muscle | Minoxidil- severe, nitrates- severe, DHPs- mild
40
Describe the use of diuretics as antihypertensives
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
How would you treat hypotension?
Only if life threatening | Sympathomimetics- adrenaline to increase TPR/CO
42
Describe drug elimination
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
Describe metabolism of drugs
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
What are active metabolites?
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
Briefly describe paracetamol metabolism
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
Describe drug elimination from the kidney
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
How can you calculate renal clearance of drug X?
Clearance= [X]u x Urine flow rate/ [X]p
48
List causes of emesis
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
Describe the control for emesis
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
List some antiemetics that are neuroleptics
``` 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
List antiemetics that are selective 5-HT3 receptor antagonists
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
How does cisplatin have it's emetic effects?
Thins the GI mucous | Local inflammation activates enterchromaffin cells (mast cells) degranulates and releases 5-HT
53
How does aprepitant have anti-emetic effect?
Substance P receptor antagonist- vagal neurotransmitter | used fro ciplatin induced emesis and postoperative emesis, combined with a 5-HT3 receptor anatagonist
54
List antiemetics that are steroids
Dexamethosone- reduce inflammation | Additive with 5-HT and substance P antagonists
55
List antiemetics that are benzodiazepines
Diazepam- neuronal suppression | Metaclopramide + Dexamethosone + diazepam
56
List antiemetics that are cannabinoids
Cannabis sativa- Nabilone | Euphoria and sedation
57
How would you treat motion sickness?
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
Briefly describe chemotherapy
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
Describe alkylating agents
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
Describe platinum based chemotherapy
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
Describe antimetabolites
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
Describe mitotic inhibitors
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
Describe topoisomerase inhibitors
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
Describe Anti-tumour antibiotics
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
Describe Mitomycin
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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