The Adrenergic System III

Question 1

How do we measure blood pressure?

Answer 1

By the use of a sphygmomanometer (blood pressure cuff)
It gives two numbers: the systolic pressure (maximum pressure in the arteries after the ventricles contract) and the diastolic pressure (minimum pressure between ventricular contractions)
BP is reported as systolic/diastolic (e.g., 120/80)

Question 2

What is high blood pressure? What is important?

Answer 2

The definitions of high blood pressure will vary greatly and which parameters are most important will also change
In general:
Blood pressure must be more stringently controlled in diabetics than non-diabetics
As you get older than 65, systolic pressure will rise
Shorter people will tend to have lower blood pressure than taller people

Question 3

What is considered normal blood pressure?

Answer 3

Systolic: 90-120
And
Diastolic: 60-80

Question 4

What is considered high blood pressure?

Answer 4

Systolic: over 139-159
Or
Diastolic: over 89-99

Question 5

What is considered high blood pressure for diabetics?

Answer 5

Systolic: over 140
or
Diastolic: over 80

Question 6

What is a hypertensive crisis?

Answer 6

Medical emergency. Patient requires IMMEDIATE emergency medical treatment
Systolic: over 180
or
Diastolic: over 110

Question 7

Does a single high blood pressure reading mean the patient is hypertensive?

Answer 7

No. Other factors need to be considered (what time of day, did the person eat recently, etc.). Other readings need to be taken

Question 8

What are adrenergic receptors and responses important for controlling blood pressure?

Answer 8

In the kidneys, beta1 stimulation releases renin
In the arterioles (peripheral vascular skeletal muscle), alpha 1 stimulation causes vasoconstriction and beta2 stimulation causes vasodilation
In the heart, beta1 stimulation increase heart rate and contractile force

Question 9

Mathematically, what is blood pressure?

Answer 9

BP = CO * SVR (aka TPR)
BP = HR * SV * SVR

Question 10

What can blood pressure result from?

Answer 10

Increased cardiac output via heart rate or stroke volume

Increased total peripheral resistance (probably more important)

Question 11

How do NA and A affect blood pressure?

Answer 11

They activate alpha1 receptors, so they increase TPR
They activate beta1 receptors, so they increase CO
Adrenaline activates beta1, so it increases TPR
The net effect is a small increase in blood pressure, but it depends on the amounts

Question 12

Given the physiologic definition of blood pressure, there are two main ways to controlling blood pressure. What are they?

Answer 12

Decrease TPR via vasodilation

Decrease CO via decreasing HR and/or decreasing SV or contractile force

Question 13

How do we cause vasodilation?

Answer 13

Block alpha1 receptors to prevent NA and A induced vasoconstriction
Block AT1 receptor with AT1 receptor antagonist
Production of NO, hydrochlorothiazide, hydrazine
Calcium channel blockers (nifedipine, felodipine, amlodipine only)

Question 14

How do we decrease SV or contractile force?

Answer 14

Block beta1 receptors to prevent NA and A induced increase in HR and contractile force
Calcium channel blockers (verapamil and diltiazem only)(

Question 15

What are alpha-receptor antagonists used for?

Answer 15

There are many uses including controlling high blood pressure, as well as treating benign prostatic hyperplasia (BPH; aka benign prostatic hypertrophy)

Question 16

What is a major problem with alpha-receptor antagonists? Why is this?

Answer 16

A major problem with alpha-receptor antagonists is (mush like antimuscarinics) many drugs that are otherwise targeted to other receptor groups have some alpha-rectpeor antagonist activity
The main reason for this is the flexible and “generic” SAR for alpha-receptor antagonists which means that many drugs have unintended alpha-receptor antagonist activity (cause of many side effects)

Question 17

What are the minimum requirements to ensure alpha adrenergic antagonist activity (see diagram)?

Answer 17

1. N must be charged for affinity and is often a tertiary amine. But sometimes R1 may be H (secondary amine)
2. R1 and R2 must be CH3 or larger than t-butyl
3. (C)n may be 1 to 3 heavy atoms (normally carbon)
4. X may not be present but if it is, it is usually capable of forming H bonds
5. There may be two rings attached to X but only one is needed and one or both are aromatic
6. The aromatic ring substitution(s) R3 may not be present, however if it/they are having para and meta substituents will favour binding to alpha1 receptors over alpha2 receptors

Question 18

What are the uses of alpha adrenergic antagonists?

Answer 18

Hypertension (major use)
Benign prostatic hyperplasia (BPH; major use)
Raynaud’s disease (congenital peripheral vasoconstriction)

Question 19

What are the two types of alpha adrenergic antagonists?

Answer 19

Non-selective (not used much anymore; Phenoxybenzamine, which is irreversible, phentolamine, which is reversible)
Selective (most important are alpha1 quinazolines, such as parson, terazosin, doxazosin; tamsulosin for BHP)

Question 20

Describe the mechanism of phenoxybenzamine

Answer 20

Ionized form of the drug is stable
At physiological pH, it becomes unionized and is unstable
It has the basic SAR need to bind to the alpha1 and alpha2 receptors
Once bound to the alpha receptor, the drug can dissociate as a reversible competitive antagonist
OR
It can react with a nucleophile (Nu) in the receptor (typically a Cys or Ser residue)
When covalently bound to the receptor it is now an irreversible non-competitive inhibitor

Question 21

What is phenoxybenzamine?

