Flashcards in Pharmacology Deck (147)
Adrenaline activates B2 adrenoceptors in the heart to cause increased heart rate. True/False?
Acts on B1 adrenoceptors
Which muscarinic receptor does ACh act on in the heart to cause decreased heart rate?
What does adenylyl cyclase do?
Increases production of cAMP
Which channels, when blocked, decrease the slope of the SA node action potential?
Name a drug that is a selective blocker of HCN channels and for what heart condition it is mainly used
Used for angina
Sympathetic stimulation decreases AV nodal delay. True/False?
Sympathetic stimulation causes increased automaticity. What is this?
Increased tendency for non-nodal regions to acquire spontaneous conduction activity
Sympathetic stimulation causes a decrease in the duration of systole. True/False?
What factors increase venous return?
Increased skeletal muscle activity
Adrenergic effects on blood vessels
Increased depth + frequency of respiration
What is the function of ryanodine receptors with regards to calcium action + action potentials?
Enable release of Ca++ from sarcoplasmic reticulum through the process of calcium-induced calcium release
What is the function of SERCA with regards to calcium action + action potentials?
Removes Ca++ from the cytoplasm to bring about relaxation
What happens when phosphalamban is phosphorylated with regards to calcium action + action potentials?
This increases Ca++ storage in the SR and also activates SERCA to promote relaxation
What happens when troponin I is phosphorylated with regards to calcium action + action potentials?
Decreases affinity of troponin C for calcium, thus accelerating relaxation
Name a B1 agonist drug used sometimes in heart failure
Propranolol is a selective B2 receptor antagonist. True/False?
It is non-selective
Name a selective B1 antagonist drug
Give some clinical uses of B-blockers
Heart failure (low-dose)
Give some adverse effects of B-blockers
Aggravate heart failure
Which class of drug is atropine?
Non-selective muscarinic antagonist
Name the main clinical use of atropine
Reverse bradycardia modestly
What are the dangers of digoxin?
It has a low therapeutic ratio and is thus toxic, especially in hypokalaemia
Can cause heart block
What is an indirect effect of digoxin?
Slows AV node conduction to increase refractory period
What does Levosimendan do?
Binds to troponin C to increase its affinity for Ca++
In the smooth muscle cell, calcium binds with _____, which undergoes a conformation change. The __-__ complex then interacts with _____ to activate it. The active ____ then phosphorylates ___-__ which, when phosphorylated, ultimately causes contraction.
In the smooth muscle cell, calcium binds with calmodulin, which undergoes a conformation change. The Ca-CaM complex then interacts with MLCK to activate it. The active MLCK then phosphorylates myosin-LC which, when phosphorylated, ultimately causes contraction.
In the endothelial cell, Ca-CaM complex activates ___ which binds _-____ and __ to form NO, which rapidly diffuses into the smooth muscle cell (to ultimately cause relaxation).
In the endothelial cell, Ca-CaM complex activates eNOS which binds l-arginine and O2 to form NO, which rapidly diffuses into the smooth muscle cell (to ultimately cause relaxation).
In the smooth muscle cell, NO does 2 things:
1] activates ___ ____ which synthesises cGMP from ___. cGMP activates protein kinase _ which ultimately causes relaxation.
2] keeps Ca-dependent _ channel open, allowing _ to efflux, leaving _ve charge in the cell which causes membrane potential to ______ so we get relaxation.
In the smooth muscle cell, NO does 2 things:
1] activates guanylate cyclase which synthesises cGMP from GTP. cGMP activates protein kinase A which ultimately causes relaxation.
2] keeps Ca-dependent K channel open, allowing K to efflux, leaving -ve charge in the cell which causes membrane potential to hyperpolarise so we get relaxation.
How do organic nitrates (GTN) work in the smooth muscle cell?
Combines with SH groups to liberate NO, which then acts like endogenous NO in signalling pathways
Nitrates cause arteriolar dilation at low doses. True/False?
Mainly cause venorelaxation, but can cause arteriolar dilation at high doses
How do nitrates help in angina?
Decrease preload + afterload
Improve perfusion to ischaemic zone (dilates collateral vessels)
Name 2 examples of organic nitrates used clinically
Why is it important to have nitrate-low periods?
Repeated use can develop tolerance and reduce efficacy
Endothelin-1 causes vasodilation. True/False?
Which substances cause upregulation of endothelin production?
Which substances cause downregulation of endothelin production?
Name antagonists of the endothelin-1 receptor used in treating pulmonary hypertension
Name a renin inhibitor
Renin inhibitors (aliskiren) can be used in conjunction with an ARB or ACEi. True/False?
What are the effects of ACE?
Converts AT I to AT II
Name an ACEi used in Tayside
Name an ARB used in Tayside
What are the main differences between ACEi and ARBs?
ARBs do not inhibit bradykinin and do not produce dry cough
How do calcium antagonists work?
Prevent opening of Ca channels to limit intracellular Ca++ to reduce heart rate and force of contraction
Verapamil is selective for cardiac L-type channels. True/False?
Amlodipine is selective for which L-type channels?
Smooth muscle L-type channels
Amlodipine is preferred to verapamil - why?
Minimises unwanted effects on cardiac muscle, e.g. heart block
Why is verapamil useful in arrhythmias?
Slows conduction of AV node, can help reduce AF
K+ channel openers act primarily on arterial smooth muscle. True/False?
Name two K+ channel opener drugs
Name two alpha blockers
What is the main/overall action of diuretics?
Increase Na, Cl and water excretion
Indirectly relax vasculature
What is the undesirable effect of diuretics?
Loss of K+
Name a thiazide diuretic and conditions it is used in
Mild heart failure, hypertension
Name a loop diuretic and conditions it is used in
Chronic heart failure, acute pulmonary oedema
What are some side effects of diuretics?
What is the main side effect of dihydropyridine Ca antagonists?
Name conditions in which amlodipine can be used
In addition to hypertension and angina, verapamil can be used for what?
SVT arrhythmias (AF, VT) but NOT alongside B blockers
ACEi and ARBs are safe in pregnancy. True/False?
NEVER use in pregnancy
Name conditions in which nitrates can be used
Acute heart failure
Name some antiplatelet agents
Name some anticoagulants
What do fibrinolytics simply do?
Dissolve formed clots
Name a commonly used fibrinolytic
CV disease is associated with low LDL and HDL. True/False?
High LDL and/or low HDL causes CV disease
The bigger the HDL:LDL ratio, the better (in terms of health). True/False?
What are the components of a lipoprotein?
Hydrophobic core + hydrophilic coat
What makes up the hydrophobic core of a lipoprotein?
What makes up the hydrophilic coat of a lipoprotein?
Name the major lipoproteins
What does HDL contain?
apoA1 and apoA2
What does LDL contain?
What does VLDL contain?
What do chylomicrons contain?
What is the function of apoB lipoproteins (LDL, VLDL, chylomicrons)?
Deliver triglycerides to muscle for ATP genesis + to adipocytes for storage
Chylomicrons are formed in liver cells and transport triglycerides formed in the liver. True/False?
VLDL is formed in the liver and takes part in the endogenous pathway
What is the exogenous pathway of triglyceride transport?
Chylomicrons formed in intestinal cells to transport dietary triglycerides
What are the three stages of the life cycle of apoB lipoproteins?
Which enzyme breaks down triglyceride into 2 fatty acids and monoglycerol?
Why does the triglyceride molecule need to be broken down?
It is insoluble and cannot be absorbed into the enterocyte
What happens when monoglyceride and 2 fatty acids are in the enterocyte?
Combine to reform triglyceride
Which receptor enables amphipathic cholesterol to enter the enterocyte?
What needs to be added to the chylomicron to allow its export from the enterocyte?
Exported chylomicron enters the blood and is deposited into the venous system. True/False?
Deposited into lymphatics and then the venous system
Where and how is VLDL assembled?
Liver cells, from free fatty acids derived de novo + from adipose tissue
Before chylomicron and VLDL can offload their contents, they need to be activated. How does this happen?
HDL transfers apoCII to VLDL and chylomicrons which facilitates their binding
Which enzyme hydrolyses apoB lipoprotein (chylomicron, VLDL, LDL)?
Lipoprotein lipase (LPL)
What facilitates binding of chylomicrons and VLDL to LPL?
apoCII (that was transferred from HDL)
What does LPL do to apoB lipoproteins?
Attacks and hydrolyses core triglycerides to fatty acids and glycerol which can be absorbed
What are chylomicron and VLDL remnants?
Particles depleted of triglyceride but still containing cholesterol ester
apoCII is returned to HDL in exchange for which apoprotein? How does this facilitate clearance of apoB lipoprotein?
apoCII is returned to HDL in exchange for apoE, a high affinity ligand for receptor-mediated clearance
All apoB100 and apoB48 remnants are cleared via receptor-mediated clearance. True/False?
Only 50% of apoB100 remnants are cleared this way
What happens to the remaining apoB100 remnants?
Eventually become LDL
Which receptor is vital for LDL clearance? Where is it importantly located?
LDL receptor in liver
How does cholesterol release from LDL influence cholesterol release by hepatocytes?
The more cholesterol returning to the liver (in LDL), the less liver is synthesised by hepatocytes
How does cholesterol release inhibit cholesterol synthesis by hepatocytes?
Inhibits HMG CoA reductase
Downregulates LDL receptor expression
Why is LDL "bad" cholesterol?