Answer 21

An irreversible antagonist
The effects last for days because the receptors are irreversibility alkylated resulting in long term antagonist activity (new receptors must be made to restore receptors to normal activity)

Question 22

What are the uses of phenoxybenzamine?

Answer 22

Used the treat pheochromocytoma (adrenal gland tumour producing increased NA and A)
For non selective receptor antagonists, patient may get reflex tachycardia due to decreased blood pressure
May also decrease the effectiveness of the baroreceptor reflex because of inhibition of alpha1 receptors in vasculature
Also has antimuscarinic activity and increases release of histamine

Question 23

Describe phentolamine SAR

Answer 23

It has no alpha-agonist activity (like xylometazoline and clonidine)
Receptor affinity is enhanced by additional aromatic ring substitution to N
It is not selective for alpha1 or alpha2 receptors
It has antimuscarinic activity ad causes the release of histamine
It is used to treat cocaine and amphetamine induced hypertensive crisis

Question 24

Describe quinazolines SAR

Answer 24

N in the X position in this case
The meta and para substituents on the aromatic ring increase affinity for alpha1 receptors vs alpha2
R is typically a heterocyclic ring
Guanidine-like group is important for increasing affinity for alpha receptors (unlike alpha receptor agonists, this does not increase affinity for alpha2 receptors)

Question 25

What are the uses of quinazolines?

Answer 25

They decrease BP without increasing HR or CO (no or very little reflex tachycardia) They do not bind to muscarinic or histamine receptors do not increase release of histamine They are very selective for alpha1 receptors and they do not block alpha2 receptors They are used to treat hypertension They are used to treat BPH (especially terazosin and doxazosin)

Question 26

Describe Prazosin

Answer 26

Brand name: Minipress Highly metabolized by the liver. Very high first pass metabolism results in low bioavailability. Planarity of molecule results in increase in metabolism

Question 27

Describe Terazosin

Answer 27

Brand name: Hytrin Less potent than parson but same maximal efficacy More soluble in water than parson with higher bioavailability and longer half life Induces apoptosis of prostate smooth muscle cells, not dependent on alpha1 blockade. More useful than prazosin for BPH

Question 28

Describe Doxazosin

Answer 28

Brand name: Cardura Like terazosin, induces apoptosis of prostate smooth muscle cells, not dependant on alpha1 blockade. More useful than prazosin for BPH

Question 29

What is the dosing for quinazolines?

Answer 29

For all quinazolines, starting dose is 1 mg HS to reduce the incidence of postural hypotension (aka orthostatic hypotension). Dose it titrated to BP

Question 30

Describe the metabolism of quinazolines

Answer 30

Phase I O- or N-dealkylation by CYP450 enzymes results in an active metabolite Phase II reactions cause conjugation and/or elimination

Question 31

What are the side effects of quinazolines?

Answer 31

``` Orthostatic hypotension (because of the decrease in effectiveness of baroreceptor reflex Syncope (passing out or fainting can happen because of orthostatic hypotension; starting at a low dose of 1 mg and increase slow) ```

Question 32

What is orthostatic hypotension

Answer 32

A significant drop in BP that occurs when changing from a sitting or lying position to a standing position Also called postural hypotension Patients taking quinazolines are most at risk a few hours to days after initiating dose, changing a dose or adding another antihypertensive drug. But it can be a long term problem

Question 33

What is tamsulosin?

Answer 33

Brand name: Flomax Alpha1 receptor antagonist with some selectivity for alpha1A (and alpha1D) subtypes compared to alpha1B (10-40 times more potent at alpha1A than alpha1B) This selectivity favours blockade of alpha1A receptors in the prostate Tamsulosin is used in the treatment of BPH It has little or no effect on blood pressure

Question 34

How are alpha1 antagonists used to treat BPH?

Answer 34

Alpha1-antagonist efficacy in BPH results from relaxation of smooth muscle via alpha1 receptor antagonism in the bladder and prostate Because of the distribution of alpha1 receptors in the bladder prostate alpha1-antaonists reduce bladder obstruction possibly by affecting the tone in the sphincters without affecting muscular contractility of the bladder

Question 35

What are some unintended alpha-antagonists?

Answer 35

Promethazine (antihistamine) Imipramine (antidepressant) Chlorpromazine neuroleptic (antipsychotic) Haloperidol neuroleptic (antipsychotic) Many of these compounds also fit the SAR for muscarinic antagonists

Question 36

What are general alpha-adrenergic antagonist side effects?

Answer 36

Orthostatic hypotension and syncope Hypotension Dizziness, lightheadedness Nasal congestion (dilation of the blood vessels in nasal mucosa) Headache (vasodilation of the meninges, causing vascular headache) Reflex tachycardia (especially with non-selective alpha blockers) None of these side effects are likely to be causes by tamsulosin at normal doses

Question 37

What are recommendations for syncope?

Answer 37

These recommendations are more important for those taking quinazolxines for high BP Ask the patient to be careful for the first few days after initiation or increasing dose of alpha-adrenergic antagonists When sitting or lying down, get up slowly and steady yourself with something like the arm rests of the chair you were sitting on or a table, etc.