Uptake during endothelial injury causes LDL oxidation to atherogenic OXLDL
Macrophages uptake OXLDL, converting cholesterol into foam cells, forming a fatty streak and ultimately a plaque
Why is HDL "good" cholesterol?
Accepts excess cholesterol and delivers it to the liver (reverse cholesterol transport)
It then interacts with scavenger receptors that enable uptake of cholesterol into hepatocytes
What are the drugs of choice for reducing LDL (and moderately increasing HDL)? Give examples
Statins - simvastatin, atorvastatin
How do statins work?
Inhibit HMG CoA reducatase, causing decrease in de novo cholesterol synthesis + increase in LDL receptor expression to enhance cholesterol clearance
When and how are statins administered?
Orally at night
What other drugs can be used for decreasing triglycerides?
Fibrates - bezafibrate, gemfibrozil
How do fibrates work?
Inhibit PPAR-alpha to enhance LPL production
What do bile acid binding resins do?
Cause excretion of bile salts, causing more cholesterol to be converted into bile salts
Name some bile acid binding resin drugs and a notable side effect
Can cause GI irritation
What does Ezetimibe do?
Inhibits NPC1L1 protein to reduce cholesterol absorption by enterocytes, ultimately causing decrease in LDL
What are the 3 components of Virchow's triad? What do they predispose to?
Abnormal blood flow
Vessel wall injury
Increased coagulability of blood
These predispose to thrombosis
An arterial thrombus is a white thrombus. True/False?
What colour is a venous thrombus?
Where do white thrombi commonly lodge?
Brain (detached embolus from left heart)
Where do red thrombi commonly lodge?
Lung (detached embolus from right heart)
What do VIIa, XIa and XIIa do downstream in the blood coagulation pathway?
Activate X to Xa
What does Xa do downstream in the blood coagulation pathway?
Activates II to IIa
[prothrombin to thrombin]
What does IIa (thrombin) do downstream in the blood coagulation pathway?
Activates fibrinogen to fibrin, the component of fibrin clots
What happens in response to endothelial damage in terms of platelets?
Adhere to site of injury and become activated, attracting other platelets, causing aggregation
What mediators do activated platelets secrete/synthesize? What do they do?
ADP, 5-HT, TXA2
Enhance platelet aggregation
Name the inactive precursors of the main clotting factors involved in coagulation
II, VII, IX, X
What do the inactive precursors of clotting factors require initially in order to be able to become activated?
What does the enzyme which carries out gamma-carboxylation of clotting factor precursors require?
[in its reduced, hydroquinone form]
What are the two forms of Vitamin K that exist?
K1 from diet
K2 from bacteria in intestine
How does warfarin work?
Competitively binds to vitamin K reductase, causing inhibition and thus reducing hydroquinone VK [ultimately inactivating clotting factor precursors]
How is warfarin administered? How fast is its onset of action?
What is the main risk with anticoagulant drugs?
Risk of haemmorhage
How does liver disease potentiate activity of warfarin?
Decreased clotting factors
How does a high metabolic rate potentiate the activity of warfarin?
Increased clearance of clotting factors
How does pregnancy decrease the effect of warfarin?
Increased synthesis of clotting factors
How might a warfarin overdose be treated?
Vitamin K/clotting factor infusion
What does Antithrombin III (ATIII) do?
Inhibits IIa and Xa to inhibit coagulation
How does heparin cause anticoagulation?
Accelerates inhibition of IIa and Xa through ATIII - increases affinity of the latter for the former
Heparin must bind to ATIII and IIa in order to inhibit IIa. True/False?
Heparin must bind to ATIII and Xa in order to inhibit Xa. True/False?
Only needs to bind to ATIII
LMWH inhibits IIa but not Xa. True/False?
Inhibits Xa but not IIa
Give examples of LMWHs
How is heparin administered?
Intravenously or subcutaenously
How is LMWH administered?
Name an oral active inhibitor of thrombin
Name an oral active inhibitor of Xa
What is the role of vWF in platelet pathway?
Acts as a bridge to help platelets adhere to damaged endothelium
Which enzyme aids platelet synthesis of TXA2?
Which receptor does ADP bind with to enhance platelet aggregation?
Which drug blocks this receptor?
Clopidogrel blocks this
Which platelet receptors does fibrinogen bind with to enhance platelet aggregation?
Which drug blocks this?
Which drug blocks the synthesis of TXA2 through inhibiting COX enzyme?
How is aspirin administered?
How is clopidogrel administered?
What is the role of plasmin in the coagulation cascade?
Enforces fibrin degradation to form fibrin fragments (clot lysis)
How do fibrinolytic drugs work?
Activate plasminogen to form plasmin to cause clot lysis
Give examples of fibrinolytic drugs